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Next, the researchers injected A£] oligomers into the brains of non-transgenic mice, with or without blocking GSK-3£] or £\2AARs. On their own, A£] oligomers activated GSK-3£], resulting in tau hyperphosphorylation in the hippocampus. In the presence of lithium, a GSK-3£] inhibitor, or idazoxan, an £\2AAR blocker, both GSK-3£] activation and tau hyperphosphorylation were curbed. The findings implicated the adrenergic pathway in the instigation of tau hyperphosphorylation by A£] oligomers.

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¤S ¤ß®®Àò±o¬ü°êªº±M§Q¤¤ ( United States Patent : 10,149,845 )

Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical

[ Claims ] :

1. A method for alleviating a symptom of dementia or mild cognitive impairment, the method comprising: administering orally to a subject in need thereof benzoic acid or a pharmaceutically acceptable salt thereof at an amount of 200 mg to 2000 mg per day.

...

5. The method of claim 1, wherein the subject is administered with a pharmaceutical acceptable salt of benzoic acid, which is sodium benzoate, potassium benzoate, calcium benzoate, or lithium benzoate.

...

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United States Patent : 10,039,730

Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical

[ Claims ] :

1. A pharmaceutical composition for mitigating a symptom associated with schizophrenia, comprising: 500 milligrams to 10 grams of a first active ingredient, which is benzoic acid, or a pharmaceutically acceptable salt thereof; and an effective amount of a second active ingredient, which is selected from the group consisting of olanzapine, aripiprazole, clozapine, amisulpride, chlorpromazine, flupenthixol, haloperidol, quetiapine, sulpiride, ziprasidone, and zotepine.

...

7. The pharmaceutical composition of claim 1, wherein the first active ingredient is a pharmaceutically acceptable salt of benzoic acid, which is selected from the group consisting of sodium benzoate, potassium benzoate, calcium benzoate, and lithium benzoate.

³Ì«á¤@­Ó´N¬O lithium benzoate

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www.ncbi.nlm.nih.gov/pmc/articles/PMC1142193/

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Lithium for schizophrenia: supporting evidence from a 12-year, nationwide health insurance database and from Akt1-deficient mouse and cellular models

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www.nature.com/articles/s41598-019-57340-8

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AKT/GSK3 signaling pathway and schizophrenia

www.ncbi.nlm.nih.gov/pmc/articles/PMC3304298/

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Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade

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www.pnas.org/content/101/14/5099

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The Akt-GSK-3 signaling cascade in the actions of dopamine.

www.ncbi.nlm.nih.gov/pubmed/17349698

Figure 1. Dual role of £]-arrestins in GPCR-mediated slow synaptic transmission.

Figure 2. Regulation of Akt and GSK-3 by drugs affecting monoamine systems and related signaling events.

(¬Ý¤F¹Ï1 , ¹Ï2 ±N¦³§U©ó²z¸Ñ¸Ó¸ô®|ªº¯ÅÁp¾÷¨î)

. Involvement of Akt and GSK-3 in the action of psychotropic drugs

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F179. Abnormalities in the AKT-mTOR Signaling Pathway in Schizophrenia

www.biologicalpsychiatryjournal.com/article/S0006-3223(19)30866-2/fulltext

Downregulated AKT-mTOR signaling pathway proteins in dorsolateral prefrontal cortex in Schizophrenia

www.nature.com/articles/s41386-020-0614-2

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t­È = 5/SQRT(100*(1/72+1/72))= 3 ; p = 0.003189 ( ¤p©ó0.05 ); ®ÄªG¶q = 5/SQRT(100) = 0.5 , power=84.6%

·í¥H´Á¤¤¤ÀªRªº¼Ë¥»¼Æ174 , §Y¨â²Õ¼Ë¥»¼Æ¦U¬°36¨Ó­pºâ

t­È = 5/SQRT(100*(1/36+1/36))= 2.121 ; p = 0.03747( ¤@¼Ë¤p©ó0.05 ) ; ®ÄªG¶q = 5/SQRT(100) = 0.5

¦ý¬O power¥u¦³55% , ¥²¶·®ÄªG¶q°ª©ó0.67 , power¤~·|¹F¨ì80%

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one sample variance ( S )=120.88 ( §Ypooled variance £m2= 114.632 ) ®É

t­È = 5/SQRT(114.632*(1/72+1/72))= 2.802 ; p = 0.005799 ( ¤p©ó0.05 ); ®ÄªG¶q = 5/SQRT(114.632) = 0.467 , power=79.5%

®ÄªG¶q¤j©ó0.471®É , power·|¤j©ó80%

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t­È = 5/SQRT(114.632*(1/36+1/36))= 1.981 ; p = 0.05152( «Ü±µªñ0.05 ) ; ®ÄªG¶q = 5/SQRT(114.632) = 0.467 , power=49.8%

®ÄªG¶q¤j©ó0.671®É , power·|¤j©ó80%

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• Phase II/III registrational trial is designed to detect an ES >= 0.5 with 85% power

• A sample size reassessment and adjustment will be performed prior to enrolling the remaining patients to be able to detect an ES >= 0.2* with 80% power on the entire trial

*ES=0.2 is the minimally clinical meaningful treatment effect.

(ºK¦Û¤ß®®2018/04²³ø ¹ù¥Sªº¦sÀÉ drive.google.com/file/d/1LIuw7n1lcTiQcy1O5Rx969XDlIotSAko/view P.23 )

°²³]­ì³W¹º°Ñ¼Æ: ¨â²Õ¥­§¡®t¡µ1=5 , pooled variance £m1=100

£\=0.05 , £]=0.15 , z(1-£\/2) ¡Ü1.96 , z(1-£]) ¡Ü1.037

©Ò¥H­ì³W¹º¼Ë¥»¼Æ(¨C²Õ) N1=2*(1.96+1.037)^2*100/5^2¡Ü72 , Á`¼Ë¥»¼Æ=2*72=144

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t­È = 5/SQRT(100*(1/72+1/72))= 3 ; p = 0.003189 ( ¤p©ó0.05 ); ®ÄªG¶q = 5/SQRT(100) = 0.5

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t­È = 5/SQRT(100*(1/36+1/36))= 2.121 ; p = 0.03747( ¤@¼Ë¤p©ó0.05 ) ; ®ÄªG¶q = 5/SQRT(100) = 0.5

´Á¤¤¤ÀªR®É detect an ES >= 0.2* with 80% power on the entire trial

¥O´Á¤¤¤ÀªRªº one sample variance ¬° S(§Y±N¨â²Õ¦X¤@©Òºâ±oªºÅܲ§¼Æ) , pooled variance £m2¡ÜS ¡V (¡µ1)^2/4

²{¦b §Ú­Ì¨Ó¤Ï±À·í¤£¥²¼W¥[¼Ë¥»¼Æ®Éªº³Ì¤jS­È ( ¦¹®Éªº£\=0.05 ,£]=0.2 , z(1-£\/2) ¡Ü1.96 , z(1-£]) ¡Ü0.842 )

72=2*( S ¡V 5^2/4)*(1.96+0.842)^2/5^2

==> S=120.88

==> pooled variance £m2=( S ¡V 5^2/4) ¡Ü 114.632

®ÄªG¶qES=5/SQRT(114.632)=0.467 ¤j©ó 0.2

©Ò¥H , ¬O§_¥i¥H³o¼Ë»¡ : ·í´Á¤¤¤ÀªR®É©Ò­pºâ¥Xªºone sample variance ( S )¤p©ó120.88®É , ³£¤£¥Î¼W¥[¼Ë¥»¼Æ???

