TWI573588B - Use of benzoic acid salt in the manufacture of a pharmaceutical composition for treating dementia or mild cognitive impairment - Google Patents
Use of benzoic acid salt in the manufacture of a pharmaceutical composition for treating dementia or mild cognitive impairment Download PDFInfo
- Publication number
- TWI573588B TWI573588B TW103110838A TW103110838A TWI573588B TW I573588 B TWI573588 B TW I573588B TW 103110838 A TW103110838 A TW 103110838A TW 103110838 A TW103110838 A TW 103110838A TW I573588 B TWI573588 B TW I573588B
- Authority
- TW
- Taiwan
- Prior art keywords
- day
- dementia
- benzoate
- sodium benzoate
- alzheimer
- Prior art date
Links
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本發明一般有關失智症或輕度認知障礙之新穎療法,更具體而言,為有關苯甲酸鹽在製造用於預防或治療失智症或輕度認知障礙之組成物中之用途。 The present invention relates generally to novel therapies for dementia or mild cognitive impairment, and more particularly to the use of benzoates for the manufacture of compositions for the prevention or treatment of dementia or mild cognitive impairment.
在高齡化社會中,失智症在中高齡者中之盛行率迅速增加,且其日益惡化的臨床過程對於患者和其家人雙方而言是沉重的負擔。阿茲海默症(Alzheimer’s disease)(後文中稱為“AD”)之早期偵測和介入對於結果是關鍵的(1)。輕度認知障礙(Mild Cognitive Impairment)(後文中稱為“MCI”),特別是失憶型MCI(後文中稱為“aMCI”),為危險因子,而且可為AD之前驅期。輕度和中度AD之主流療法為乙醯膽鹼酯酶抑制劑(後文中稱為“AChEI”)。然而,乙醯膽鹼酯酶抑制劑之功效和耐受性並不令人滿意。此外,AChEI對MCI並未顯示令人信服的功效(2-4),暗示MCI發病背後有其他機轉。 In an aging society, the prevalence of dementia among middle-aged people is rapidly increasing, and its deteriorating clinical process is a heavy burden for both patients and their families. Early detection and intervention of Alzheimer's disease (hereinafter referred to as "AD") is critical to the outcome (1). Mild Cognitive Impairment (hereinafter referred to as "MCI"), especially amnesiac MCI (hereinafter referred to as "aMCI"), is a risk factor and can be a prodromal phase of AD. The mainstream therapy for mild and moderate AD is an acetylcholinesterase inhibitor (hereinafter referred to as "AChEI"). However, the efficacy and tolerability of acetylcholinesterase inhibitors are not satisfactory. In addition, AChEI did not show convincing efficacy on MCI (2-4), suggesting that there are other mechanisms behind the onset of MCI.
雖然NMDA受體(後文中稱為NMDAR)活性對於認知功能而言是必要的,尚無法完整了解其於AD中的角色。由麩氨酸導致的NMDAR過度活化造成細胞死亡。興奮性毒性(excitotoxicity)為AD之理論之一,特別是在晚期(54)。在NMDAR過度活化之假說的基礎上(7),發展NMDAR拮抗劑治療AD。美金剛胺(memantine)為具有低親合力之非競爭型NMDAR部分拮抗劑,其據稱可藉由預防鈣之過度流入而阻擋NMDAR過度活化(8-10),而且已用於中度-重度AD之治療。然而,美金剛胺在早期階段(包含MCI和輕度AD)之功效有限(12)。NMDAR拮抗劑,諸如MK-801,在體外和體內研究中亦皆誘發細胞凋亡和神經退化(13)。K他命(Ketamine)是另一種NMDAR拮抗劑,其在雙盲、隨機以及安慰劑控制之試驗中損害健康人類之空間學習和口頭資訊能力(14)。此等發現引起了NMDAR拮抗劑在早期AD中可能損害認知和記憶之疑慮。 Although the NMDA receptor (hereinafter referred to as NMDAR) activity is essential for cognitive function, it is not yet fully understood its role in AD. Excessive activation of NMDAR by glutamate causes cell death. Excitotoxicity is one of the theories of AD, especially in the advanced stage (54). Based on the hypothesis of NMDAR overactivation (7), NMDAR antagonists were developed to treat AD. Memantine is a non-competitive NMDAR partial antagonist with low affinity, which is said to block NMDAR overactivation (8-10) by preventing excessive calcium influx, and has been used for moderate-to-severe Treatment of AD. However, memantine has limited efficacy in the early stages (including MCI and mild AD) (12). NMDAR antagonists, such as MK-801, also induce apoptosis and neurodegeneration in both in vitro and in vivo studies (13). Ketamine is another NMDAR antagonist that impairs spatial learning and verbal information in healthy humans in double-blind, randomized, and placebo-controlled trials (14). These findings raise concerns that NMDAR antagonists may impair cognitive and memory in early AD.
最佳NMDAR活化對於突觸可塑性(15)、記憶以及認知功能(16)有關鍵性。NMDAR介導之神經傳導的衰減可在老化的腦中造成神經可塑性之喪失和認知缺陷,其可能說明了為何有臨床症狀惡化和腦部萎縮(17)。在人類可觀察到大腦皮質和海馬迴中之NMDAR密度減少與年齡相關(18)。較早期研究亦從患有AD之患者之屍體檢驗和神經外科組織發現甘胺酸依賴性之放射性結合物與大腦皮質中之NMDAR結合的減少(19,20)。D-環絲胺酸為在NMDAR之甘胺酸位置之部分促效劑,而且在一些臨床研究中報導其 可活化患有AD之患者之腦中的NMDAR(21),且改善該等患者在阿茲海默症評估量表(ADAS-cog)之認知次級量表上之分數(22)。 Optimal NMDAR activation is critical for synaptic plasticity (15), memory, and cognitive function (16). NMDAR-mediated attenuation of nerve conduction can cause loss of neural plasticity and cognitive deficits in aging brains, which may explain why clinical symptoms worsen and brain atrophy (17). NMDAR density reduction in the cerebral cortex and hippocampal gyrus is observed in humans to be age-related (18). Earlier studies also found a reduction in the binding of glycine-dependent radioconjugates to NMDAR in the cerebral cortex from necropsy and neurosurgical tissue in patients with AD (19, 20). D-cycloserine is a partial agonist at the glycine site of NMDAR and has been reported in several clinical studies. NMDAR (21) in the brain of patients with AD can be activated and the scores of these patients on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) are improved (22).
目前的研究認為NMDAR增強對於早期和輕度失智症可能是有益的。人類大腦皮質和海馬迴中發現麩氨酸之含量和合成的減少與年齡相關(18,55),其中最顯著和一致的發現為在高齡者和患有AD之患者中NMDAR密度減少(18)。在患有AD之患者之血清中亦觀察到較低量之D-絲胺酸和較高量之L-絲胺酸(56)。因此,除了膽鹼系統以外,NMDA神經傳導之功能異常亦可能在AD之病態生理學中扮演重要角色。 Current research suggests that NMDAR enhancement may be beneficial for early and mild dementia. The reduction in glutamate content and synthesis in the human cerebral cortex and hippocampus is age-related (18,55), with the most significant and consistent finding being a reduction in NMDAR density in elderly patients and patients with AD (18) . Lower amounts of D-serine and higher amounts of L-serine (56) were also observed in the serum of patients with AD. Therefore, in addition to the choline system, dysfunction of NMDA nerve conduction may also play an important role in the pathophysiology of AD.
有許多增強NMDA活化之方式。其中之一為抑制D-胺基酸氧化酶(DAAO)(其係負責分解D-絲胺酸和D-丙氨酸之過氧小體之黃素酵素)之活性(24-26),藉以提高D-胺基酸(為針對NMDAR之共促效劑位置之神經傳導物)的量。最近數據表示老化與D-絲胺酸量減少相關且藉以損害NMDAR傳導,而且D-絲胺酸治療顯著地減少神經元死亡之程度,暗示D-絲胺酸具有對抗細胞凋亡之神經保護效果(27)。此外,來自出生後之小鼠前腦之神經幹細胞可合成D-絲胺酸,藉以刺激幹細胞之增生和神經細胞分化(28)。 There are many ways to enhance NMDA activation. One of them is to inhibit the activity of D-amino acid oxidase (DAAO), which is responsible for the decomposition of D-serine and D-alanine, the peroxisome flavin (24-26). The amount of D-amino acid (which is the neurotransmitter for the co-actinator position of NMDAR) is increased. Recent data indicate that aging is associated with a decrease in the amount of D-serine and thereby impairing NMDAR conduction, and D-serine treatment significantly reduces the extent of neuronal death, suggesting that D-serine has neuroprotective effects against apoptosis. (27). In addition, neural stem cells from the forebrain of the mouse after birth can synthesize D-serine to stimulate proliferation of stem cells and differentiation of nerve cells (28).
通過抑制DAAO來增強NMDAR可作為一種減少D-絲胺酸之腎毒性之安全方式(29),特別是在高齡者族群中。苯甲酸鈉為DAAO抑制劑。苯甲酸存在於許多植物中,而且為食物(包含乳製品)之天然組分(30)。苯甲酸和其鹽一般 被認為是安全的(GRAS),包含苯甲酸鈉,亦為廣泛用於製造果凍、緩衝劑、醬油、加工肉品等之食物防腐劑(31)。 Enhancing NMDAR by inhibiting DAAO can be a safe way to reduce the nephrotoxicity of D-serine (29), especially in the elderly population. Sodium benzoate is a DAAO inhibitor. Benzoic acid is found in many plants and is a natural component of foods (including dairy products) (30). Benzoic acid and its salts are generally It is considered safe (GRAS) and contains sodium benzoate. It is also a food preservative widely used in the manufacture of jelly, buffers, soy sauce, processed meat, etc. (31).
有許多其他臨床前研究支持DAAO抑制劑之CNS效果,然而卻未檢驗其對記憶之效果(32-34)。NMDAR介導之神經傳導對於學習和記憶是重要的。業經報導NMDAR之功能不足在AD之病態生理學中扮演重要角色,特別在早期階段。增強NMDAR活化可為一種新穎治療方式。增強NMDAR活性之其中一種方法係藉由阻斷NMDA共促效劑之代謝而提高其量。苯甲酸鈉對於疼痛緩解(35,36)等NMDAR模式相關作用有效,而且部分地預防神經膠細胞之細胞死亡(37)。苯甲酸鹽之CNS生物可利用率良好(38)。為了測試DAAO抑制是否對失智症之早期階段是有益的,發明者進行此試驗以檢驗苯甲酸鈉在患有MCI或輕度AD之患者中的功效和安全性。 There are many other preclinical studies that support the CNS effect of DAAO inhibitors, but their effects on memory have not been tested (32-34). NMDAR-mediated nerve conduction is important for learning and memory. It has been reported that the insufficiency of NMDAR plays an important role in the pathophysiology of AD, especially in the early stages. Enhancing NMDAR activation can be a novel treatment modality. One of the ways to enhance NMDAR activity is to increase the amount of NMDA co-activator by blocking its metabolism. Sodium benzoate is effective in NMDAR mode-related effects such as pain relief (35, 36) and partially prevents cell death of glial cells (37). The CNS bioavailability of benzoate is good (38). To test whether DAAO inhibition is beneficial for the early stages of dementia, the inventors conducted this trial to test the efficacy and safety of sodium benzoate in patients with MCI or mild AD.
