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Molecular Targets of Tannic Acid in Alzheimer¡¦s Disease.

www.ncbi.nlm.nih.gov/pubmed/28176625

Abstract

Tannic acid (TA)has strong antioxidant/free radical scavenging, antiinflammatory, anti-viral/bacterial, and anti-carcinogenic properties.

TA¨ã¦³±j§Ü®ñ¤Æ¾¯/¦Û¥Ñ°ò²M°£¡A§Üª¢¡A§Ü¯f¬r/²Óµß©M§Ü­PÀù©Ê

The neuroprotective effects of TA against AD have been shown in several in vitro and in vivo models of AD.

Apart from its potent antioxidant and anti-inflammatory roles, evidence suggests that TA is also a natural inhibitor of £]-secretase (BACE1) activity and protein expression.

BACE1 is the primary enzyme responsible for the production and deposition of A£] peptide.

TA also destabilises neurotoxic amyloid beta (A£]) fibrils in vitro.

Apart from its effects on the A£] cascade, TA can also inhibit the in vitro aggregation of tau peptide, a core component of intracellular neurofibrillary tangles (NFTs).

This review summarizes the relevance of TA and TA-related vegetable extracts (tannins) in the pathogenesis of AD and its enzymatic targets.

It also highlights the significance of TA as an important lead compound against AD.

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BIT¡¦s 16th Annual Congress of International Drug Discovery Science and Technology-2018

Theme: Rethinking the Next Big Things in Pharma Innovations

Time: August 16-19, 2018

Place: Boston Marriott Cambridge, USA

www.iddst.com/iddst2018/ScientificProgram3_5.asp

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Session 3704: CNS and Neurodegenerative Disorders Drugs and Therapies

Day 3: Afternoon, Saturday, August 18, 2018

13:30-16:20

Chair: Dr. Guochuan E Tsai, CEO, SyneuRx Neuroscience; Professor-in-Residence, David Geffen School of Medicine, University of California at Los Angeles, USA

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Title:

Facilitating NMDA System Balance to Address CNS Disorders

Dr. Guochuan E Tsai, CEO, SyneuRx Neuroscience; Professor-in-Residence, David Geffen School of Medicine, University of California at Los Angeles, USA

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Cancer Association of South Africa (CANSA)

Fact Sheet and Position Statement on Sodium Benzoate and Vitamin C

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Sodium Benzoate and Vitamin C in South African Soft Drinks

Every single sample tested negative for benzene. CANSA can, therefore, confirm that all

citrus drinks (those potentially containing Vitamin C) and the preservative Sodium Benzoate

which were tested were found to be safe for consumption.

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Effect of Long-term Administration of Sodium Benzoate to a Patient with Partial Ornithine Carbamoyl Transferase Deficiency

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An 8-year-old girl with partial ornithine carbamoyl transferase deficiency was treated with sodium benzoate (200 mg/kg/day) for 13 months.

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No adverse effect of sodium benzoate were detected by clinical and laboratory examinations.

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Sodium benzoate - my experience

2018/3/6

A few days into my trial of Sodium Benzoate¡K Having had good results from Glycine, although I couldn¡¦t hack the queezy stomach, I thought I¡¦d see if NaBen was as effective and more easily tolerated. Sarcosine didn¡¦t work for me¡K

2018/4/18(¥b¤p®É«eªº¶K¤å¡^

Well it¡¦s roughly 5 weeks¡K All going well, I seem to be sleeping better, less tired during the day and a bit more motivation. Unlike glycine which made me verge on hypomania, this is much more subtle, which appeals to me. I definitely notice a change for the better and will continue to take it I think.

Whilst physically I feel well, I find myself with nothing to do, where I was content to lie down all day before starting sodium benzoate - I now feel alert and want to do more. I need to change my behaviour to fit my new physical state, old habits die hard¡K I expect that will take some time to achieve though, perhaps CBT would be the answer. At least I feel able to make changes now and hopefully I can follow through and turn things around.

The main thing is that I feel more able to get on with my life, less drained and not so down in the dumps contemplating the point of existance.