¦¹®É ( §Ypooled variance £m2= 114.632 )

t­È = 5/SQRT(114.632*(1/72+1/72))= 2.802 ; p = 0.005799 ( ¤p©ó0.05 ); ®ÄªG¶q = 5/SQRT(114.632) = 0.467

·í¥H¨â²Õ¼Ë¥»¼Æ¦U¬°36¨Ó­pºâ

t­È = 5/SQRT(114.632*(1/36+1/36))= 1.981 ; p = 0.05152( «Ü±µªñ0.05 ) ; ®ÄªG¶q = 5/SQRT(114.632) = 0.467

¥H¤W¤ÀªR¬O¥H¨â²Õ¥­§¡®t¡µ1=5 , pooled variance £m1=100¬°°ò¦°Ñ¼Æ©Ò±o¨ìªºµ²ªG

µM¦Ó§Ú­Ì³£ª¾¹D SND-13 2a´Áªº¨â²Õ¥­§¡®t¡µ°ª¹F 12.7

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( °Ñ¦Ò¤å¥ó : Blinded Sample Size Adjustment www.researchgate.net/publication/241646347_Blinded_Sample_Size_Adjustment )

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• Phase II/III registrational trial is designed to detect an ES >= 0.5 with 85% power

• A sample size reassessment and adjustment will be performed prior to enrolling the remaining patients to be able to detect an ES >= 0.2* with 80% power on the entire trial

*ES=0.2 is the minimally clinical meaningful treatment effect.

(ºK¦Û¤ß®®2018/04²³ø drive.google.com/file/d/1LIuw7n1lcTiQcy1O5Rx969XDlIotSAko/view P.23 )

°²³]­ì³W¹º°Ñ¼Æ: ¨â²Õ¥­§¡®t¡µ1=5 , pooled variance £m1=100

£\=0.05 , £]=0.15 , z(1-£\/2) ¡Ü1.96 , z(1-£]) ¡Ü1.037

©Ò¥H­ì³W¹º¼Ë¥»¼Æ(¨C²Õ) N1=2*(1.96+1.037)^2*100/5^2¡Ü72 , Á`¼Ë¥»¼Æ=2*72=144

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t­È = 5/SQRT(100*(1/72+1/72))= 3 ; p = 0.003189 ( ¤p©ó0.05 ); ®ÄªG¶q = 5/SQRT(100) = 0.5

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t­È = 5/SQRT(100*(1/36+1/36))= 2.121 ; p = 0.03747( ¤@¼Ë¤p©ó0.05 ) ; ®ÄªG¶q = 5/SQRT(100) = 0.5

´Á¤¤¤ÀªR®É detect an ES >= 0.2* with 80% power on the entire trial

¥O´Á¤¤¤ÀªRªº one sample variance ¬° S(§Y±N¨â²Õ¦X¤@©Òºâ±oªºÅܲ§¼Æ) , pooled variance £m2¡ÜS ¡V (¡µ1)^2/4

²{¦b §Ú­Ì¨Ó¤Ï±À·í¤£¥²¼W¥[¼Ë¥»¼Æ®Éªº³Ì¤jS­È ( ¦¹®Éªº£\=0.05 ,£]=0.2 , z(1-£\/2) ¡Ü1.96 , z(1-£]) ¡Ü0.842 )

72=2*( S ¡V 5^2/4)*(1.96+0.842)^2/5^2

==> S=120.88

®ÄªG¶qES=5/SQRT(120.88)=0.455 ¤j©ó 0.2

©Ò¥H , ¬O§_¥i¥H»¡ ·íºâ¥Xªºone sample variance ( S )¤p©ó120.88®É , ³£¤£¥Î¼W¥[¼Ë¥»¼Æ?

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•Existing therapies have a mean effect size~=0.3 (total score).

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www.accessdata.fda.gov/drugsatfda_docs/label/2019/209500s000lbl.pdf

14 CLINICAL STUDIES

CAPLYTA was evaluated for the treatment of schizophrenia in two placebo-controlled trials.

Study 1 (NCT01499563)¡KA total of 335 patients were randomized to¡K

Study 2 (NCT02282761)¡KA total of 450 patients were randomized to¡K

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1.

ITI-007-301¸ÕÅç

Intra-Cellular Therapies Announces Positive Top-Line Results From the First Phase 3 Trial of ITI-007 in Patients With Schizophrenia and Confirms the Unique Pharmacology of ITI-007 in a Separate Positron Emission Tomography Study

Sep 16, 2015

ir.intracellulartherapies.com/news-releases/news-release-details/intra-cellular-therapies-announces-positive-top-line-results

Primary and Key Secondary Efficacy Endpoints

ITI-007 60 mg met the primary efficacy endpoint by demonstrating a statistically significant improvement versus placebo on the PANSS total score, in the intent-to-treat (ITT) study population (least squares [LS] mean change from baseline -14.5 points, effect size [ES]=0.30, p=0.022 versus -10.3 points change from baseline for placebo). ITI-007 showed a dose-related improvement in symptoms of schizophrenia with the 40 mg dose approximating the trajectory of improvement seen with the 60 mg dose, but the effect with 40 mg did not reach statistical significance on the primary endpoint (-12.9 points, ES=0.18, p=0.164). The pre-specified primary statistical analysis used a Mixed-Effect Model Repeated Measure (MMRM) method for handling missing data in the ITT study population and was corrected for multiple comparisons.

ITI-007 60 mg met the key secondary endpoint demonstrating a statistically significant improvement versus placebo on the CGI-S, a well-established and clinically useful rating tool to determine a global level of illness severity (ES=0.39, p=0.003). ITI-007 40 mg also demonstrated a statistically significant improvement versus placebo on the CGI-S (ES=0.30, p=0.025), though not formally tested against placebo since it did not separate on the primary endpoint.

2.