基於以上證據支持,發明者提出NMDA促進劑因其在學習和記憶以及神經新生和神經可塑性中之角色,而可對於AD之早期衰減過程和MCI是有益的,因此完成本發明。 Based on the above evidence support, the inventors have proposed that NMDA promoters may be beneficial to the early decay process of AD and MCI due to their roles in learning and memory as well as neuronal and neuroplasticity, thus completing the present invention.
本發明提供苯甲酸鹽在製造用於預防或治療失智症或MCI之組成物中之用途。 The present invention provides the use of a benzoate in the manufacture of a composition for the prevention or treatment of dementia or MCI.
於本申請案之一態樣中,苯甲酸鹽可為苯甲酸鈉、苯甲酸鉀或苯甲酸鈣,而且較佳地,苯甲酸鹽為苯甲酸鈉。 In one aspect of the present application, the benzoate may be sodium benzoate, potassium benzoate or calcium benzoate, and preferably the benzoate is sodium benzoate.
於本申請案之另一態樣中,苯甲酸鹽之有效量可為200毫克(mg)/天至2000mg/天,較佳為500mg/天至900mg/ 天,以及更佳為750mg/天。 In another aspect of the present application, the effective amount of the benzoate may range from 200 milligrams (mg) per day to 2000 mg per day, preferably from 500 mg per day to 900 mg per day. The day, and more preferably 750 mg / day.
於本申請案之又一態樣中,苯甲酸鈉之有效量為200mg/天至2000mg/天,較佳為500mg/天至900mg/天,以及更佳為750mg/天。 In still another aspect of the present application, the effective amount of sodium benzoate is from 200 mg/day to 2000 mg/day, preferably from 500 mg/day to 900 mg/day, and more preferably 750 mg/day.
於本申請案之一態樣中,失智症包括早期失智症。於本申請案之一個具體實施例中,早期失智症包括輕度AD。 In one aspect of this application, dementia includes early dementia. In one embodiment of the present application, early dementia includes mild AD.
於本申請案之一態樣中,MCI包括失憶型MCI。 In one aspect of the present application, the MCI includes amnesiac MCI.
第1圖顯示兩個處理組之流程圖和配置。 Figure 1 shows the flow chart and configuration of two processing groups.
以下闡釋性具體實施例係經提供以闡釋本發明之揭示內容。發明所屬技術領域中具有通常知識者在閱讀此說明書之揭示內容後能明顯理解此等和其他優點以及效果。 The following illustrative embodiments are provided to illustrate the disclosure of the present invention. These and other advantages and effects will be apparent to those of ordinary skill in the art of the invention.
如本文所使用,術語“失智症”意指嚴重影響智力和社交能力以致於干擾每日功能,包含記憶喪失、語言問題、無法學習或記得新資訊等之症狀集合(78)。術語“早期失智症”意指患有失智症之患者之CDR(臨床失智症評量表)分數不超過1之病症。 As used herein, the term "dementia" means a collection of symptoms that severely affect intellectual and social ability to interfere with daily functions, including memory loss, language problems, inability to learn or remember new information (78). The term "early dementia" means a condition in which the CDR (Clinical Dementia Rating Scale) score of a patient suffering from dementia does not exceed one.
如本文所使用,術語“阿茲海默症(AD)”意指一種由於腦之一般性退化而可能發生於中年或老年,並且符合神經性和溝通性障礙和中風之國家機構及阿茲海默症與相關障礙協會(National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association)標準之漸進式精神惡化疾病。過度的麩胺酸性神經傳導,特別是透過N-甲基-D-天冬胺酸受體(NMDAR),會導致與AD之病態生理學相關之神經毒性(5,6),尤其是晚期AD。術語“輕度阿茲海默症”意指患有失智症之患者之CDR(臨床失智症評量表)分數為0.5或1之病症。 As used herein, the term "Alzheimer's disease (AD)" means a national institution and Az that may occur in middle or old age due to general degeneration of the brain, and which is consistent with neurological and communicative disorders and strokes. National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association) The progressive progressive mental deterioration of the disease. Excessive glutamate acid nerve conduction, particularly through the N-methyl-D-aspartate receptor (NMDAR), leads to neurotoxicity associated with the pathophysiology of AD (5,6), especially in advanced AD . The term "mild Alzheimer's disease" means a condition in which the CDR (Clinical Dementia Rating Scale) score of 0.5 or 1 in a patient suffering from dementia.
如本文所使用,術語“輕度認知障礙(MCI)”意指一種CDR(臨床失智症評量表)分數小於1之認知障礙。術語“失憶型輕度認知障礙(aMCI)”意指一種其中記憶主要受到影響之MCI。 As used herein, the term "mild cognitive impairment (MCI)" means a cognitive disorder in which the CDR (Clinical Dementia Rating Scale) score is less than one. The term "amnesic mild cognitive impairment (aMCI)" means an MCI in which memory is primarily affected.
如本文所使用,術語“臨床失智症評量表(CDR)”意指一種評估失智症之病期嚴重性之評估系統。臨床失智症評比為五分量表,其中CDR-0暗示無認知損害,接著剩餘四分為各期之失智症:0.5至1內之CDR=非常輕度至輕度失智症,1至2內之CDR=輕度至中度,2至3內之CDR=中度至重度,以及CDR>3=重度。 As used herein, the term "clinical dementia scale (CDR)" means an assessment system for assessing the severity of a period of dementia. The clinical dementia is a five-point scale, in which CDR-0 implies no cognitive impairment, and then the remaining four are divided into dementia in each period: CDRs within 0.5 to 1 = very mild to mild dementia, 1 to CDRs within 2 = mild to moderate, CDRs within 2 to 3 = moderate to severe, and CDR > 3 = severe.
本發明檢驗作為D-胺基酸氧化酶(DAAO)抑制劑之苯甲酸鈉在治療失憶型MCI(aMCI)和輕度AD之功效和安全性。 The present invention tests the efficacy and safety of sodium benzoate as a D-amino acid oxidase (DAAO) inhibitor in the treatment of amnesiac MCI (aMCI) and mild AD.
發明者在台灣之四個主要的醫學機構中進行隨機、雙盲、安慰劑控制之試驗。患有aMCI或輕度AD之60位患者以250至750mg/天之苯甲酸鈉或安慰劑治療24週。每8週,針對阿茲海默症評估量表-認知次級量表(ADAS-cog, 為主要結果判定項目)和整體功能(藉由臨床醫師訪視為基礎的整體改變-附加照護者提供之資訊(Clinician Interview Based Impression of Change plus Caregiver Input)(CIBIC-plus)評估)進行測量。於研究起始點和結束時進行附加認知功能測驗(Additional cognition composite)。 The inventors conducted randomized, double-blind, placebo-controlled trials in four major medical institutions in Taiwan. Sixty patients with aMCI or mild AD were treated with sodium benzoate or placebo at 250 to 750 mg/day for 24 weeks. Every 8 weeks, the Alzheimer's Assessment Scale-Cognitive Subscale (ADAS-cog, Measurements were made for the primary outcome determination project and the overall function (Clinician Interview Based Impression of Change plus Caregiver Input (CIBIC-plus) assessment). An additional cognition composite was performed at the start and end of the study.
從台灣的四個主要醫學機構-位於高雄的高雄長庚紀念醫院精神科部和神經內科部、位於台中的中國醫藥大學附設醫院精神部、位於台中的台中榮民總醫院精神部以及位於台中的林新醫院神經內科部的門診部門徵募患者。此研究係由該四處之人體試驗委員會(IRB)核准,而且根據修訂版之赫爾辛基宣言(Declaration of Helsinki)進行。在完整的醫學和神經學檢查之後,由研究醫師(包括精神科醫師和神經科醫師)評估患者。 From the four main medical institutions in Taiwan - the Department of Psychiatry and Neurology of Kaohsiung Chang Gung Memorial Hospital in Kaohsiung, the Department of Psychiatry of the Chinese Medical University in Taichung, the Ministry of Spirit of Taichung Veterans General Hospital in Taichung, and the Forest in Taichung The outpatient department of the Department of Neurology of the New Hospital recruited patients. The study was approved by the Human Research Committee (IRB) and was based on the revised Declaration of Helsinki. After a complete medical and neurological examination, the patient is evaluated by a research physician, including a psychiatrist and a neurologist.
若患者符合下列,則被邀請加入此研究:1)符合NINCDS-ADRDA(神經性和溝通性障礙和中風之國家機構及阿茲海默症與相關障礙協會)(39)之可能AD的標準且其臨床失智症評量表(CDR)(40)分數為1,或符合可能為退化病程之aMCI之標準(41),其被定義為由資料提供者證實之主觀記憶抱怨以及整體認知和功能性的障礙而符合NINCDS-ADRDA之標準且其CDR分數為0.5;2)年齡為50至90歲;3)身體健康且所有實驗室評估(包含尿/血常規、生化測試以及心電圖)在正常範圍內;4)其簡易智能狀態檢查(Mini-Mental State Examination)(MMSE)(42)分數為17至 26;5)具有足夠教育水準而能有效地溝通且能完成研究之評估;以及6)同意參與此研究,並且簽署受試者同意書。對於已進行AChEI療法之患者,必須在加入研究之前持續服用AChEI至少三個月。AChEI劑量必須在研究期間維持不變。至於尚未進行AChEI療法之患者,在研究過期間禁止使用AChEI或其他抗失智症用藥。 If the patient meets the following criteria, they are invited to join the study: 1) meet the criteria for possible AD of NINCDS-ADRDA (National Institutions of Neurological and Communicative Disorders and Stroke and Association of Alzheimer's and Related Disorders) (39) and The Clinical Dementia Rating Scale (CDR) (40) score is 1, or meets the criteria for aMCI, which may be a degenerative course (41), which is defined as subjective memory complaints and overall cognitive and functional evidence as confirmed by the data provider. Sexual disorder complies with NINCDS-ADRDA criteria and has a CDR score of 0.5; 2) age is 50 to 90 years; 3) good health and all laboratory assessments (including urine/blood routine, biochemical tests, and electrocardiogram) are in the normal range 4) its Mini-Mental State Examination (MMSE) (42) score is 17 to 26; 5) an assessment that has sufficient educational standards to communicate effectively and complete the study; and 6) agree to participate in the study and sign the subject consent form. For patients who have undergone AChEI therapy, they must continue taking AChEI for at least three months prior to the study. The AChEI dose must remain unchanged during the study period. For patients who have not been treated with AChEI, AChEI or other anti-dementia medications are prohibited during the study period.