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www.ncbi.nlm.nih.gov/pmc/articles/PMC5265239/

Analysts have identified five unmet needs in the schizophrenia marketplace. They include:

Drugs that enhance cognition

Drugs that treat negative symptoms (such as lethargy, apathy, and social withdrawal)

Drugs that provide improved options for treatment-resistant patients

Drugs with enhanced safety profiles

Drugs that increase compliance

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Clozapine Underutilization: Addressing the Barriers

National Association of State Mental Health Program Directors

66 Canal Center Plaza, Suite 302, Alexandria, VA 22314 703-739-9333 FAX: 703-548-9517

nasmhpd.org/sites/default/files/Assessment%201_Clozapine%20Underutilization.pdf

Clozapine¡¦s Efficacy

Clozapine is the most effective antipsychotic for patients with schizophrenia who do not respond to treatment with first- or second-generation antipsychotics. [1] Several meta- analyses of controlled trials and systematic reviews of clozapine provide evidence of its superiority. [2-7] The most recent meta-analysis[8] reported that clozapine (effect size relative to placebo= 0.88) was almost twice as efficacious as other available antipsychotics.

Broader Range Effectiveness of Clozapine

Clozapine is recognized as superior to other antipsychotics in several treatment guidelines and recommendations for treatment resistant schizophrenia. The Schizophrenia Patient Outcomes Research Team (PORT)[12] summarizes the large evidence-based literature supporting clozapine as the gold standard and recommends that patients with persistent positive symptoms of schizophrenia receive an adequate trial of clozapine

In addition to schizophrenia and schizoaffective disorder, accumulating evidence supports clozapine¡¦s utility for a variety of other disorders and conditions, such as the treatment of hostility and aggression,[17] treatment-resistant bipolar disorder,[18] psychogenic polydipsia/hyponatremia,[19] Parkinson¡¦s disease psychosis[20] and psychosis in Lewy body dementia,[21] borderline personality disorder[22], and tardive dyskinesia (TD).[23] Growing evidence also suggests clozapine may be an option in youth with early onset schizophrenia.[24] Importantly, clozapine is the only antipsychotic with a Food and Drug Administration approval for suicidality.

Underuse of Clozapine

Overcoming Barriers to Clozapine Use

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Alkermes Receives Refusal Letter From FDA On NDA Filing For ALKS 5461

April 02, 2018, 07:23:00 AM EDT By RTT News

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Acute Amino Acid D‑Serine Administration, Similar to Ketamine,Produces Antidepressant-like Effects through Identical Mechanisms

pubs.acs.org/doi/abs/10.1021/acs.jafc.7b04217?src=recsys&journalCode=jafcau

Acute Antidepressant Effects of D-Serine

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·|­û¡G²q·Q10136148  µoªí®É¶¡:2018/3/19 ¤U¤È 05:02:48²Ä 774 ½g¦^À³
The NMDA receptor ¡¥glycine modulatory site¡¦ in schizophrenia: d-serine, glycine, and beyond

www.sciencedirect.com/science/article/pii/S1471489214001714?via%3Dihub

Darrick T Balu (1,2) ;Joseph T Coyle (1,2)

1.Department of Psychiatry, Harvard Medical School, Boston, MA 02115, USA

2.Laboratory for Psychiatric and Molecular Neuroscience, McLean Hospital, Belmont, MA 02478, USA

Highlights

• NMDA receptor (NMDAR) hypofunction contributes to the etiology of schizophrenia.

• Serine racemase, a risk gene for schizophrenia, is expressed primarily in neurons.

• Knocking out serine racemase replicates many features of schizophrenia.

• Restoring d-serine levels reverses this schizophrenia-like neuropathology.

• «ì´_D-µ·®ò»Ä¤ô¥­¥i°fÂà³oºØºë¯«¤Àµõ¯g¼Ë¯«¸g¯f²z¾Ç¡C

• Enhancing NMDAR function may be an effective treatment strategy for schizophrenia.

• ¼W±jNMDAR¥\¯à¥i¯à¬Oºë¯«¤Àµõ¯gªº¦³®ÄªvÀøµ¦²¤¡C

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Protection of TGF-£]1 against Neuroinflammation and Neurodegeneration in A£]1¡V42-Induced Alzheimer¡¦s Disease Model Rats

journals.plos.org/plosone/article?id=10.1371/journal.pone.0116549

In the current study we administered TGF-£]1 via intracerebroventricle (ICV) and intranasal (IN) routes in AD model rats to investigate its antiinflammatory and neuroprotective effects.

The AD rat model was prepared by bilateral hippocampal injection of amyloid-£] (A£])1¡V42.