ITI-007-302¸ÕÅç

Intra-Cellular Therapies Announces Top-Line Results from the Second Phase 3 Trial of ITI-007 in Patients with Schizophrenia (Study ¡¥302)

Sep 28, 2016

ir.intracellulartherapies.com/news-releases/news-release-details/intra-cellular-therapies-announces-top-line-results-second-phase

ITI-007 60 mg and 20 mg demonstrated a change from baseline on the PANSS total score of -14.6 points and -15.0 points respectively versus a -15.1 point change in placebo. Risperidone, the active control, demonstrated a change from baseline on the PANSS total score of -20.5 points.

In the context of the ITI-007 development program, ITI-007 60 mg improved symptoms of schizophrenia with the same magnitude of change from baseline on the PANSS total score across all three studies (-13.2 points in Study ¡¥005, -14.5 points in Study ¡¥301 as compared with -13.2 points at week 4 and -14.6 points at week 6 in Study ¡¥302). The magnitude of change for ITI-007 60 mg was similar to the active control, risperidone (-13.4 points) in Study ¡¥005. The trajectory of improvement with ITI-007 60 mg was similar across all three studies.

An unusually high placebo response was observed in this study compared with previous studies (-15.1 point change from baseline on PANSS total score in Study ¡¥302 in contrast to -7.4 points in Study ¡¥005 and -10.3 points in Study ¡¥301).

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ITI-007-302ªº¸ÕÅç : PANSSÁ`¤À®t²§ , ¥Ñ©ó¦w¼¢¾¯®ÄÀ³¤Ó°ª , ¨â²Õ¥¼¹FÅãµÛ

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Lumateperone ( ITI-007 ) SCZÃÄÃÒÀò§å

FDA Approves Intra-Cellular Therapies¡¦ Novel Antipsychotic, CAPLYTA® (lumateperone) for the Treatment of Schizophrenia in Adults

Dec 23, 2019

ir.intracellulartherapies.com/news-releases/news-release-details/fda-approves-intra-cellular-therapies-novel-antipsychotic

(Google ½Ķ , ¦³»Ý­nªº¤j¤j ½Ð°Ñ­ì¤å)

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¸T§Ò¯g¡G CAPLYTA¸T§Ò©ó¹ïLumateperone©ÎCAPLYTAªº¥ô¦ó¦¨¤À¹L±Óªº±wªÌ¡C

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ACNP 58th Annual Meeting: Poster Session III

www.nature.com/articles/s41386-019-0547-9#Sec590

W201

Efficacy and Safety of Lumateperone 42 Mg in the Treatment of Schizophrenia: A Pooled Analysis of Randomized Clinical Trials

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¬ì¾Ç¸ÕÅç¤@©w­n¦¨¥\¤ñ¸û­«­n , ÁÙ¬O¸ÕÅç§ÖÂI§¹¦¨¤ñ¸û­«­n ?

liawbf.pixnet.net/blog/post/49252305

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The authors discuss the involvement of NMDAR mediated neurotransmission in a variety of CNS disorders including schizophrenia [1], cognitive deficits in schizophrenia [2, 3], depression [4], aging [5], mild cognitive impairment and Alzheimer¡¦s dementia [6], attention deficit hyperactivity disorder [7], frontal lobe synaptic plasticity [8] as well as autism spectrum disorder [9].

§@ªÌ°Q½×¤FNMDAR¤¶¾Éªº¯«¸g¶Ç»¼©Ò¯A¤Îªº¦hºØ¤¤¼Ï¯«¸g¨t²Î¯e¯f¡A¥]¬A:ºë¯«¤Àµõ¯g[1]¡Aºë¯«¤Àµõ¯gªº»{ª¾¯Ê³´[2¡A3]¡A§íÆ{¯g[4]¡A°I¦Ñ[5]¡A»´«×»{ª¾»Ùê©Mªüº¸¯ý®üÀq¤óè§b[6]¡Aª`·N¯Ê³´¦h°Ê»Ùê[7]¡AÃB¸­¬ðIJ¥i¶ì©Ê[8]¥H¤Î¦Û³¬¯gÃШt»Ùê[9]¡C

...

In developing the NMDA treatment for CNS disorder, we predicted DAAO inhibition could be the last missing approach in regulating the grand regulator of CNS, NMDAR-mediated neurotransmission.

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Regulating the CNS Grand Regulator; N-methyl-D-aspartate Receptor-Mediated Neurotransmission

www.eurekaselect.com/120179/article

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12TH CLINICAL TRIALS ON ALZHEIMER¡¦S DISEASE (CTAD) DECEMBER 4-7, 2019 - SAN DIEGO, USA

1.

Biogen Inc. (BIIB) Aducanumab Phase 3 Topline Results Conference (Transcript)

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2.

Biogen¡¦s aducanumab showed mixed results in Alzheimer¡¦s studies

Dec. 5, 2019 11:41 AM ET|About: Biogen Inc. (BIIB)|By: Douglas W. House, SA News Editor

seekingalpha.com/news/3524067-biogens-aducanumab-showed-mixed-results-in-alzheimers-studies

3.

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Wild Biotech Day Sparks $7.6 Billion Shuffle for Neurology Trio

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Global Biochemical Profiling Identifies £]-Hydroxypyruvate as a Potential Mediator of Type 2 Diabetes in Mice and Humans

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(Increased £]-hydroxypyruvate levels may be causative in initiating impairments in GSIS and the development of T2DM. What is the potential mechanism underlying the increased £]-hydroxypyruvate levels in these mice? d-amino acid oxidase (DAO) deaminates d-serine to £]-hydroxypyruvate and benzoate inhibits the activity of DAO (Fig. 1). ... There was a significant inverse correlation between £]-hydroxypyruvate and d-serine in humans. Thus, at least some £]-hydroxypyruvate is derived from d-serine via DAO.)

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Altered levels of dopamine transporter in the frontal pole and dorsal striatum in schizophrenia

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Published: 02 December 2019

www.nature.com/articles/s41537-019-0087-7

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These data raise the possibility that high levels of DAT in BA 10 (Brodmann¡¦s area 10) could be contributing to lower synaptic cortical dopamine, whereas lower levels of DAT could be contributing to a hyperdopaminergic state in the dorsal striatum.

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jamanetwork.com/journals/jamapsychiatry/fullarticle/1746121

This study demonstrated that sodium benzoate, a DAAO inhibitor, can improve a wide variety of symptom domains of schizophrenia. After 6 weeks of benzoate treatment, PANSS total scores decreased by a mean of 21%. This decrement would be less than clinically significant for patients with acute exacerbation[REF 61].However, it is beneficial for patients with a high level of symptoms who had been stabilized with antipsychotics for 3 months or longer in this study, as reflected by the improvement of CGI severity scores from 4.6 to 3.5. The ESs observed (Table 2 and Table 3) are larger than those in other trials of NMDA-enhancing agents, with most less than 0.4.11 The large ESs could be due to the good central nervous system bioavailability of benzoate (vs the other small polar amino acids and DAAO inhibitors tested before) to raise the D-amino acid pool by the inhibition of DAAO. It is encouraging that benzoate treatment improves schizophrenia in those who are still highly symptomatic despite treatment with antipsychotics. It remains to be determined whether the treatment is beneficial for the entire spectrum of symptom severity.