排除標準包括明顯有腦血管疾病史;哈金斯氏缺血分數(Hachinski Ischemic Score)>4;有除了AD以外的重大神經、精神或醫學病症;物質(包含酒精)濫用或依賴;有妄想、幻覺或譫妄症狀;嚴重視覺或聽力損失;無法遵循研究程序。 Exclusion criteria included a clear history of cerebrovascular disease; Hachinski Ischemic Score > 4; major neurological, psychiatric, or medical conditions other than AD; substance (including alcohol) abuse or dependence; Illusion or paralysis; severe visual or hearing loss; unable to follow the research procedure.
以雙盲方式,隨機指定所有患者接受24週之苯甲酸鈉或安慰劑治療。於研究起始點和第8、16以及24週結束時評估功效和安全性。將250mg之苯甲酸鈉或安慰劑填充入相同囊劑放進經編碼之藥瓶中。至於劑量,首8週以250至500mg/天(每日一次或兩次250mg)開始,接著視臨床需要從第9週開始增加250至500mg/天,第17週開始再增加250至500mg/天。由於研究中之受試者年齡較高,發明者使用劑量為250至750mg/天。由研究藥劑師將受試者以每6位為一組、以1:1之比例、隨機分配接受苯甲酸鈉或安慰劑。 All patients were randomized to receive either 24-weth sodium benzoate or placebo in a double-blind manner. Efficacy and safety were assessed at the start of the study and at the end of weeks 8, 16 and 24. 250 mg of sodium benzoate or placebo was filled into the same capsule and placed in a coded vial. As for the dose, the first 8 weeks start with 250 to 500 mg / day (250 mg once or twice daily), then increase from 250 to 500 mg / day from the 9th week, and 250 to 500 mg / day from the 17th week. . Since the subjects in the study were older, the inventors used a dose of 250 to 750 mg/day. Subjects were randomized to receive either sodium benzoate or placebo in a 1:1 ratio by the study pharmacist.
除了研究藥劑師之外,受試者、照護者以及研究人員皆不知此分配。照護者和研究醫師密切監控受試者的醫療 依從性和安全性,並且由研究人員進行藥丸計數。 Subjects, caregivers, and researchers were not aware of this assignment except for the study of pharmacists. Caregivers and research physicians closely monitor the subject's medical care Compliance and safety, and the pills are counted by the investigator.
主要結果為在第0、8、16以及24週測量之阿茲海默症評估量表-認知次級量表(ADAS-cog)(43)。ADAS-cog為AD臨床試驗中最常用的認知評估方法。其係由11個項目所組成,包含字詞回憶、命名能力、命令、結構能力(constructional praxis)、構思能力(ideational praxis)、定向感、字詞辨識、指令記憶、口語能力、找詞困難以及理解力。ADAS-cog分數範圍為0(最佳)至70(最差)。 The primary outcome was the Alzheimer's Assessment Scale-Cognitive Subscale (ADAS-cog) (43) measured at weeks 0, 8, 16 and 24. ADAS-cog is the most commonly used cognitive assessment method in AD clinical trials. It consists of 11 projects, including word recall, naming ability, command, constructional praxis, ideology (pration), orientation, word recognition, instruction memory, speaking ability, difficulty in finding words, and understanding. The ADAS-cog score ranges from 0 (best) to 70 (worst).
次要結果包括在第8、16以及24週測量之臨床醫師訪視為基礎的整體改變-附加照護者提供之資訊(CIBIC-plus)(44)以及在研究起始點和結束時進行附加認知功能測驗(Additional cognition composite)。 Secondary outcomes included a general change based on clinical visits measured at weeks 8, 16 and 24 - information provided by additional caregivers (CIBIC-plus) (44) and additional cognition at the start and end of the study Additional cognition composite.
CIBIC-plus為以全面性、半結構化之面試(包括照護者提供之資訊)為基準之整體性改變評估。CIBIC-plus係範圍為1至7之7分評比量表,其中1表示明顯改善;4表示無改變;以及7表示明顯惡化。 CIBIC-plus is a holistic change assessment based on a comprehensive, semi-structured interview (including information provided by caregivers). The CIBIC-plus ranged from 1 to 7 for a 7-point scale, with 1 indicating a significant improvement; 4 indicating no change; and 7 indicating a significant deterioration.
附加認知功能測驗(Additional cognition composite)係藉由處理速度(語文流利度)、工作記憶(WMS-III,空間廣度測驗(Spatial Span))(45)以及口語學習和記憶測驗(WMS-III,字詞測驗)(45)之T分數之平均。將處理速度、工作記憶以及口語學習和記憶測驗之原始分數標準化至平均為50和標準差為10之T分數,以使各試驗可相互比較。附加認知功能測驗與ADAS-cog合併使用可以使認知評估更完 整。業經發現處理速度之降低與老化相關(46,47)。患有AD之患者中之工作記憶(48)及口語學習和記憶(49)功能亦衰退。 Additional cognition composite is based on processing speed (language fluency), working memory (WMS-III, Spatial Span) (45), and oral learning and memory test (WMS-III, word The word test) (45) the average of the T scores. The processing speed, working memory, and the raw scores of the spoken and memory tests were normalized to a T score of 50 on average and a standard deviation of 10 to allow each trial to be compared to each other. Additional cognitive function tests combined with ADAS-cog can improve cognitive assessment whole. It has been found that a reduction in processing speed is associated with aging (46, 47). Working memory (48) and oral learning and memory (49) in patients with AD also declined.
治療之全身性副作用係在研究起始點和第8、16以及24週,以身體和神經學的檢查、包含CBC和生化之實驗室檢驗評估,並且以Udvalg for Kliniske Undersogelser(UKU)副作用評估量表(50)查核。 Systemic side effects of treatment were at the start of the study and at weeks 8, 16 and 24, with physical and neurological examinations, laboratory tests including CBC and biochemistry, and Udvalg for Kliniske Undersogelser (UKU) side effects. Table (50) check.
臨床評估係由受過訓練且有評估量表使用經驗之研究精神科醫師和神經科醫師進行。評分者間信度係以ANOVA檢定分析。僅在研究前訓練期間達到0.90之級內相關係數之評分者可對受試者評分。評分者至少每季會面一次以進行訓練和信度再測試,以維持高評分者間信度和避免評分者偏移(drift)。在整個試驗期間,個別患者係由相同的研究精神科醫師或神經科醫師評估,使評分者間變異性減至最小。 Clinical evaluation is performed by a research psychiatrist and neurologist who is trained and has experience in using the assessment scale. The inter-rater reliability was analyzed by ANOVA assay. Reached only during pre-study training The scorer of the correlation coefficient within the order of 0.90 can score the subject. The scorer meets at least once a quarter for training and reliability retesting to maintain high-scoring inter-personal confidence and avoid scorer drift. Individual patients were assessed by the same study psychiatrist or neurologist throughout the trial to minimize inter-rater variability.
以卡方檢定(chi-square test)(或費雪精準檢定(Fisher’s exact test))來比較類別變項之差異,以Student兩樣本t檢定(Student’s two-sample t-test)(若分布非常態,則用曼-惠內U檢定(Mann-Whitney U test))比較兩組之間之連續變項。以廣義估計方程式(GEE)方法(以治療、訪視以及治療-訪視交互作用作為固定效果,截距作為唯一隨機效果,基準值作為共變量)比較重複測量評估(ADAS-cog)中從基準線之改變的平均值以SAS/STAT(SAS Institute, Cary,North Carolina)“PROC GENMOD”AR(自迴歸)(1)工作相關結構之程序進行GEE分析,但用邊際模式取代混合效果模式。以治療有效程度(柯恩氏d(Cohen’s d))判定苯甲酸鈉治療相較於安慰劑而產生之連續變項之改善幅度(51)。 Use the chi-square test (or Fisher's exact test) to compare the differences between the category variables, using the Student's two-sample t -test (Student's two-sample t- test) (if the distribution is abnormal) Then, the Mann-Whitney U test was used to compare the continuous variables between the two groups. The generalized estimating equation (GEE) method (with treatment, visit and treatment-visit interaction as a fixed effect, intercept as the only random effect, and the reference value as a covariate) was compared from the benchmark in the repeated measures assessment (ADAS-cog). The mean value of the line change was analyzed by the SAE/STAT (SAS Institute, Cary, North Carolina) "PROC GENMOD" AR (autoregressive) ( 1 ) work-related structure of the GEE analysis, but the mixed mode was replaced by the marginal mode. A therapeutically effective extent (Keen Shi d (Cohen's d)) is determined compared to a placebo treatment, sodium benzoate and the magnitude of the improvement is generated (51) of continuous variables.
最終,所有60位經隨機分配之患者完成至少一次追蹤,而且其中50位(90%)完成24週試驗(顯示在第1圖)。GEE分析中沒有針對不完整之數據使用插補。 Eventually, all 60 randomly assigned patients completed at least one follow-up, and 50 of them (90%) completed the 24-week trial (shown in Figure 1). There is no imputation for incomplete data in the GEE analysis.
CIBIC-plus無研究起始點之分數,因其評分是依據自起始點之變化。Student以兩樣本t檢定(或若分布非常態,則用曼-惠內U檢定)評估在第8、16、24週和終點時兩組之間之CIBIC-plus分數差。 CIBIC-plus has no score for the starting point of the study because its score is based on changes from the starting point. Student assessed the CIBIC-plus score difference between the two groups at weeks 8, 16, 24 and the end point with a two-sample t-test (or a Mann-Whit U test if the distribution was abnormal).
以費雪精準檢定比較兩組之間之退出率之差。以柯恩氏w(Cohen’s w)測定類別變數之有效程度(52)。所有數據係用IBM SPSS Statistics(18.0版本;SPSS Inc.)或SAS 9.3版本分析。臨床測量之所有p值係基於雙尾檢定,其具有顯著性水平為0.05。 The difference between the exit rates between the two groups was compared by Fisher's precision check. In Keen Shi w (Cohen's w) measured effectiveness (52) category of variables. All data was analyzed using IBM SPSS Statistics (version 18.0; SPSS Inc.) or SAS 9.3. All p values for clinical measurements were based on a two-tailed assay with a significance level of 0.05.