TGF-£]1 was administered via ICV one hour prior to A£]1¡V42 injection or via both nares seven days after A£]1¡V42 injection.

ICV administration of TGF-£]1 before A£]1¡V42 injection remarkably ameliorated A£]1¡V42-induced neurodegeneration and prevented A£]1¡V42-induced increases in glia-derived proinflammatory mediators (TNF-£\, IL-1£] and iNOS), as well as T cell-derived proinflammatory cytokines (IFN-£^, IL-2, IL-17 and IL-22), in the hypothalamus, serum or cerebrospinal fluid (CSF) in a concentration-dependent manner.

TGF-£]1 pretreatment also prevented A£]1¡V42-induced decreases in the neurotrophic factors, IGF-1, GDNF and BDNF, and in the antiinflammatory cytokine, IL-10.

Similarly, IN administration of TGF-£]1 after A£]1¡V42 injection reduced neurodegeneration, elevation of proinflammatory mediators and cytokines, and reduction of neurotrophic and antiinflammatory factors, in the hypothalamus, serum or CSF.

These findings suggest that TGF-£]1 suppresses glial and T cell-mediated neuroinflammation and thereby alleviates AD-related neurodegeneration.

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Sodium Benzoate, a Food Additive and a Metabolite of Cinnamon, Enriches Regulatory T Cells via STAT6-Mediated Upregulation of TGF-£].

www.ncbi.nlm.nih.gov/pubmed/27605008

These studies identify a new function of NaB in upregulating TGF-£] via activation of STAT6, which may be beneficial in MS patients.

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Primary Outcome Measures :

Mean change from baseline in Positive and Negative Syndrome Scale (PANSS) total score [ Time Frame: 8 weeks after randomized treatment ]

Mean change from baseline in Positive and Negative Syndrome Scale (PANSS) total score

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Synaptic and Extrasynaptic NMDA Receptors Are Gated by Different Endogenous Coagonists

www.sciencedirect.com/science/article/pii/S0092867412007866

Highlights

► Synaptic and extrasynaptic NMDARs are gated by d-serine and glycine, respectively

► d-serine and glycine differentially impact NMDAR membrane diffusion

► Synaptic NMDARs mediate LTP and excitotoxicity

► Both synaptic and extrasynaptic receptors are required for LTD induction

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Lithium treatment for bipolar disorder linked to lowest risk of rehospitalisation

February 28, 2018, Karolinska Institutet

medicalxpress.com/news/2018-02-lithium-treatment-bipolar-disorder-linked.html

Lithium protects against suicide

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Co-crystals of substituted glycine and uses thereof

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¬Q¤ÑSage¤½¥¬¥h¦~°]³ø¡A¥þ¦~Á«¤F2.7»õ¬üª÷¡AEPS-7.09¤¸¡A2016¦~¬OÁ«·l1.59»õ¡AEPS-4.75¡A¶}¤F¤@°ïÁ{§É¡AÁ«·l·íµM«ùÄò¥[¤j¡A§Ú¬Ý¤µ¦~EPS»¡¤£©w­nÁ«¨ì10¤¸¡A¦]¬°¤fªAªºSage217°£¤FÄ~Äò°µMDDªº¤T´Á¥~¡AÁÙ­n¶}©l°µBipolar depression, Parkinson¡¦s, sleep disorders¡A¦pªGBrexanplone²£«á¼~Æ{¯àÀò±oÃÄÃÒ¡A2019¤W¥b¦~´N·|¶}½æ¡AÁ«·l±¡ªp´N¥i¯à´î½w¡C

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¤@¶}©l§Ú¤]¯Ç´e¦ó¥HP=0.0451´N¥i¥H®³¨ìBTD¡A«á¨Ó¬d·s»D½Z¤~ª¾¹D¡AFDA¤£¬O¥ú¾Ì³o­ÓÁ{§É¼Æ¾Úµ¹BTD¡A¦Ó¬O³s¦P«e¤@­Ó©¬ª÷´Ë¤ó¯gºë¯«²§±`ªº³¡¤ÀÁ{§É¼Æ¾Ú¤@°_¤ÀªR(-020 Study)¡A¦]¬°-020 Study¦¬®×¯f¤H¤¤¤j¬ù¥|¤À¤§¤@¬O»´·L¥¢´¼¡C·s»D½Z¬O³o»ò¼gªº¡AThe Breakthrough Therapy Designation for dementia-related psychosis was granted, in part, based on results of ACADIA¡¦s Phase II -019 Study with pimavanserin in Alzheimer¡¦s disease psychosis and results of the company¡¦s Phase III -020 Study with pimavanserin in Parkinson¡¦s disease psychosis. This is the second Breakthrough Therapy Designation for pimavanserin.