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Nevertheless, any add-on therapy that outperforms placebo may be attributed to counteracting the adverse effects of antipsychotic drugs. Future studies with a prospective design and a larger sample size are needed to clarify this issue.

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In treatment refractory patients even a small improvement of symptoms such as a 20% or better a 25% PANSS reduction may be clinically important. However, in acutely ill, non-refractory patients a 50% criterion (i.e. clinically much improved) seems to be a more appropriate reflection of clinically meaningful improvement, because such patients usually respond well to antipsychotic drugs (Cole, 1964).

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[ PSAPPÂà´Þ¹« : www.alzforum.org/research-models/psapp ]

Tannic Acid Is a Natural £]-Secretase Inhibitor That Prevents Cognitive Impairment and Mitigates Alzheimer-like Pathology in Transgenic Mice

³æ¹ç»Ä¬O¤@ºØ¤ÑµMªº£]-¤Àªc酶§í»s¾¯¡A¥i¹w¨¾»{ª¾»Ùê¨Ã´î»´Âà°ò¦]¤p¹«ªºªüº¸¯ý®üÀq¤ó¯g¼Ë¯fª¬

www.ncbi.nlm.nih.gov/pmc/articles/PMC3307267/

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. ¤fªA³æ¹ç»ÄªvÀø¥i´î»´PSAPP¤p¹«ªº¹L«×¬¡ÅD©M»{ª¾»Ùê

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Gallic Acid Disrupts A£]1-42 Aggregation and Rescues Cognitive Decline of APP/PS1 Transgenic Mouse

www.biorxiv.org/content/biorxiv/early/2018/02/02/258848.full.pdf

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Comparative biophysical characterization: A screening tool for acetylcholinesterase inhibitors

www.ncbi.nlm.nih.gov/pmc/articles/PMC6544338/

Published online 2019 May 31

. ªüº¸¯ý®üÀq¤ó¯g¡]AD¡^¬Oè§b¯gªº¥D­n­ì¦]¡A¦û©Ò¦³Ã¨§b¯g¯f¨Òªº75¢H¡CAD¶i®iªº¯f²z¥Í²z¹Lµ{¯A¤Î¯«¸g¤¸©M¬ðIJÅÜ©Ê¡A¨ä¥D­n¯S¼x¦b©óÁxÆP¯à»Ùê( cholinergic impairment )¡C¦¹¥\¯à¨Ï¤A酰ÁxÆPà­酶§í¨î¾¯¡]AChEi¡^¦¨¬°·í«e¥Î©óªvÀøADè§b´Áªº¥D­nÃĪ«¡A¨ä¤¤¥[Äõ¥L±Ó ( galantamine )¬O°ß¤@ªº¤ÑµMª«½è¡C

. The study aims to evaluate the interactions between natural molecules and AChE by Surface Plasmon Resonance (SPR). The molecules like alkaloids, polyphenols and substrates of AChE have been considered for the study with a major emphasis on affinity and kinetics. To better understand the activity of small molecules, the investigation is supported by both experimental and theoretical approach such as fluorescence, Circular Dichroism (CD) and molecular docking studies. Amongst the screened ones tannic acid showed promising results compared with others.

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. ®Ú¾Ú¥Ø«eªº±¡ªp¡A»P¨ä¥L¦X¦¨ÃĪ«¤À¤l¬Û¤ñ¡A¤ÑµM²£ª«¡]¦p¦h×ô¡^ªº¨Ãµo¯g³Ì¤Ö¡A¨Ã¥B¥i¯à¹ïªý¤îADªº¶i®i¦³¯q¡C¦b³o¨Ç·í«eªº¬ã¨s¤¤¡A¤wÃÒ©ú»P¥Íª«ÆP¬Û¤ñ¡A¦h×ô¬O§í¨îAChEªº¦³«e³~ªº¤À¤l¡Cºî¤W©Ò­z¡AAChE¹ï¦UºØ¤À¤lªí²{¥X¤£¦Pªº¿Ë©M¤O¡A¨ä¤¤³æ¹ç»Ä¨ã¦³³Ì°ªªº¿Ë©M¤O¡A¨ä¦¸¬O¥d¤ÚÁxÆP¡AATCI¡A¾F­f¤T×ô ( pyrogallol ,³æ¹ç»Ä¥NÁª« )¡A©@°Ø¦]¡A¤Ú¨§µß¯À¡AåÚ¥Ö¯À¡A¨à¯ù¯À¤ô¦Xª«¡AÆQ»Älycorine¡AĪ¤B¤ô¦Xª«¡Agalamer4©M¥[Äõ¥L±Ó²B·Í»ÄÆQ ( galanthamine hydrobromide )¡C

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med.sina.com/article_detail_103_1_74137.html

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A second hydroxyl radical scavenger, sodium benzoate, and an iron chelator, deferoxamine, had similar protective effects on renal function. ¡K

books.google.com.tw/books?id=_3mmDwAAQBAJ&pg=PT571&lpg=PT571&dq=Iron+chelators+sodium+benzoate&source=bl&ots=tgKB3lGWIf&sig=ACfU3U2aIhDSJ6M049L8i7j4hwdQDyoxKA&hl=zh-TW&sa=X&ved=2ahUKEwjW8JSxp-nlAhXlFqYKHdteBBkQ6AEwDnoECAcQAQ#v=onepage&q=Iron%20chelators%20sodium%20benzoate&f=false

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As people age, iron deposits in different areas of the brain may impair normal cognitive function and behavior. Abnormal iron metabolism generates hydroxyl radicals through the Fenton reaction, triggers oxidative stress reactions, damages cell lipids, protein and DNA structure and function, and ultimately leads to cell death.

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( www.ncbi.nlm.nih.gov/pmc/articles/PMC6139360/ )

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COMPOSITIONS CONTAINING TANNIC ACIDS AND USES THEREOF

Description :

patentscope.wipo.int/search/en/detail.jsf?docId=US246621780&tab=PCTDESCRIPTION&_cid=P20-K2YKPS-40812-1

Drawings :

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1.

Iron in Neurodegeneration ¡V Cause or Consequence?

ÅK¦b¯«¸g°h¦æ©Ê¯e¯f¤¤¡V­ì¦]ÁÙ¬O«áªG¡H

www.ncbi.nlm.nih.gov/pmc/articles/PMC6405645/

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we summarize the modes of action by which iron might act as primary or secondary disease trigger in neurodegenerative disorders.