60位患者符合條件並接受隨機分配(顯示在第1圖)。於研究起始時,苯甲酸鈉組(N=30)和安慰劑組(N=30)之間之人口學特徵、教育程度、發病年齡、病程長短、CDR分數、身體質量指數(BMI)以及AChEI使用等皆相似(p>0.05)(顯示於表1)。AChEI劑量係在治療範圍內,而且兩組之間之AChEI劑量相似(顯示於表1)。在第8、16以及 24週時,苯甲酸鈉之平均劑量分別為275.0±76.3、525.0±100.6以及716.7±182.6mg/天。 Sixty patients were eligible and randomized (shown in Figure 1). Demographic characteristics, educational attainment, age at onset, duration of disease, CDR score, body mass index (BMI), and AChEI between the sodium benzoate group (N=30) and the placebo group (N=30) at the start of the study The use was similar ( p > 0.05) (shown in Table 1). The AChEI dose was within the therapeutic range and the AChEI doses were similar between the two groups (shown in Table 1). At weeks 8, 16 and 24, the average dose of sodium benzoate was 275.0 ± 76.3, 525.0 ± 100.6 and 716.7 ± 182.6 mg / day, respectively.
AChEI表示乙醯膽鹼酯酶抑制劑;BMI表示身體質量 指數;CDR表示臨床失智症評量表;NA表示無關聯。 AChEI represents an acetylcholinesterase inhibitor; BMI represents body mass Index; CDR indicates clinical dementia scale; NA indicates no association.
a 費雪精準檢定。 a Fisher's precision check.
b 獨立t試驗。 b Independent t test.
c 曼-惠內U檢定。 c Man-Hui Ne U test.
表2中顯示兩組患者之主要和次要結果兩者之平均±SD分數,包含ADAS-cog、附加認知功能測驗及CIBIC-plus。在第0週(研究起始點)時,兩組之ADAS-cog和附加認知功能測驗無顯著差異(分別為p=0.75和0.27)。 Table 2 shows the mean ± SD scores for both primary and secondary outcomes for both groups, including ADAS-cog, additional cognitive function tests, and CIBIC-plus. At week 0 (study starting point), there was no significant difference in ADAS-cog and additional cognitive function tests between the two groups ( p = 0.75 and 0.27, respectively).
24週治療期間以廣義估計方程式(GEE)分析所得之阿茲海默症評估量表-認知次級量表(ADAS-cog)之測量、臨床醫師訪視為基礎的整體改變-附加照護者提供之資訊(CIBIC-plus)之測量的結果。附加認知功能測驗:處理速度、工作記憶以及口語學習和記憶之複合測試分數。 Measurement of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and clinical physician visit as a basis for overall change during the 24-week treatment period using the Generalized Estimation Formula (GEE) - provided by additional caregivers The result of the measurement of CIBIC-plus. Additional cognitive function tests: composite test scores for processing speed, working memory, and spoken language learning and memory.
a 估算值為GEE方法多元線性迴歸模式中之治療-訪 視交互作用之係數。第一階自迴歸共變異數矩陣用於患者內部之重複測量。p值係以雙尾檢定為基準。 a Estimated value is the coefficient of treatment-visit interaction in the multiple linear regression model of the GEE method. The first order autoregressive covariance matrix is used for repeated measurements within the patient. The p value is based on a two-tailed test.
b 獨立t檢定。 b Independent t test.
c 使用曼-惠內U檢定,因為CIBIC-plus分數之分布非常態。 c Use the Man-Huinet U test because the distribution of the CIBIC-plus score is abnormal.
至於主要結果,相較於安慰劑治療,苯甲酸鈉在整個研究中對ADAS-cog分數改善更佳(在第8、16和24週和研究結束點時,苯甲酸鈉組之從研究起始點之平均差分別為3.8、5.4、5.9以及5.9,而安慰劑組則分別為2.4、1.7、2.7以及1.7;p分別=0.3730、0.0021、0.0116以及0.0031),而在研究結束點之有效程度為0.86(顯示於表2)。在GEE模式中控制研究起始點之ADAS-cog分數,所得結果亦相似(顯示於表S1)。 As for the primary outcome, sodium benzoate improved the ADAS-cog score better throughout the study compared to placebo (at the 8th, 16th, and 24th week and at the end of the study, the sodium benzoate group from the starting point of the study) The mean difference was 3.8, 5.4, 5.9, and 5.9, respectively, while the placebo group was 2.4, 1.7, 2.7, and 1.7, respectively; p = 0.3730, 0.0021, 0.0116, and 0.0031, respectively, and the effective level at the end of the study was 0.86 ( Shown in Table 2). The ADAS-cog scores at the starting point of the study were controlled in the GEE mode and the results were similar (shown in Table S1).
*估算值為GEE方法多元線性迴歸模式中之治療-訪視交互作用之係數。自迴歸共變異數矩陣用於患者內部之重複測量。p值係以雙尾檢定為基準。 * Estimated as the coefficient of treatment-visit interaction in the multiple linear regression model of the GEE method. The autoregressive covariance matrix is used for repeated measurements within the patient. The p value is based on a two-tailed test.
ADAS-cog:阿茲海默症評估量表-認知次級量表。 ADAS-cog: Alzheimer's Disease Assessment Scale - Cognitive Subscale.
粗體p值表示達統計顯著性。 The bold p value indicates statistical significance.
至於次要結果,相較於安慰劑,苯甲酸鈉於研究結束點之附加認知功能測驗較佳(p=0.007,有效程度=0.78)。相較於安慰劑治療,苯甲酸鈉治療亦在第16週(p=0.015)、第24週(p=0.016)以及研究結束點(p=0.012,有 效程度=0.73)產生更佳之CIBIC-plus分數(顯示於表2)。 As for the secondary outcome, the additional cognitive function test for sodium benzoate at the end of the study was better compared to placebo ( p = 0.007, effective = 0.78). Compared with placebo treatment, sodium benzoate treatment also produced a better CIBIC-plus score at week 16 ( p = 0.015), week 24 ( p = 0.016), and study end point ( p = 0.012, effective = 0.73). (Displayed in Table 2).
苯甲酸鈉組之退出率(3.3%)低於安慰劑組之退出率(16.7%),但未達統計之顯著差異(p=0.195)。 The withdrawal rate of the sodium benzoate group (3.3%) was lower than that of the placebo group (16.7%), but did not reach a statistically significant difference ( p = 0.195).
至於子群分析,吾等進一步檢驗CDR 0.5和CDR 1子群中之苯甲酸鈉相對於安慰劑之功效。在ADAS-cog方面,在CDR 1子群中,苯甲酸鈉在第16、24週和研究結束點時產生比安慰劑治療更大的改善(p分別=0.0151、0.0387以及0.0092)。然而,在CDR 0.5子群中,苯甲酸鈉在整個研究中並無優於安慰劑治療(p>0.05)(顯示於表3)。 For subgroup analysis, we further examined the efficacy of sodium benzoate in the CDR 0.5 and CDR 1 subpopulations relative to placebo. In the ADAS-cog, sodium benzoate produced greater improvement at the 16th, 24th, and end of study than placebo treatment in the CDR 1 subpopulation ( p = 0.0151, 0.0387, and 0.0092, respectively). However, in the CDR 0.5 subpopulation, sodium benzoate was not superior to placebo ( p > 0.05) throughout the study (shown in Table 3).
雖然ADAS-cog廣泛用於AD臨床試驗,其對MCI可能較不敏感(67)。改善偵測MCI之反應性的策略之一為增加額外認知測試。業經發現患有MCI者在神經心理功能有受損(68),諸如,處理速度(69)、工作記憶(70)以及口語學習和記憶(71)。在本發明之aMCI子群中,苯甲酸鈉在附加認知功能測驗(其係由處理速度、工作記憶以及口語學習/記憶所組成)方面顯示邊緣顯著性,但在ADAS-cog分數方面則否。吾等結果呼應對於細微缺陷更敏感之額外神經心理測試應用於MCI試驗之建議。 Although ADAS-cog is widely used in AD clinical trials, it may be less sensitive to MCI (67). One of the strategies to improve the responsiveness of detecting MCI is to add additional cognitive tests. Those with MCI have been found to have impaired neuropsychological function (68), such as speed of treatment (69), working memory (70), and oral learning and memory (71). In the aMCI subgroup of the present invention, sodium benzoate exhibits marginal significance in terms of additional cognitive function tests (which consist of processing speed, working memory, and spoken language learning/memory), but not in terms of ADAS-cog scores. Our results echo the recommendations of the MCI trial for additional neuropsychological testing that is more sensitive to subtle defects.
縮寫與表1和2中者相同。 The abbreviations are the same as those in Tables 1 and 2.
a 估算值為GEE方法多元線性迴歸模式中之治療-訪視交互作用之係數。第一階自迴歸共變異數矩陣用於患者內部之重複測量。p值係以雙尾檢定為基準。 a Estimated value is the coefficient of treatment-visit interaction in the multiple linear regression model of the GEE method. The first order autoregressive covariance matrix is used for repeated measurements within the patient. The p value is based on a two-tailed test.
就改善附加認知功能測驗而言,苯甲酸鈉在CDR 1子群中顯示更佳之功效(p=0.041),而且在CDR 0.5子群中有邊緣顯著性(p=0.063)(顯示於表4)。至於CIBIC-plus,在第24週和研究結束點時,苯甲酸鈉在CDR 1子群中較安慰劑治療產生更大的改善(p分別=0.040和0.018),但在CDR 0.5子群中則否(顯示於表5)。 In terms of improving the additional cognitive function test, sodium benzoate showed better efficacy in the CDR 1 subpopulation ( p = 0.041) and marginal significance in the CDR 0.5 subpopulation ( p = 0.063) (shown in Table 4). As for CIBIC-plus, at week 24 and at the end of the study, sodium benzoate produced a greater improvement in the CDR 1 subgroup than placebo treatment ( p = 0.040 and 0.018, respectively), but not in the CDR 0.5 subgroup. (Displayed in Table 5).
苯甲酸鈉亦無改善aMCI子群中之CIBIC-plus分數。一種可能的解釋為MCI個體中功能性損害很微小所產生之天花板效應,因而限制進一步改善之空間。 Sodium benzoate also did not improve the CIBIC-plus score in the aMCI subpopulation. One possible explanation is the ceiling effect produced by the tiny impairment of functional impairment in MCI individuals, thus limiting the room for further improvement.
p值係以雙尾檢定為基準。附加認知功能測驗表示處理速度、工作記憶、口語學習以及記憶之複合測驗分數。CDR表示臨床失智症評量表。 The p value is based on a two-tailed test. The additional cognitive function test represents a composite test score for processing speed, working memory, spoken language learning, and memory. The CDR represents the clinical dementia scale.
p值係以雙尾檢定為基準。利用曼-惠內U檢定,因為CIBIC-plus分數之分布非常態。 The p value is based on a two-tailed test. Utilizing the Man-Hui-U test, the distribution of CIBIC-plus scores is abnormal.
CDR表示臨床失智症評量表; CDR represents the clinical dementia scale;
CIBIC-plus表示臨床醫師訪視為基礎的整體改變-附加照護者提供之資訊。 CIBIC-plus represents the overall change that the clinician visits as a basis - information provided by additional caregivers.