Additional clinical evidence for efficacy of pimavanserin in dementia-related psychosis was observed in the Phase III -020 Study in patients with Parkinson¡¦s disease psychosis. Approximately a quarter of the patients enrolled in the -020 Study also suffered from mild dementia. In a pre-specified subgroup analysis of these patients, those treated with pimavanserin observed a significant im-provement in psychosis compared to placebo. This effect was larger than the overall average effect observed in the study.

·s»D½Z³sµ²©ó¦¹ir.acadia-pharm.com/phoenix.zhtml?c=125180&p=irol-newsArticle&ID=2304720

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ACADIA ªº Pimavanserin , ¦Ñ¥v¤j¤j¤]¦b { °ê»Ú¨ú±oBTDªºCNS¤½¥q¥«­È} ¤@¤å¤¤½Í¹L

mychannel.pchome.com.tw/channel/class/class_paper_open.htm?d=2017-02-15&e=snoopychiang&t=.htm&j=2404&f=main&v=1

ªvÀøAlzheimer¡¦s Disease Psychosis(ADP)ªº¤G´ÁÁ{§É

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PimavanserinªºADP¤G´Á³ø§i , «ê¦b¤µ¤Ñ¦­¤W¦b{ THE LANCET Neurology } ¤½¶}

www.thelancet.com/journals/laneur/article/PIIS1474-4422(18)30039-5/fulltext

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www.businesswire.com/news/home/20171103005668/en/ACADIA-Pharmaceuticals-Presents-Data-Phase-II-Study

[[

Pimavanserin met the primary endpoint in the study, showing a statistically significant reduction in psychosis versus placebo as measured by the Neuropsychiatric Inventory-Nursing Home (NPI-NH) Psychosis score at week 6 of dosing (delta = 1.84, p=0.0451, effect size [Cohen¡¦s d] = 0.32).

The proportion of responders at week 6 that had an NPI-NH Psychosis score improvement of ≥ 30% was 55.2% for pimavanserin-treated patients versus 37.4% for placebo (p=0.0159).

...

No significant differences were observed between pimavanserin and placebo for

Clinical Global Impression of Change (ADCS-CGIC) or the Cohen-Mansfield Agitation Inventory Short Form (CMAI-SF), nor on the exploratory endpoints of the mean change in NPI-NH Psychosis score at week 12 or the Alzheimer¡¦s Disease Cooperative Study - Activities of Daily Living (ADCS-ADL).

...

Data presented at CTAD ( Clinical Trials on Alzheimer¡¦s Disease ) from a pre-specified subgroup analysis demonstrated a substantively larger and significant reduction in psychosis in pimavanserin-treated patients with more severe psychosis, further underscoring the effect seen on the primary result.

Approximately one-third of patients in the study had more severe psychotic symptoms (NPI-NH Psychosis score ≥12). In this subgroup, pimavanserin demonstrated a statistically significant reduction in psychosis versus placebo on the NPI-NH Psychosis score at week 6 (delta = 4.43, p=0.0114, effect size [Cohen¡¦s d] = 0.73).

Additionally, the proportion of responders at week 6 that had an NPI-NH Psychosis score improvement of ≥ 30% was 88.9% for pimavanserin-treated patients versus 43.3% for placebo (p=0.0004).

]]

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Jacobo E. Mintzerµ¥¾ÇªÌ¦b

[Behavioral and psychological signs and symptoms of dementia: a practicing psychiatrist¡¦s viewpoint ]

www.ncbi.nlm.nih.gov/pmc/articles/PMC3181597/

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[[ Alzheimer¡¦s disease typically presents with two often overlapping syndromes, one cognitive, the other behavioral.

The behavioral syndrome is characterized by psychosis, aggression, depression, anxiety, agitation, and other common if less well-defined symptoms subsumed under the umbrella entity ¡§behavioral and psychological symptoms of dementia¡¨ ( BPSD ),

itself divided into a number of subsyndromes: psychosis, circadian rhythm (sleepwake) disturbance, depression, anxiety, and agitation, it is BPSD with its impact on care providers that ultimately precipitates the chain of events resulting in long-term institutional care.]]