ÅKªº¿n²Ö¬O³\¦h¯«¸g°h¦æ©Ê¯e¯fªº¼Ð»x©Ê¯S¼x¡C¹Ï1´yø¤F¯«¸gÅܩʤ¤»PÅK¿n²Ö¦@©w¦ìªº¥\¯à»Ùê³~®|¡C¦b³o¸Ì¡A§Ú­Ì¦^ÅU¤FÅK¹ï¯«¸gÅܩʪºÃöÁä¾÷¨îªº°^Äm¡A¨Ãµû¦ô¤F¨ä¹ïµo¯f¾÷²zªº¼vÅT¡C

2.

Iron Deposition Leads to Hyperphosphorylation of Tau and Disruption of Insulin Signaling

ÅK¨I¿n·|¾É­PTau¹L«×ÁC»Ä¤Æ¨Ã¯}Ãa¯Ø®q¯À«H¸¹

www.ncbi.nlm.nih.gov/pmc/articles/PMC6593079/

Published online 2019 Jun 19

3.

Cellular Senescence and Iron Dyshomeostasis in Alzheimer¡¦s Disease

ªüº¸¯ý®üÀq¤ó¯f¤¤ªº²Ó­M°I¦Ñ©MÅK°ÊºA¥¢¿Å

www.ncbi.nlm.nih.gov/pmc/articles/PMC6630536/

Published online 2019 Jun 19.

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4.

Brain iron is associated with accelerated cognitive decline in people with Alzheimer pathology

¸£ÅK»Pªüº¸¯ý®üÀq¤ó¯f±wªÌªº¥[³t»{ª¾¤U­°¦³Ãö

www.ncbi.nlm.nih.gov/pmc/articles/PMC6698435/

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Cortical iron has been shown to be elevated in Alzheimer¡¦s disease (AD).

Thus, cortical iron might act to propel cognitive deterioration upon the underlying proteinopathy of AD, possibly by inducing oxidative stress or ferroptotic cell death, or may be related to an inflammatory response.

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Alzheimer¡¦s Disease and Its Potential Alternative Therapeutics

www.ncbi.nlm.nih.gov/pmc/articles/PMC6777730/

´£¨ì¤F´XºØ¤À¤l¼Ð¹v»PADªº¯f²z¥Í²z¦³Ãö¡A¨Ò¦ptau¡]£n¡^³J¥Õ¡A¾ý¯»¼Ë£]¡]A£]¡^¡A¾ý¯»¼Ë«eÅé³J¥Õ¡]APP¡^¡AÁÙ¦³³\¦h ; ¨Ã¥B¦b¯e¯f¶i®i¤¤ÁÙÆ[¹î¨ì¤F´XºØ¤ÏÀ³¡A¨Ò¦p¯«¸gµo¥Í( neurogenesis ) ´î¤Ö¡A¯«¸gª¢¯g¡A®ñ¤ÆÀ³¿E©MÅK¶W­t²ü( iron overload )¡C

¦b¦Õ¼ô¯à¸Ô¤¤³Ì­¯¥Íªº , ¦¹¨è¤]³Ì¤Þµo§Ú­Ì¿³½ìªº , ¤j·§´NÄÝ : ÅK¶W­t²ü

Iron and Alzheimer¡¦s Disease: From Pathogenesis to Therapeutic Implications

www.ncbi.nlm.nih.gov/pmc/articles/PMC6139360/

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E.8.6.1 Trial being conducted both within and outside the EEA : Yes

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Canada

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Poland

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United Kingdom

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www.coulterpartners.com/neuroscience-and-cns-therapeutics/

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2.

www.globenewswire.com/news-release/2019/09/16/1916030/0/en/Antipsychotic-Drugs-Market-Size-to-Reach-USD-20-539-5-Million-by-2026-Schizophrenia-Segment-to-Witness-Rapid-Growth-says-Fortune-Business-Insights.html

www.fortunebusinessinsights.com/industry-reports/antipsychotic-drugs-market-101390

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www.medgadget.com/2019/08/antidepressant-drugs-market-size-share-current-trends-opportunities-competitive-analysis-and-forecast-to-2019-2025.html

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½²±Ð±Âªº¦Ñ®v Joseph T. Coyle ±Ð±Â¦b2019¦~ªì¦^ÅU¤F«äı¥¢½Õ¯g¨¦®ò»Ä¯à¯«¸g¶Ç»¼§ïÅܪºÃÒ¾Ú¡A¯S§O¬ON-¥Ò°ò-d¤Ñ¥V®ò»Ä¨üÅé¡]NMDAR¡^¥\¯à¥i¯à¬O«äı¥¢½Õ¯gªº­«­n¯f¦]¡C

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4. Joseph T. Coyle±Ð±Â»{¬°­f¥Ò»Ä¶uÁÙ¥i¥H»¤¾É¤H­ì¥N¯«¸g¤¸©M¬P§Î½¦½è²Ó­M¤¤ªº¸£·½©Ê¯«¸gÀç¾i¦]¤l(BDNF)ªí¹F¡A³o¥i¯à¬O­f¥Ò»Ä¶u´î»´«äı¥¢½Õ¯gª¬ªº¥t¤@ºØ³~®|¡C

¥t¥~ , DAAO§í¨î¾¯(­f¥Ò»Ä¶u)¤]¥i¥H´î½w³o¨Ç¦h¤ÚÓi«ú§Ü¾¯©Ò³y¦¨ªº°Æ§@¥Î¶Ü ?

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1994¦~¿Õ¨©º¸¸gÀپǼú±o¥DJohn F. Nash¡AJr. ´£¿ô¡A«äı¥¢½Õ¯gÃĪ«ªº¶}µo¨ä³Ì²×¥Øªº¤£¬O¶}µo¯à°÷§í¨î¬Y¨Ç¯gª¬¡]¨Ò¦p§Üºë¯«¯fÃÄ¡^ªºÃĪ«¡A¦Ó¬O¶}µo¯à°÷ªÈ¥¿°ò¥»¯f²z¾Ç¥H«ì´_«äı¥¢½Õ¯g±wªÌ©Ò³QÅѨúªº´r®®·P©M¬¡ÅD©ÊªºÃĪ«¡C¹ù¥Sªº´£¥Ü¸¡°¼³Q»\°Ï ( VTA ) ¬O´r®®¨t²Î©Î¬O³øÀv°j¸ô¡]reward circuit¡A¼úÀy§@¥Î»P¦æ¬°¨ë¿Eªº¥D­n¨Ó·½¡^ªº¤@³¡¤À , ­f¥Ò»Ä¶u¬O§_¦³¦¹¿E¶V´r®®·Pªº¥\¯à©O?