儘早辨識和治療AD是重要的,以可能地阻止其病程(53)。本發明係第一個施用DAAO抑制劑,在本文中為苯甲酸鈉,作為早期認知衰減之新穎療法。結果顯示對所有受試者整體而言,苯甲酸鈉在改善ADAS-cog分數、附加認知功能測驗(其係由處理速度、工作記憶、口語學習以及記憶所組成)以及整體性功能方面之功效比安慰劑更佳。子群比較發現在患有輕度AD之患者,苯甲酸鈉在所有結果測量皆較佳。在aMCI子群中,苯甲酸鈉在改善附加認知功能測驗顯示邊緣顯著性。此外,苯甲酸鈉亦展現良好的安全性。 It is important to identify and treat AD as early as possible to potentially prevent its course of disease (53). The present invention is the first to administer a DAAO inhibitor, herein referred to as sodium benzoate, as a novel therapy for early cognitive attenuation. The results showed that sodium benzoate was more effective in improving the ADAS-cog score, the additional cognitive function test (which consists of processing speed, working memory, oral learning, and memory) and overall sexual function compared to all subjects. The agent is better. Subgroup comparisons found that sodium benzoate was better measured in all outcomes in patients with mild AD. In the aMCI subgroup, sodium benzoate showed marginal significance in improving the additional cognitive function test. In addition, sodium benzoate also shows good safety.
在劑量方面,苯甲酸鈉在第16週和第24週時有較安慰劑更佳之功效,平均劑量分別為525mg/天和716mg/天,這可能暗示500至750mg/天之苯甲酸鈉較250mg/天更有效。另一種可能性為較長的苯甲酸鈉治療期間產生較 佳之治療反應。 In terms of dose, sodium benzoate had better efficacy than placebo at weeks 16 and 24, with average doses of 525 mg/day and 716 mg/day, respectively, suggesting that 500 to 750 mg/day of sodium benzoate is more than 250 mg/day. More effective. Another possibility for longer sodium benzoate treatment during treatment Good treatment response.
AChEI常使用以治療AD(57,58),但由於療效弱且有副作用之風險,而不建議用於治療MCI(59,60)。來自英國精神藥理學會(British Association for Psychopharmacology)之共識聲明認為AChEI和memantine皆對於治療MCI無效(61)。其他常用於治療MCI之化合物,諸如,維生素E(62)、葉酸(63)、ω-3脂肪酸(64)、piracetam(65)以及銀杏(66),亦沒有明確的認知增強效果的證據。苯甲酸鈉一般而言是安全的,而且在此小樣本數研究中,苯甲酸鈉針對aMCI之療效達到改善之趨勢。 AChEI is often used to treat AD (57, 58), but is not recommended for the treatment of MCI due to its weak efficacy and risk of side effects (59, 60). A consensus statement from the British Association for Psychopharmacology states that both AChEI and memantine are ineffective for treating MCI (61). Other compounds commonly used to treat MCI, such as vitamin E (62), folic acid (63), omega-3 fatty acids (64), piracetam (65), and ginkgo (66), have no clear evidence of cognitive enhancement. Sodium benzoate is generally safe, and in this small sample size study, the efficacy of sodium benzoate for aMCI has improved.
成人腦部之小腦中偵測到非常高濃度之DAAO,然而前腦(諸如,前額葉皮質和海馬迴)中儘管表現強,其活性卻低(75,76)。前腦和小腦間DAAO之細胞定位和功能可能不同:DAAO在小腦中為膠細胞性(glial),但在大腦皮質中主要為神經元性(neuronal)。然而,DAAO抑制劑對於前腦D-絲胺酸量之效果不一致。大部分的DAAO抑制劑可在前腦中造成D-絲胺酸可測量的增加(如在小腦中所觀察到),但一些DAAO抑制劑卻可能不會(77)。不過,小腦涉及於認知功能。苯甲酸鈉可能不僅可藉由腦部機制,亦可藉由小腦機制發揮其促認知效果。 Very high concentrations of DAAO are detected in the cerebellum of the adult brain, whereas in the forebrain (such as the prefrontal cortex and hippocampus), although their performance is strong, their activity is low (75, 76). The cellular localization and function of DAAO between the forebrain and cerebellum may be different: DAAO is glia in the cerebellum, but mainly neuronal in the cerebral cortex. However, the effects of DAAO inhibitors on the amount of D-serine in the forebrain are inconsistent. Most DAAO inhibitors cause a measurable increase in D-serine in the forebrain (as observed in the cerebellum), but some DAAO inhibitors may not (77). However, the cerebellum is involved in cognitive function. Sodium benzoate may exert its cognitive effects not only through the brain mechanism but also through the cerebellar mechanism.
本發明意味著作為DAAO抑制劑之苯甲酸鈉對於患有早期AD之患者的認知和整體功能是有益的,而且對於aMCI可能為有益的。使用苯甲酸鈉於早期AD和aMCI將對不斷增加的患有認知衰減之老化族群帶來希望。本申請 案之結果意味著針對早期失智症之苯甲酸鈉治療可能係由於神經新生之活化和抗細胞凋亡。 The present invention means that sodium benzoate, which is a DAAO inhibitor, is beneficial for cognition and overall function in patients with early AD, and may be beneficial for aMCI. The use of sodium benzoate in early AD and aMCI will bring hope to an increasing number of aging communities with cognitive decline. This application The result of the case means that sodium benzoate treatment for early dementia may be due to activation of nerve regeneration and anti-apoptosis.
苯甲酸鈉和安慰劑皆有良好耐受性。僅安慰劑組中一位患者在第16週時報告有頭暈現象。該副作用係輕微的,而且無需要醫學治療。在每次訪視中以UKU副作用評估量表評估後,苯甲酸鈉組中沒有報告有副作用。沒有因為副作用而退出者。 Both sodium benzoate and placebo are well tolerated. Only one patient in the placebo group reported dizziness at week 16. This side effect is mild and does not require medical treatment. No side effects were reported in the sodium benzoate group after evaluation by the UKU Side Effects Assessment Scale in each visit. There are no exits due to side effects.
常規血球計數和生化檢驗皆在正常範圍內,而且在治療之後維持不變(數據未顯示)。 Both routine blood counts and biochemical tests were within the normal range and remained unchanged after treatment (data not shown).
此研究成果係由台灣科技部(NSC 99-3114-B-182A-003、NSC 101-2314-B-182A-073-MY2以及NSC-101-2325-B-039-009)、台灣卓越臨床試驗與研究中心(DOH102-TD-B-111-004)以及台灣中國醫藥大學附設醫院(CMU 101-AWARD-13、DMR-99-153)所支持。 This research was carried out by the Ministry of Science and Technology of Taiwan (NSC 99-3114-B-182A-003, NSC 101-2314-B-182A-073-MY2 and NSC-101-2325-B-039-009), Taiwan Excellence Clinical Trial Supported by the Research Center (DOH102-TD-B-111-004) and the Hospital of China Medical University of Taiwan (CMU 101-AWARD-13, DMR-99-153).
上述詳盡的具體實施例僅闡釋以揭露本發明之原理和作用,而不限制本發明之範疇。發明所屬技術領域中具有通常知識者應了解根據本發明之揭示內容中之精神和原理之所有修飾和改變應落入所附加之申請專利範圍之範疇內。說明書和實施例認定為僅為例示性,而本發明之實際範疇係由以下申請專利範圍表示。 The above detailed description is merely illustrative of the principles and functions of the invention and is not intended to limit the scope of the invention. It is to be understood by those of ordinary skill in the art that all modifications and changes in the spirit and scope of the present invention are intended to fall within the scope of the appended claims. The specification and examples are to be considered as illustrative only, and the scope of the invention
本申請案中所列之以下參考文獻係如個別併入般之方式,各以引用方式併入本文。 The following references, which are listed in this application, are hereby incorporated by reference in their entirety in their entirety herein in their entirety.
1. Budd D, Burns LC, Guo Z, L'Italien G, Lapuerta P (2011): Impact of early intervention and disease modification in patients with predementia Alzheimer's disease: a Markov model simulation. ClinicoEconomics and outcomes research: CEOR. 3:189-195. 1. Budd D, Burns LC, Guo Z, L'Italien G, Lapuerta P (2011): Impact of early intervention and disease modification in patients with predementia Alzheimer's disease: a Markov model simulation. ClinicoEconomics and outcomes research: CEOR. 3: 189-195.
2. Loy C, Schneider L (2006): Galantamine for Alzheimer's disease and mild cognitive impairment. Cochrane Database Syst Rev.CD001747. 2. Loy C, Schneider L (2006): Galantamine for Alzheimer's disease and mild cognitive impairment. Cochrane Database Syst Rev. CD001747.
3. Raschetti R, Albanese E, Vanacore N, Maggini M (2007): Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials. PLoS medicine. 4:e338. 3. Raschetti R, Albanese E, Vanacore N, Maggini M (2007): Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials. PLoS medicine. 4:e338.
4. Birks J, Flicker L (2006): Donepezil for mild cognitive impairment. Cochrane Database Syst Rev.CD006104. 4. Birks J, Flicker L (2006): Donepezil for mild cognitive impairment. Cochrane Database Syst Rev. CD006104.
5. Lipton SA, Rosenberg PA (1994): Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med. 330:613-622. 5. Lipton SA, Rosenberg PA (1994): Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med. 330:613-622.
6. Kalia LV, Kalia SK, Salter MW (2008): NMDA receptors in clinical neurology: excitatory times ahead. Lancet Neurol. 7:742-755. 6. Kalia LV, Kalia SK, Salter MW (2008): NMDA receptors in clinical neurology: excitatory times ahead. Lancet Neurol. 7:742-755.
7. Choi DW (1992): Excitotoxic cell death. Journal of neurobiology. 23:1261-1276. 7. Choi DW (1992): Excitotoxic cell death. Journal of neurobiology. 23:1261-1276.
8. Scarpini E, Scheltens P, Feldman H (2003): Treatment of Alzheimer's disease: current status and new perspectives. Lancet neurology. 2:539-547. 8. Scarpini E, Scheltens P, Feldman H (2003): Treatment of Alzheimer's disease: current status and new perspectives. Lancet neurology. 2:539-547.
9. Gardoni F, Mauceri D, Malinverno M, Polli F, Costa C, Tozzi A, et al. (2009): Decreased NR2B subunit synaptic levels cause impaired long-term potentiation but not long-term depression. J Neurosci. 29:669-677. 9. Gardoni F, Mauceri D, Malinverno M, Polli F, Costa C, Tozzi A, et al. (2009): Decreased NR2B subunit synaptic levels cause impaired long-term potentiation but not long-term depression. J Neurosci. 669-677.
10. Pallàs M, Camins A (2006): Molecular and Biochemical Features in Alzheimer disease. Curr Pharm Des. 12:4389-4408. 10. Pallàs M, Camins A (2006): Molecular and Biochemical Features in Alzheimer disease. Curr Pharm Des. 12:4389-4408.