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There is no drug approved by the FDA for dementia-related psychosis.

In October 2017, the FDA granted Breakthrough Therapy Designation for pimavanserin for the treatment of dementia-related psychosis.

Dementia-related psychosis includes psychosis in Alzheimer¡¦s disease, dementia with Lewy bodies, Parkinson¡¦s disease dementia, vascular deme

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Biogen shares plunge after company makes change to Alzheimer¡¦s drug trials

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A spokesperson for Biogen (Nasdaq: BIIB) said the company had decided to increase the sample size of two closely watched trials by 510 patients, to a total of 3,210 patients, ...

The decision was reached after Biogen conducted a pre-planned, blinded review of the data, which showed

¡§variability in the primary endpoint that was greater than the study protocol assumed,¡¨ the spokesperson said, referring to the primary goal of the studies.

¡§Because the (review) was based on fully blinded data, we do not know treatment effect, and we do not believe this impacts our assumptions on efficacy,¡¨ the spokesperson added. The company remains on target to complete enrollment by mid-2018, he said.

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Drug candidates in clinical trials for Alzheimer¡¦s disease

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Merck Stops Phase 3 Trial of Verubecestat in Early Alzheimer¡¦s Patients Amid Concerns Over Benefit

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The decision follows a cease-trial recommendation by an external Data Monitoring Committee, after a recent interim safety analysis concluded the APECS study (NCT01953601) was unlikely to show positive treatment benefit compared to the risk could be established by continuing.

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3. Sodium Benzoate, a Metabolite of Cinnamon and a Food Additive, Upregulates Neuroprotective Parkinson Disease Protein DJ-1 in Astrocytes and Neurons

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Co-crystals of sodium benzoate and uses thereof

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Exemplary co-former compounds of Formula (I) include, but are not limited to:

(sorbic acid) ,

(trans-cinnamic acid) , or

(nicotinic acid) .

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AAV9: a potential blood-brain barrier buster

www.ncbi.nlm.nih.gov/pmc/articles/PMC2835088/

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°]°È³ø§iÅã¥Ü¡Aù¤ó­p¹ºµô´î¥|´ÚÃĪ«¡CLampalizumab¬O°ß¤@¤@´Ú³B©ó±ß´Á¬ã¨s¶¥¬qªº²£«~¡A¨ä¥L¤TºØÃĪ«³£¦bªì´Á¶}µo¶¥¬q¡C¦¹¥~ù¤ó¤]²×¤î¤F¨â¶µ¸~½F¾Ç¶µ¥Ø©M¤@¶µ¦®¦bªvÀøºë¯«¤Àµõ¯gªº¬ã¨s¡C

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vTv Therapeutics Announces Presentation Of Phase 2b Azeliragon Results At The 2016 Alzheimer¡¦s Association International Conference (AAIC)

Published: Jul 28, 2016

www.biospace.com/article/releases/vtv-therapeutics-announces-presentation-of-phase-2b-azeliragon-results-at-the-2016-b-alzheimer-s-association-international-b-conference-aaic-/

Results of Responder Analysis

A responder analysis was investigated in the mild disease population (MMSE 21-26) from an 18-month, placebo controlled Phase 2b trial in mild-to-moderate Alzheimer¡¦s disease.

The analysis was performed using a cut-point of a 7-point increase in ADAS-Cog11 score (an accepted measure of meaningful change in degree of dementia, Vellas et al. 2007) to measure disease progression. For the 7-point cut-point measure, subjects with mild Alzheimer¡¦s disease taking 5 mg/day azeliragon had a significant reduction in time-to-progression, with a hazard ratio of 0.5 (log-rank p=0.02) compared with placebo.

As previously reported, subjects with mild-to-moderate Alzheimer¡¦s disease in the trial treated with 5mg/day of azeliragon had a mean decreased decline in ADAS-Cog11 at 18 months compared to placebo (ADAS-Cog11: 3.1, p=0.008). Patients in the study with mild disease had an even larger benefit in decreasing deterioration in both cognitive outcomes (ADAS-Cog11: 4.0, p=0.018) and functional measures (CDR-sb: 1.0, p= 0.01).

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