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( Mounting evidence suggests that understanding the glutamatergic dysregulation in schizophrenia may provide a way forward in developing ¡¥curative¡¦ treatments. )

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°Ñ¦Ò¸ê®Æ©M¤åÄm :

www.ncbi.nlm.nih.gov/pmc/articles/PMC4014674/

onlinelibrary.wiley.com/doi/full/10.1111/pcn.12823

www.ncbi.nlm.nih.gov/pubmed/28671605

www.reangel.com/Article.php?LI=109

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www.clinicaltrialsregister.eu/ctr-search/trial/2017-001168-39/PL

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¼w°ê : www.clinicaltrialsregister.eu/ctr-search/trial/2017-001170-42/DE

­^°ê : www.clinicaltrialsregister.eu/ctr-search/trial/2017-001170-42/GB

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www.clinicaltrialsregister.eu/ctr-search/trial/2017-001168-39/PL

An Adaptive, Phase IIb/III, Double-Blind, Randomized, Placebo- Controlled, Multi-Center Study of the Safety and Efficacy of NaBen® (sodium benzoate), a D-Amino Acid Oxidase Inhibitor, as an Add-on Treatment for Schizophrenia in Adolescents.

Date on which this record was first entered in the EudraCT database: 2019-10-07

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(The present results demonstrated for the first time that stimulating the glycine-binding sites of NMDA receptors alleviates antipsychotic-induced EPS by activating the nigrostriatal dopaminergic pathway, suggesting that glycine-binding site stimulants are beneficial not only for efficacy, but also for side-effect management.)

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United States Patent 10,039,730

United States Patent 9,675,604

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Keeping up with the therapeutic advances in schizophrenia: a review of novel and emerging pharmacological entities

Amanda Krogmann,1,† Luisa Peters,1,† Laura von Hardenberg,1 Katja Bödeker,1 Viktor B. Nöhles,1 and Christoph U. Correll1,2,3

cdn.neiglobal.com/content/cnsspectrums/cnscme/2019/19cns04_schiz.pdf

Schizophrenia remains one of the most severe medical diseases. Current dopamine modulating first-generation and second-generation antipsychotics target mainly positive symptoms, but not/inadequately negative and cognitive symptoms. Additional challenges include nonadherence and adverse effects, especially cardiometabolic dysregulation.

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TABLE 1.

Selected novel and emerging non-pharmacological and pharmacological treatments for schizophrenia (¾÷Âà)

TABLE 2.

Selected novel and emerging pharmacological treatments for schizophrenia targeting total (including positive and negative) symptoms (Á{§Éµ²ªG)

TABLE 3.

Selected novel and emerging pharmacological treatments for schizophrenia targeting negative and cognitive symptoms (Á{§Éµ²ªG)

Table 4:

Selected novel and emerging pharmacological treatments for schizophrenia targeting residual and treatment-resistant total symptoms (Á{§Éµ²ªG)

TABLE 5.

Selected novel and emerging pharmacological treatments for schizophrenia targeting the amelioration of antipsychotic non-adherence and body weight gain (Á{§Éµ²ªG)

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Sample Size Re-estimation in Clinical Trials

University of Bath, UK

people.bath.ac.uk/mascj/talks_2016/CJ_PSI_slides.pdf

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P. 6/41

A two treatment comparison with binary response

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SB^2----N1------- N2-------- N3 ----- N=2*³Ì¤j­È( N1 , N2 , N3 )-----144*(SB^2/£mA^2)

200 --71.9---- 67.8 ----- 67.4 --------------143.7------------------------- 144

175 --62.9---- 58.8 ----- 58.4 --------------125.7------------------------- 126

150 ---53.9---- 49.7------ 49.4 --------------107.8------------------------- 108

125----44.9---- 40.7------ 40.4---------------89.8 -------------------------- 90

100----35.9---- 31.6------ 31.4---------------71.9--------------------------- 72

75------26.9---- 22.6------ 22.5---------------53.9--------------------------- 54

50------18.0---- 13.5------ 13.5---------------35.9 -------------------------- 36

£mA^2= 175 ¡µA^2= 43.75

SB^2----N1------- N2-------- N3 ----- N=2*³Ì¤j­È( N1 , N2 , N3 )-----144*(SB^2/£mA^2)

200 --82.1---- 78.1 ----- 77.6 --------------164.2------------------------- 164.6

175 --71.9---- 67.8 ----- 67.4 --------------143.7------------------------- 144

150 ---61.6---- 57.5------ 57.1 --------------123.2------------------------- 123.4

125----51.3---- 47.1------ 46.8---------------102.7-------------------------- 102.9

100----41.1---- 36.8------ 36.6---------------82.1--------------------------- 82.3

75------30.8---- 26.5------ 26.3---------------61.6--------------------------- 61.7

50------20.5---- 16.1------ 16.0---------------41.1-------------------------- 41.2

£mA^2= 150 ¡µA^2= 37.5

SB^2----N1------- N2-------- N3 ----- N=2*³Ì¤j­È( N1 , N2 , N3 )-----144*(SB^2/£mA^2)

200 95.8 91.9 91.3 191.6 192.0

175 83.8 79.9 79.3 167.7 168.0

150 71.9 67.8 67.4 143.7 144.0

125 59.9 55.7 55.4 119.8 120.0

100 47.9 43.7 43.4 95.8 96.0

75 35.9 31.6 31.4 71.9 72.0

50 24.0 19.6 19.5 47.9 48.0

£mA^2= 125 ¡µA^2= 31.25

SB^2----N1------- N2-------- N3 ----- N=2*³Ì¤j­È( N1 , N2 , N3 )-----144*(SB^2/£mA^2)

200 115.0 111.2 110.5 229.9 230.4

175 100.6 96.8 96.1 201.2 201.6

150 86.2 82.3 81.7 172.5 172.8

125 71.9 67.8 67.4 143.7 144.0

100 57.5 53.3 53.0 115.0 115.2

75 43.1 38.9 38.6 86.2 86.4

50 28.7 24.4 24.3 57.5 57.6

£mA^2= 100 ¡µA^2= 25

SB^2----N1------- N2-------- N3 ----- N=2*³Ì¤j­È( N1 , N2 , N3 )-----144*(SB^2/£mA^2)

200 143.7 140.2 139.2 287.4 288.0

175 125.7 122.1 121.3 251.5 252.0

150 107.8 104.0 103.3 215.6 216.0

125 89.8 85.9 85.3 179.6 180.0

100 71.9 67.8 67.4 143.7 144.0

75 53.9 49.7 49.4 107.8 108.0

50 35.9 31.6 31.4 71.9 72.0

£mA^2= 75 ¡µA^2= 18.75

SB^2----N1------- N2-------- N3 ----- N=2*³Ì¤j­È( N1 , N2 , N3 )-----144*(SB^2/£mA^2)

200 191.6 188.4 187.1 383.2 384.0

175 167.7 164.3 163.2 335.3 336.0

150 143.7 140.2 139.2 287.4 288.0

125 119.8 116.0 115.3 239.5 240.0

100 95.8 91.9 91.3 191.6 192.0

75 71.9 67.8 67.4 143.7 144.0

50 47.9 43.7 43.4 95.8 96.0

£mA^2= 50 ¡µA^2= 12.5

SB^2----N1------- N2-------- N3 ----- N=2*³Ì¤j­È( N1 , N2 , N3 )-----144*(SB^2/£mA^2)

200 287.4 284.9 282.9 574.8 576.0

175 251.5 248.7 247.0 503.0 504.0

150 215.6 212.5 211.1 431.1 432.0

125 179.6 176.4 175.1 359.3 360.0

100 143.7 140.2 139.2 287.4 288.0

75 107.8 104.0 103.3 215.6 216.0

50 71.9 67.8 67.4 143.7 144.0

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1.