11. Reisberg B, Doody R, Stöffler B, Schmitt F, Ferris S, Möbius HJ (2003): Memantine in Moderate-to-Severe Alzheimer Disease. N Engl J Med. 348:1333-1341. 11. Reisberg B, Doody R, Stöffler B, Schmitt F, Ferris S, Möbius HJ (2003): Memantine in Moderate-to-Severe Alzheimer Disease. N Engl J Med. 348:1333-1341.
12. Schneider LS, Dagerman KS, Higgins JP, McShane R (2011): Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol. 68:991-998. 12. Schneider LS, Dagerman KS, Higgins JP, McShane R (2011): Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol. 68:991-998.
13. Yoon WJ, Won SJ, Ryu BR, Gwag BJ (2003): Blockade of ionotropic glutamate receptors produces neuronal apoptosis through the Bax-cytochrome C-caspase pathway: the causative role of Ca2+ deficiency. J Neurochem. 85:525-533. 13. Yoon WJ, Won SJ, Ryu BR, Gwag BJ (2003): Blockade of ionotropic glutamate receptors producing neuronal apoptosis through the Bax-cytochrome C-caspase pathway: the causative role of Ca2+ deficiency. J Neurochem. 85:525-533 .
14. Rowland LM, Astur RS, Jung RE, Bustillo JR, Lauriello J, Yeo RA (2005): Selective cognitive impairments associated with NMDA receptor blockade in humans. Neuropsychopharmacology. 30:633-639. 14. Rowland LM, Astur RS, Jung RE, Bustillo JR, Lauriello J, Yeo RA (2005): Selective cognitive impairments associated with NMDA receptor blockade in humans. Neuropsychopharmacology. 30:633-639.
15. Mattson MP (2008): Glutamate and neurotrophic factors in neuronal plasticity and disease. Ann N Y Acad Sci. 1144:97-112. 15. Mattson MP (2008): Glutamate and neurotrophic factors in neuronal plasticity and disease. Ann NY Acad Sci. 1144:97-112.
16. Tilleux S, Hermans E (2007): Neuroinflammation and regulation of glial glutamate uptake in neurological disorders. J Neurosci Res. 85:2059-2070. 16. Tilleux S, Hermans E (2007): Neuroinflammation and regulation of glial glutamate uptake in neurological disorders. J Neurosci Res. 85:2059-2070.
17. Olney JW, Farber NB (1995): Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry. 52:998-1007. 17. Olney JW, Farber NB (1995): Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry. 52:998-1007.
18. Segovia G, Porras A, Del Arco A, Mora F (2001): Glutamatergic neurotransmission in aging: a critical perspective. Mech Ageing Dev. 122:1-29. 18. Segovia G, Porras A, Del Arco A, Mora F (2001): Glutamatergic neurotransmission in aging: a critical perspective. Mech Ageing Dev. 122:1-29.
19. Procter AW, Stirling JM, Stratmann GC, Cross AJ, Bowen DM (1989): Loss of glycine-dependent radioligand binding to the N-methyl-D-aspartate-phencyclidine receptor complex in patients with Alzheimer's disease. Neurosci Lett. 101:62-66. 19. Procter AW, Stirling JM, Stratmann GC, Cross AJ, Bowen DM (1989): Loss of glycine-dependent radioligand binding to the N-methyl-D-aspartate-phencyclidine receptor complex in patients with Alzheimer's disease. Neurosci Lett. 101 :62-66.
20. Procter AW, Wong EH, Stratmann GC, Lowe SL, Bowen DM (1989): Reduced glycine stimulation of [3H]MK-801 binding in Alzheimer's disease. J Neurochem. 53:698-704. 20. Procter AW, Wong EH, Stratmann GC, Lowe SL, Bowen DM (1989): Reduced glycine stimulation of [3H]MK-801 binding in Alzheimer's disease. J Neurochem. 53:698-704.
21. Chessell IP, Procter AW, Francis PT, Bowen DM (1991): D-cycloserine, a putative cognitive enhancer, facilitates activation of the N-methyl-D-aspartate receptor-ionophore complex in Alzheimer brain. Brain Res. 565:345-348. 21. Chessell IP, Procter AW, Francis PT, Bowen DM (1991): D-cycloserine, a putative cognitive enhancer, facilitats activation of the N-methyl-D-aspartate receptor-ionophore complex in Alzheimer brain. Brain Res. 565: 345-348.
22. Tsai GE, Falk WE, Gunther J, Coyle JT (1999): Improved cognition in Alzheimer's disease with short-term D-cycloserine treatment. Am J Psychiatry. 156:467-469. 22. Tsai GE, Falk WE, Gunther J, Coyle JT (1999): Improved cognition in Alzheimer's disease with short-term D-cycloserine treatment. Am J Psychiatry. 156:467-469.
23. Lane HY, Lin CH, Green MF, Hellemann G, Huang CC, Chen PW, et al. (2013): A Randomized, Double-Blind, Placebo-Controlled Add-on Treatment of Benzoate, a D-Amino Acid Oxidase Inhibitor, for Schizophrenia. JAMA Psychiatry. 70: 1267-1275. 23. Lane HY, Lin CH, Green MF, Hellemann G, Huang CC, Chen PW, et al. (2013): A Randomized, Double-Blind, Placebo-Controlled Add-on Treatment of Benzoate, a D-Amino Acid Oxidase Inhibitor, for Schizophrenia. JAMA Psychiatry. 70: 1267-1275.
24. Fukui K, Miyake Y (1992): Molecular cloning and chromosomal localization of a human gene encoding D-amino-acid oxidase. The Journal of biological chemistry. 267:18631-18638. 24. Fukui K, Miyake Y (1992): Molecular cloning and chromosomal localization of a human gene encoding D-amino-acid oxidase. The Journal of biological chemistry. 267:18631-18638.
25. Vanoni MA, Cosma A, Mazzeo D, Mattevi A, Todone F, Curti B (1997): Limited proteolysis and X-ray crystallography reveal the origin of substrate specificity and of the rate-limiting product release during oxidation of D-amino acids catalyzed by mammalian D-amino acid oxidase. Biochemistry. 36:5624-5632. 25. Vanoni MA, Cosma A, Mazzeo D, Mattevi A, Todone F, Curti B (1997): Limited proteolysis and X-ray crystallography reveal the origin of substrate specificity and of the rate-limiting product release during oxidation of D-amino Acids catalyzed by mammalian D-amino acid oxidase. Biochemistry. 36:5624-5632.
26. Sasabe J, Miyoshi Y, Suzuki M, Mita M, Konno R, Matsuoka M, et al. (2012): D-amino acid oxidase controls motoneuron degeneration through D-serine. Proc Natl Acad Sci U S A. 109:627-632. 26. Sasabe J, Miyoshi Y, Suzuki M, Mita M, Konno R, Matsuoka M, et al. (2012): D-amino acid oxidase controls motoneuron degeneration through D-serine. Proc Natl Acad Sci US A. 109:627 -632.
27. Esposito S, Pristera A, Maresca G, Cavallaro S, Felsani A, Florenzano F, et al. (2012): Contribution of serine racemase/d-serine pathway to neuronal apoptosis. Aging Cell 11:588-598. 27. Esposito S, Pristera A, Maresca G, Cavallaro S, Felsani A, Florenzano F, et al. (2012): Contribution of serine racemase/d-serine pathway to neuronal apoptosis. Aging Cell 11:588-598.
28. Huang X, Kong H, Tang M, Lu M, Ding JH, Hu G (2012): D-Serine regulates proliferation and neuronal differentiation of neural stem cells from postnatal mouse forebrain. CNS Neurosci Ther. 18:4-13. 28. Huang X, Kong H, Tang M, Lu M, Ding JH, Hu G (2012): D-Serine regulates proliferation and neuronal differentiation of neural stem cells from postnatal mouse for ebrain. CNS Neurosci Ther. 18:4-13.
29. Smith SM, Uslaner JM, Hutson PH (2010): The Therapeutic Potential of D-Amino Acid Oxidase (DAAO) Inhibitors. The open medicinal chemistry journal. 4:3-9. 29. Smith SM, Uslaner JM, Hutson PH (2010): The Therapeutic Potential of D-Amino Acid Oxidase (DAAO) Inhibitors. The open medicinal chemistry journal. 4:3-9.
30. WHO-Concise International Chemical Assessment Document No.26. WHO G, 2000 http://www.inchem.org/documents/cicads/cicads/cicad26.htm. 30. WHO-Concise International Chemical Assessment Document No. 26. WHO G, 2000 http://www.inchem.org/documents/cicads/cicads/cicad26.htm.
31. World Health Organization (2000): Concise International Chemical Assessment. Document No. 26. Geneva: World Health Organization. Available at: http://www.who.int/ipcs/publications/cicad/cicad26_rev_1.pdf .. 31. World Health Organization (2000): Concise International Chemical Assessment. Document No. 26. Geneva: World Health Organization. Available at: http://www.who.int/ipcs/publications/cicad/cicad26_rev_1.pdf ..
32. Smith SM, Uslaner JM, Yao L, Mullins CM, Surles NO, Huszar SL, et al. (2009): The behavioral and neurochemical effects of a novel D-amino acid oxidase inhibitor compound 8 [4H-thieno [3,2-b]pyrrole-5-carboxylic acid] and D-serine. The Journal of pharmacology and experimental therapeutics. 328:921-930. 32. Smith SM, Uslaner JM, Yao L, Mullins CM, Surles NO, Huszar SL, et al. (2009): The behavioral and neurochemical effects of a novel D-amino acid oxidase inhibitor compound 8 [4H-thieno [3, 2-b]pyrrole-5-carboxylic acid] and D-serine. The Journal of pharmacology and experimental therapeutics. 328:921-930.
33. Adage T, Trillat AC, Quattropani A, Perrin D, Cavarec L, Shaw J, et al. (2008): In vitro and in vivo pharmacological profile of AS057278, a selective d-amino acid oxidase inhibitor with potential anti-psychotic properties. Eur Neuropsychopharmacol. 18:200-214. 33. Adage T, Trillat AC, Quattropani A, Perrin D, Cavarec L, Shaw J, et al. (2008): In vitro and in vivo pharmacological profile of AS057278, a selective d-amino acid oxidase inhibitor with potential anti-psychotic Properties. Eur Neuropsychopharmacol. 18:200-214.
34. Hashimoto K, Fujita Y, Horio M, Kunitachi S, Iyo M, Ferraris D, et al. (2009): Co-administration of a D-amino acid oxidase inhibitor potentiates the efficacy of D-serine in attenuating prepulse inhibition deficits after administration of dizocilpine. Biol Psychiatry. 65:1103-1106. 34. Hashimoto K, Fujita Y, Horio M, Kunitachi S, Iyo M, Ferraris D, et al. (2009): Co-administration of a D-amino acid oxidase inhibitor potentiates the efficacy of D-serine in attenuating prepulse inhibition deficits After administration of dizocilpine. Biol Psychiatry. 65:1103-1106.