BLINDED SAMPLE SIZE ADJUSTMENT

citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.883.4985&rep=rep1&type=pdf

DAVID R. BRISTOL*

Director, Biostatistics and Statistical Programming, Purdue Pharma L.P., Stamford, Connecticut

LINDA SHURZINSKE

Senior Manager, Biostatistics, Pfizer Global Research and Development, Ann Arbor, Michigan

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Sample size re-estimation in Adaptive Trials

www.makrocare.com/WhitePapers/sample_size_re-estimation.pdf

WHITE PAPER

Rajani V, Reshma Kesavan P, Dr. A.K. Mathai

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PANSS-positive : ES = 1.83

PANSS-negative : ES = 1.44 <====================================

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Primary Outcome Measures :

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PANSSÁ`¤À»P°ò½uªº¥­§¡ÅܤÆ

Secondary Outcome Measures :

¶§©Ê©M³±©Ê¯gª¬¶qªí¡]PANSS¡^[®É¶¡½d³ò¡GªvÀø«á8¶g]

PANSSÁ`¤À»P°ò½uªº¦Ê¤À¤ñÅܤÆ

¶§©Ê©M³±©Ê¯gª¬¶qªí¡]PANSS¡^[®É¶¡½d³ò¡GªvÀø«á8¶g]

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PANSS¤l¶qªí±o¤À©MMarder PANSS¦]¤l±o¤À[®É¶¡½d³ò¡GªvÀø«á8¶g]

PANSS¤l¶qªí±o¤À©MMarder PANSS¦]¤l±o¤Àªº¦Ê¤À¤ñÅܤÆ

­Ó¤H©MªÀ·|ÁZ®Ä¡]PSP¡^¶qªí[®É¶¡½d³ò¡GªvÀø«á8¶g]

­Ó¤H©MªÀ·|ÁZ®Ä¡]PSP¡^³W¼Òªº¦Ê¤À¤ñÅܤÆ

Other Outcome Measures :

¶§©Ê©M³±©Ê¯gª¬¶qªí¡]PANSS¡^[®É¶¡½d³ò¡G64¶g]

ºû«ùPANSSÁ`¤ÀªºªvÀø®ÄªG

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ºû«ùPSP¶qªíªºªvÀø®ÄªG

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Á{§ÉÁ`Åé¦L¶H - ÄY­«µ{«×¡]CGI-S¡^©M - §ï¶i¡]CGI-I¡^[®É¶¡½d³ò¡G64¶g]

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º~±Kº¸¹y§íÆ{¶qªí¡]HDRS¡^[®É­­¡G64¶g]

º~±Kº¸¹y§íÆ{¶qªí¡]HDRS¡^ªº¦Ê¤À¤ñÅܤÆ

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TEAEªºµo¥Í²v©MTEAE¤Þ°_ªº¬ã¨s°h¥Xµo¥Í²v

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patentscope.wipo.int/search/en/detail.jsf?docId=US211850832&tab=DRAWINGS&_cid=P22-JYTTFS-60461-4

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D-Serine Regulates Proliferation and Neuronal Differentiation of Neural Stem Cells from Postnatal Mouse Forebrain

(D- Serine½Õ¸`¥X¥Í«á¤p¹««e¸£¯«¸g·F²Ó­Mªº¼W´Þ©M¯«¸g¤¸¤À¤Æ)

www.ncbi.nlm.nih.gov/pmc/articles/PMC6493339/

ºû°ò¦Ê¬ì¹ï Neural stem cell (¯«¸g·F²Ó­M)ªº´y­z

[¯«¸g·F²Ó­M¡]NSCs¡^¬O¦Û§Ú§ó·sªº¦h¯à²Ó­M¡A¨ä­º¥ý²£¥Í©ñ®gª¬¯«¸g½¦½è¯ª²Ó­M¡A¨ä¦b­F­Lµo¨|´Á¶¡²£¥Í©Ò¦³°Êª«ªº¯«¸g¨t²Îªº¯«¸g¤¸©M¯«¸g½¦½è¡C¤@¨Ç¯«¸g¯ª²Ó­M·F²Ó­M¦b¦¨¦~¯á´Õ°Êª«¤j¸£ªº°ª«×¨ü­­°Ï°ì¤¤¦s¬¡¡A¨Ã¦b¾ã­Ó¥Í©R¹Lµ{¤¤Ä~Äò²£¥Í¯«¸g¤¸¡C¡K¯«¸g·F²Ó­M¼W´Þ·|¦]°I¦Ñ¦Ó¤U­°¡C] ¸Ô°Ñ : en.wikipedia.org/wiki/Neural_stem_cell

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¨ä¤¤´£¨ì

. NSCs ¦Û¨­·|¦X¦¨¨ÃÄÀ©ñD-µ·®ò»Ä¡C

. DAAO, MK-801(«DÄvª§©ÊNMDA¨üÅé«ú§Ü¾¯)³£·|§í¨îNSCsªº¼W´Þ

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. D -Serine ¡ADAAO©MMK-801 ³£¤£¼vÅTNSCsªº®|¦V¾E²¾¶ZÂ÷¡C

. D-µ·®ò»ÄÅãµÛ«P¶iNSCsªº¯«¸g¤¸¤À¤Æ¡CNaB¹ï¤À¤Æ¨S¦³ÅãµÛ®ÄªG¡CDAAO©ÎMK-801ÅãµÛ§í¨î¯«¸g¤¸¤À¤Æ , D-µ·®ò»Ä©ÎNaB¥i¥H´î»´DAAO»¤¾ÉªºNSCs¯«¸g¤¸¤À¤Æªº§í¨î¡CD - µ·®ò»Ä¤]¥i¥H´î»´MK-801»¤¾Éªº¯«¸g¤¸¤À¤Æ§í¨î¡C