35. Zhao WJ, Gao ZY, Wei H, Nie HZ, Zhao Q, Zhou XJ, et al. (2010): Spinal D-amino acid oxidase contributes to neuropathic pain in rats. The Journal of pharmacology and experimental therapeutics. 332:248-254. 35. Zhao WJ, Gao ZY, Wei H, Nie HZ, Zhao Q, Zhou XJ, et al. (2010): Spinal D-amino acid oxidase contributes to neuropathic pain in rats. The Journal of pharmacology and experimental therapeutics. 332: 248-254.
36. Gong N, Gao ZY, Wang YC, Li XY, Huang JL, Hashimoto K, et al. (2011): A series of D-amino acid oxidase inhibitors specifically prevents and reverses formalin-induced tonic pain in rats. The Journal of pharmacology and experimental therapeutics. 336:282-293. 36. Gong N, Gao ZY, Wang YC, Li XY, Huang JL, Hashimoto K, et al (2011):. A series of D-amino acid oxidase inhibitors specifically prevents and reverses formalin-induced tonic pain in rats The Journal. Of pharmacology and experimental therapeutics. 336:282-293.
37. Park HK, Shishido Y, Ichise-Shishido S, Kawazoe T, Ono K, Iwana S, et al. (2006): Potential role for astroglial D-amino acid oxidase in extracellular D-serine metabolism and cytotoxicity. Journal of biochemistry. 139:295-304. 37. Park HK, Shishido Y, Ichise-Shishido S, Kawazoe T, Ono K, Iwana S, et al. (2006): Potential role for astroglial D-amino acid oxidase in extracellular D-serine metabolism and cytotoxicity. Journal of biochemistry 139: 295-304.
38. Batshaw ML, Hyman SL, Coyle JT, Robinson MB, Qureshi IA, Mellits ED, et al. (1988): Effect of sodium benzoate and sodium phenylacetate on brain serotonin turnover in the ornithine transcarbamylase-deficient sparse-fur mouse. Pediatric research. 23:368-374. 38. Batshaw ML, Hyman SL, Coyle JT, Robinson MB, Qureshi IA, Mellits ED, et al. (1988): Effect of sodium benzoate and sodium phenylacetate on brain serotonin turnover in the ornithine transcarbamylase-deficient sparse-fur mouse. Pediatric Research. 23:368-374.
39. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984): Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 34:939-944. 39. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984): Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 34:939-944.
40. Morris JC (1993): The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 43:2412-2414. 40. Morris JC (1993): The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 43:2412-2414.
41. Lu PH, Edland SD, Teng E, Tingus K, Petersen RC, Cummings JL (2009): Donepezil delays progression to AD in MCI subjects with depressive symptoms. Neurology. 72:2115-2121. 41. Lu PH, Edland SD, Teng E, Tingus K, Petersen RC, Cummings JL (2009): Donepezil delays progression to AD in MCI subjects with depressive symptoms. Neurology. 72:2115-2121.
42. Folstein MF, Folstein SE, McHugh PR (1975): "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. Journal of psychiatric research. 12:189-198. 42. Folstein MF, Folstein SE, McHugh PR (1975): "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. Journal of psychiatric research. 12:189-198.
43. Rosen WG, Mohs RC, Davis KL (1984): A new rating scale for Alzheimer's disease. Am J Psychiatry. 141:1356-1364. 43. Rosen WG, Mohs RC, Davis KL (1984): A new rating scale for Alzheimer's disease. Am J Psychiatry. 141:1356-1364.
44. Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg B, et al. (1997): Validity and reliability of the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 11 Suppl 2:S22-32. 44. Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg B, et al. (1997): Validity and reliability of the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 11 Suppl 2: S22-32.
45. Wechsler D (1997): Wechsler Memory Scale, 3rd ed. Psychological Association, San Antonio, TX:Psychological Association. 45. Wechsler D (1997): Wechsler Memory Scale, 3rd ed. Psychological Association, San Antonio, TX : Psychological Association.
46. Salthouse TA (1996): The processing-speed theory of adult age differences in cognition. Psychological review. 103:403-428. 46. Salthouse TA (1996): The processing-speed theory of adult age differences in cognition. Psychological review. 103:403-428.
47. Habekost T, Vogel A, Rostrup E, Bundesen C, Kyllingsbaek S, Garde E, et al. (2013): Visual processing speed in old age. Scandinavian journal of psychology. 54:89-94. 47. Habekost T, Vogel A, Rostrup E, Bundesen C, Kyllingsbaek S, Garde E, et al. (2013): Visual processing speed in old age. Scandinavian journal of psychology. 54:89-94.
48. Carlesimo GA, Mauri M, Graceffa AM, Fadda L, Loasses A, Lorusso S, et al. (1998): Memory performances in young, elderly, and very old healthy individuals versus patients with Alzheimer's disease: evidence for discontinuity between normal and pathological aging. Journal of clinical and experimental neuropsychology. 20:14-29. 48. Carlesimo GA, Mauri M, Graceffa AM, Fadda L, Loasses A, Lorusso S, et al. (1998): Memory performances in young, elderly, and very old healthy individuals versus patients with Alzheimer's disease: evidence for discontinuity between normal And pathological aging. Journal of clinical and experimental neuropsychology. 20:14-29.
49. Chen P, Ratcliff G, Belle SH, Cauley JA, DeKosky ST, Ganguli M (2001): Patterns of cognitive decline in presymptomatic Alzheimer disease: a prospective community study. Arch Gen Psychiatry. 58:853-858. 49. Chen P, Ratcliff G, Belle SH, Cauley JA, DeKosky ST, Ganguli M (2001): Patterns of cognitive decline in presymptomatic Alzheimer disease: a prospective community study. Arch Gen Psychiatry. 58:853-858.
50. Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K (1987): The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta psychiatrica Scandinavica Supplementum. 334:1-100. 50. Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K (1987): The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta psychiatrica Scandinavica Supplementum. 334:1-100.
51. Rosenthal R RR (1991): Essentials of behavioral research: Methods and data analysis. 2nd ed. New York: McGraw Hill. 51. Rosenthal R RR (1991): Essentials of behavioral research: Methods and data analysis. 2nd ed. New York: McGraw Hill.
52. Cunningham JB M-GE (2007): Power, effect and sample size using GPower: practical issues for researchers and members of research ethics committees. Evidence Based Midwifery 5:132-136. 52. Cunningham JB M-GE (2007): Power, effect and sample size using GPower: practical issues for researchers and members of research ethics committees. Evidence Based Midwifery 5:132-136.
53. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. (2011): Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's & dementia: the journal of the Alzheimer's Association. 7:280-292. 53. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. (2011): Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines For Alzheimer's disease. Alzheimer's & dementia: the journal of the Alzheimer's Association. 7:280-292.
54. Huang YJ, Lin CH, Lane HY, Tsai GE (2012): NMDA Neurotransmission Dysfunction in Behavioral and Psychological Symptoms of Alzheimer's Disease. Current neuropharmacology. 10:272-285. 54. Huang YJ, Lin CH, Lane HY, Tsai GE (2012): NMDA Neurotransmission Dysfunction in Behavioral and Psychological Symptoms of Alzheimer's Disease. Current neuropharmacology. 10:272-285.
55. Riederer P, Hoyer S (2006): From benefit to damage. Glutamate and advanced glycation end products in Alzheimer brain. J Neural Transm. 113:1671-1677. 55. Riederer P, Hoyer S (2006): From benefit to damage. Glutamate and advanced glycation end products in Alzheimer brain. J Neural Transm. 113:1671-1677.
56. Hashimoto K, Fukushima T, Shimizu E, Okada S, Komatsu N, Okamura N, et al. (2004): Possible role of D-serine in the pathophysiology of Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry. 28:385-388. 56. Hashimoto K, Fukushima T, Shimizu E, Okada S, Komatsu N, Okamura N, et al. (2004): Possible role of D-serine in the pathophysiology of Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry. 28:385-388 .
57. Birks J (2006): Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev.CD005593. 57. Birks J (2006): Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev. CD005593.
58. Burns A, O'Brien J, Auriacombe S, Ballard C, Broich K, Bullock R, et al. (2006): Clinical practice with anti-dementia drugs: a consensus statement from British Association for Psychopharmacology. J Psychopharmacol. 20:732-755. 58. Burns A, O'Brien J, Auriacombe S, Ballard C, Broich K, Bullock R, et al. (2006): Clinical practice with anti-dementia drugs: a consensus statement from British Association for Psychopharmacology. J Psychopharmacol. 20 :732-755.
59. Fellgiebel A (2007): [Alzheimer drugs for mild cognitive impairment]. Neuropsychiatrie: Klinik, Diagnostik, Therapie und Rehabilitation: Organ der Gesellschaft Osterreichischer Nervenarzte und Psychiater. 21:230-233. 59. Fellgiebel A (2007): [Alzheimer drugs for mild cognitive impairment]. Neuropsychiatrie: Klinik, Diagnostik, Therapie und Rehabilitation: Organ der Gesellschaft Osterreichischer Nervenarzte und Psychiater. 21: 230-233 .
60. Russ TC, Morling JR (2012): Cholinesterase inhibitors for mild cognitive impairment. Cochrane Database Syst Rev. 9:CD009132. 60. Russ TC, Morling JR (2012): Cholinesterase inhibitors for mild cognitive impairment. Cochrane Database Syst Rev. 9: CD009132.
61. O'Brien JT, Burns A (2011): Clinical practice with anti-dementia drugs: a revised (second) consensus statement from the British Association for Psychopharmacology. J Psychopharmacol. 25:997-1019. 61. O'Brien JT, Burns A (2011): Clinical practice with anti-dementia drugs: a revised (second) consensus statement from the British Association for Psychopharmacology. J Psychopharmacol. 25:997-1019.
62. Farina N, Isaac MG, Clark AR, Rusted J, Tabet N (2012): Vitamin E for Alzheimer's dementia and mild cognitive impairment. Cochrane Database Syst Rev. 11:CD002854. 62. Farina N, Isaac MG, Clark AR, Rusted J, Tabet N (2012): Vitamin E for Alzheimer's dementia and mild cognitive impairment. Cochrane Database Syst Rev. 11: CD002854.
63. Malouf R, Grimley Evans J (2008): Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people. Cochrane Database Syst Rev.CD004514. 63. Malouf R, Grimley Evans J (2008): Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people. Cochrane Database Syst Rev. CD004514.
64. Sydenham E, Dangour AD, Lim WS (2012): Omega 3 fatty acid for the prevention of cognitive decline and dementia. Cochrane Database Syst Rev. 6:CD005379. 64. Sydenham E, Dangour AD, Lim WS (2012): Omega 3 fatty acid for the prevention of cognitive decline and dementia. Cochrane Database Syst Rev. 6: CD005379.
65. Flicker L, Grimley Evans G (2001): Piracetam for dementia or cognitive impairment. Cochrane Database Syst Rev.CD001011. 65. Flicker L, Grimley Evans G (2001): Piracetam for dementia or cognitive impairment. Cochrane Database Syst Rev. CD001011.
66. Birks J, Grimley Evans J (2009): Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev.CD003120. 66. Birks J, Grimley Evans J (2009): Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev. CD003120.
67. Skinner J, Carvalho JO, Potter GG, Thames A, Zelinski E, Crane PK, et al. (2012): The Alzheimer's Disease Assessment Scale-Cognitive-Plus (ADAS-Cog-Plus): an expansion of the ADAS-Cog to improve responsiveness in MCI. Brain imaging and behavior. 6:489-501. 67. Skinner J, Carvalho JO, Potter GG, Thames A, Zelinski E, Crane PK, et al. (2012): The Alzheimer's Disease Assessment Scale-Cognitive-Plus (ADAS-Cog-Plus): an expansion of the ADAS- Cog to improve responsiveness in MCI. Brain imaging and behavior. 6:489-501.
68. Salmon DP (2012): Neuropsychological features of mild cognitive impairment and preclinical Alzheimer's disease. Current topics in behavioral neurosciences. 10:187-212. 68. Salmon DP (2012): Neuropsychological features of mild cognitive impairment and preclinical Alzheimer's disease. Current topics in behavioral neurosciences. 10:187-212.
69. Price SE, Kinsella GJ, Ong B, Storey E, Mullaly E, Phillips M, et al. (2012): Semantic verbal fluency strategies in amnestic mild cognitive impairment. Neuropsychology. 26:490-497. 69. Price SE, Kinsella GJ, Ong B, Storey E, Mullaly E, Phillips M, et al. (2012): Semantic verbal fluency strategies in amnestic mild cognitive impairment. Neuropsychology. 26:490-497.
70. Rios C, Pascual LF, Santos S, Lopez E, Fernandez T, Navas I, et al. (2001): [Working memory and complex activities of everyday life in the initial stages of Alzheimer's disease]. Revista de neurologia. 33:719-722. 70. Rios C, Pascual LF, Santos S, Lopez E, Fernandez T, Navas I, et al. (2001): [Working memory and complex activities of everyday life in the initial stages of Alzheimer's disease]. Revista de neurologia. :719-722.
71. Espinosa A, Alegret M, Valero S, Vinyes-Junque G, Hernandez I, Mauleon A, et al. (2013): A longitudinal follow-up of 550 mild cognitive impairment patients: evidence for large conversion to dementia rates and detection of major risk factors involved. J Alzheimers Dis. 34:769-780. 71. Espinosa A, Alegret M, Valero S, Vinyes-Junque G, Hernandez I, Mauleon A, et al. (2013): A longitudinal follow-up of 550 mild cognitive impairment patients: evidence for large conversion to dementia rates and detection Of major risk factors involved. J Alzheimers Dis. 34:769-780.
72. Albert M, Blacker D, Moss MB, Tanzi R, McArdle JJ (2007): Longitudinal change in cognitive performance among individuals with mild cognitive impairment. Neuropsychology. 21:158-169. 72. Albert M, Blacker D, Moss MB, Tanzi R, McArdle JJ (2007): Longitudinal change in cognitive performance among individuals with mild cognitive impairment. Neuropsychology. 21:158-169.
73. Perneczky R, Pohl C, Sorg C, Hartmann J, Komossa K, Alexopoulos P, et al. (2006): Complex activities of daily living in mild cognitive impairment: conceptual and diagnostic issues. Age and ageing. 35:240-245. 73. Perneczky R, Pohl C, Sorg C, Hartmann J, Komossa K, Alexopoulos P, et al. (2006): Complex activities of daily living in mild cognitive impairment: conceptual and diagnostic issues. Age and ageing. 35:240- 245.
74. Lai CH, Lane HY, Tsai GE (2012): Clinical and cerebral volumetric effects of sodium benzoate, a D-amino acid oxidase inhibitor, in a drug-naive patient with major depression. Biol Psychiatry. 71:e9-e10. 74. Lai CH, Lane HY, Tsai GE (2012): Clinical and cerebral volumetric effects of sodium benzoate, a D-amino acid oxidase inhibitor, in a drug-naive patient with major depression. Biol Psychiatry. 71:e9-e10.
75. Kapoor R, Lim KS, Cheng A, Garrick T, Kapoor V (2006): Preliminary evidence for a link between schizophrenia and NMDA-glycine site receptor ligand metabolic enzymes, d-amino acid oxidase (DAAO) and kynurenine aminotransferase-1 (KAT-1). Brain Res. 1106:205-210. 75. Kapoor R, Lim KS, Cheng A, Garrick T, Kapoor V (2006): Preliminary evidence for a link between schizophrenia and NMDA-glycine site receptor ligand metabolic enzymes, d-amino acid oxidase (DAAO) and kynurenine aminotransferase-1 (KAT-1). Brain Res. 1106: 205-210.
76. Verrall L, Walker M, Rawlings N, Benzel I, Kew JN, Harrison PJ, et al. (2007): d-Amino acid oxidase and serine racemase in human brain: normal distribution and altered expression in schizophrenia. The European journal of neuroscience. 26:1657-1669. 76. Verrall L, Walker M, Rawlings N, Benzel I, Kew JN, Harrison PJ, et al. (2007): d-Amino acid oxidase and serine racemase in human brain: normal distribution and altered expression in schizophrenia. The European journal Of neuroscience. 26:1657-1669.
77. Strick CA, Li C, Scott L, Harvey B, Hajos M, Steyn SJ, et al. (2011): Modulation of NMDA receptor function by inhibition of D-amino acid oxidase in rodent brain. Neuropharmacology. 61:1001-1015. 77. Strick CA, Li C, Scott L, Harvey B, Hajos M, Steyn SJ, et al. (2011): Modulation of NMDA receptor function by inhibition of D-amino acid oxidase in rodent brain. Neuropharmacology. 61:1001- 1015.
78. http://www.mayoclinic.org/diseases-conditions/alzheimers-disease/expert-blog/dementia-definitions/bgp-20055922 78. http://www.mayoclinic.org/diseases-conditions/alzheimers-disease/expert-blog/dementia-definitions/bgp-20055922
Claims (12)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
TW103110838A TWI573588B (en) | 2014-03-24 | 2014-03-24 | Use of benzoic acid salt in the manufacture of a pharmaceutical composition for treating dementia or mild cognitive impairment |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
TW103110838A TWI573588B (en) | 2014-03-24 | 2014-03-24 | Use of benzoic acid salt in the manufacture of a pharmaceutical composition for treating dementia or mild cognitive impairment |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201536277A TW201536277A (en) | 2015-10-01 |
TWI573588B true TWI573588B (en) | 2017-03-11 |
Family
ID=54850664
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW103110838A TWI573588B (en) | 2014-03-24 | 2014-03-24 | Use of benzoic acid salt in the manufacture of a pharmaceutical composition for treating dementia or mild cognitive impairment |
Country Status (1)
Country | Link |
---|---|
TW (1) | TWI573588B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10064833B2 (en) | 2016-08-04 | 2018-09-04 | Syneurx International (Taiwan) Corp. | Compositions containing benzoate compound and tannic acid for treating central nervous system disorders |
CN108553456B (en) * | 2016-12-29 | 2020-09-15 | 天津中医药大学 | Use of benzoic acid and derivatives thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW201129355A (en) * | 2010-01-19 | 2011-09-01 | Guo-Chuan Emil Tsai | Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical |
-
2014
- 2014-03-24 TW TW103110838A patent/TWI573588B/en active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW201129355A (en) * | 2010-01-19 | 2011-09-01 | Guo-Chuan Emil Tsai | Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical |
Also Published As
Publication number | Publication date |
---|---|
TW201536277A (en) | 2015-10-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Lin et al. | Benzoate, a D-amino acid oxidase inhibitor, for the treatment of early-phase Alzheimer disease: a randomized, double-blind, placebo-controlled trial | |
Tsai et al. | D-alanine added to antipsychotics for the treatment of schizophrenia | |
AU2014386718B8 (en) | Use of benzoic acid salt in the manufactue of a composition for preventing or treating dementia or mild cognitive impairment | |
Levin et al. | Behavioral and cognitive effects of the N-methyl-D-aspartate receptor co-agonist D-serine in healthy humans: initial findings | |
Moretti et al. | Depression and Alzheimer's disease: symptom or comorbidity? | |
AU2005204358A1 (en) | Memantine for the treatment of mild and mild-to-moderate Alzheimer's disease | |
KR20120000560A (en) | Compositions and methods for extended therapy with aminopyridines | |
Bernard et al. | A 24-week double-blind placebo-controlled study of the efficacy and safety of the AMPA modulator S47445 in patients with mild to moderate Alzheimer's disease and depressive symptoms | |
CN112292127A (en) | Treatment of ataxia using riluzole prodrugs | |
JP6550426B2 (en) | Use of benzoate for producing a composition for preventing or treating dementia or mild cognitive impairment | |
Bhattacharya et al. | Attention enhancing effects of methylphenidate are age-dependent | |
TWI573588B (en) | Use of benzoic acid salt in the manufacture of a pharmaceutical composition for treating dementia or mild cognitive impairment | |
Reisberg et al. | Piracetam in the treatment of cognitive impairment in the elderly | |
Allali et al. | Gait and cognition: The impact of executive function. | |
US20240016875A1 (en) | Shan-zha for the treatment of depression and anxiety disorders | |
Mintzer | The search for better noncholinergic treatment options for Alzheimer's disease | |
US20170216234A1 (en) | Benzoates for use in treating dementia | |
RU2468813C1 (en) | Agent for prevention and treatment of acute and chronic cerebrovascular disease, use and method of treating | |
US20230070758A1 (en) | Methods of Treating Alzheimer's Disease | |
Alizadeh et al. | The Effect of Pharmacotherapy Combined with Speech Therapy on Functional Recovery from Aphasia | |
Lane et al. | Adjunctive transcranial direct current stimulation (tDCS) plus sodium benzoate for the treatment of early-phase Alzheimer's disease: A randomized, double-blind, placebo-controlled trial | |
Shoghi et al. | Effects of moderate intensity training and lithium on spatial learning and memory in a rat model: The role of SIRT3 and PGC1-α expression levels and brain-derived neurotropic factor | |
TW202416952A (en) | Methods of treating cns disorders | |
TW202423437A (en) | Dose regimens for use of ly3154207 in the treatment of dopaminergic cns disorders | |
US20210353586A1 (en) | Improving Sleep or Post-Sleep Performance |