. DAAO§í¨îNSCs¤¤¨¦®ò»Ä»¤¾ÉªºCa 2+ÀþÅÜ

. DAAO·|§í¨îNSCs¤¤ERK1 / 2¡ACREB©MGSK-3£]ªºÁC»Ä¤Æµ¥¦³ÃöNSCs¼W´Þ¤À¤Æ³~®|ªº«H¥O

³o½g½×¤å¬O¥Î¥X¥Íªº¤p¹«¨Ó¸ÕÅç , ¥B¦bÅé¥~

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¤º·½©ÊD-µ·®ò»Ä¥i¥H´î»´DAAO¹ïNSCs¯«¸g¤¸¼W´Þ©M¤À¤Æªº§í¨î§@¥Î¨Ã¥BÁÙ·|ÅãµÛ«P¶iNSCsªº¯«¸g¤¸¼W´Þ©M¤À¤Æ

µM¦ÓDAAO·|¥NÁ±¼D-µ·®ò»Ä ,

¦b°·±d¤HªºÅ餺§Î¦¨¤@ºØ°ÊºA¥­¿ÅªºÃ­ºAª¬ªp , ºû«ù°·±dªº´`Àô

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½²±Ð±Âªº³o¤@©Û --- DAAO§í¨î¾¯ , §í¨î¤FDAAO , ¦P®É¼W¥[¤F¤º·½©ÊD-µ·®ò»Ä

¹ïNSCs¦Ó¨¥ , ¤£¦ý´î»´DAAO¹ïNSCs¯«¸g¤¸¼W´Þ©M¤À¤Æªº§í¨î§@¥Î , ¦P®É¼W¥[ªº¤º·½©ÊD-µ·®ò»Ä¤]«P¶iNSCsªº¯«¸g¤¸¼W´Þ©M¤À¤Æ

¤ß®®ªºSND-51 , SND-1¨t¦C ³£¬ODAAO§í¨î¾¯

SND-1¨t¦C¬ï¹LBBB¨S°ÝÃD , SND-51¤À¤l¸û¤j©Î¦³µLªk¬ï¶VªººÃ¼{(?) , µM¨ä¥NÁª«¨S­¹¤l»Ä( GA ) ,¤]¬O¤@ºØDAAO§í¨î¾¯ , ¹ï¬ï¶V¤p¹«BBB¥ç¤w³Q°»´ú

patentimages.storage.googleapis.com/70/c1/b8/7dbd79cc943e44/PCTCN2016076128-appb-300005.png

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¤º·½©ÊD-µ·®ò»Ä¹ï¯«¸gªºµo¥Í( neurogenesis )¦³ÅãµÛªº«P¶i¥\¯à , ³o¹ïÀø®Ä©M»{ª¾¦³À°§U¶Ü?

¯«¸g·F²Ó­M¼W´Þ·|¦]°I¦Ñ¦Ó¤U­° , ½²±Ð±Â¥ç´¿´£¥Ü SND-13ªºÁ{§É¶V¦~»´ªº±wªÌ®ÄªG¶V¦n , ¦ý¬O§_»P¦¹¾÷¨î¥ç¦³©ÒÃö«Y , ¤]»á¥O¤H¦n©_

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04:102019/07/22 ¤¤°ê®É³ø ªL©P¸q

www.chinatimes.com/newspapers/20190722000473-260114?chdtv

¥xÆW¬ù¦³28¸U¤H¿©±w¥¢´¼¯g¡A¹w­p±N¦b2065¦~¹Gªñ90¸U¤H¡A¥Ø«e¤´¦³¤@¥b¥H¤Wªº¥¢´¼±wªÌ©|¥¼½T¶E¡CÂå®v¤ÀªR¡A­ì¦]¦b©ó­««×¥¢´¼ªÌ¥i¯à¤wª×§É¡B¥¢¯à¡A©Î¬O»´«×¥¢´¼»~¥H¬°¦Û¤v¥u¬O°O¾Ð¤£¦n¡A¦Ó¥¼«e©¹´NÂå¡C

persistence market research §Y±N¥Xª©ªº

Cognitive Impairment Disorders Treatment Market:Global Industry Trend Analysis 2013 to 2017 and Forecast 2018¡V2026

www.persistencemarketresearch.com/market-research/cognitive-impairment-disorders-treatment-market.asp

»¡

Some of the key players leading in cognitive impairment disorders treatment market are: Eli Lilly and Company, AstraZeneca, Bristol-Myers Squibb, Pfizer, Minerva Neurosciences, Intra-Cellular Therapies, Avineuro Pharmaceuticals, SyneuRx, Lundbeck, AB Science SA, AbbVie Inc, CHA Bio & Diostech Co Ltd, Echo Pharmaceuticals BV, Eisai Co Ltd, GlaxoSmithKline Plc, Grifols SA, Immungenetics AG, Otsuka Holdings Co Ltd, Merck & Co Inc, Kyowa Hakko Kirin Co Ltd and others.

¯÷Á|¨S­¹¤l»Ä(gallic acid) ¹ï»{ª¾ªº½×¤å¨Ñ°Ñ(ÁÙ¦³¤£¤Ö½×¤åµL¥H³Æ¸ü)

1.

¨S­¹¤l»Ä¥i¹w¨¾¸£«Ç¤ºª`®gÃì脲¦õµß¯À¤Þ°_ªº°O¾Ð¯Ê³´©M®ñ¤ÆÀ³¿E¡C

www.ncbi.nlm.nih.gov/pubmed/24036471

GAªºªø´Á¬I¥ÎÅãµÛ¦a¹w¨¾¤FICV-STZ¤j¹«ªº»{ª¾¯Ê³´©M¥Í¤Æ§ïÅÜ¡C³o¨Çµo²{±j½Õ¤FGA³q¹L¼W±j¸£§Ü®ñ¤Æ¨¾¿m¨t²Î¦bICV-STZ¤j¹«¤¤ªº¦³¯q§@¥Î¡C¦]¦¹¡A¥¦¥i¯à¨ã¦³ªvÀøSDAT(´²µo©Êªüº¸¯ý®üÀq¤ó«¬)ªºªvÀø»ù­È¡C

2.

¨S­¹¤l»Ä¥i§ïµ½¤j¹«ºC©Ê¸£Äéª`¤£¨¬¤Þ°_ªº»{ª¾¡A®ü°¨ªø®Éµ{¼W±j¯Ê³´©M¸£·l¶Ë¡C

www.ncbi.nlm.nih.gov/pubmed/26031016

¸£§CÄéª`¯Ê¦å¡]CHI¡^¦b¯«¸g¤¸·l¶Ë©M¦æ¬°¯Ê³´¤¤¨ã¦³­«­n§@¥Î¡A¥]¬A°O¾Ð©Mªø´Á¼W±j¡]LTP¡^·l¶Ë¡C¦b¤j¹«ªº¥Ã¤[©ÊÂù°¼ÀVÁ`°Ê¯ß³¬¶ë¤¤ÀË´ú¤F¨S­¹¤l»Ä¡]GA¡^¹ï°O¾Ð¡A®ü°¨LTP©M²Ó­M¬¡¤Oªº«OÅ@§@¥Î¡C

µ²ªGªí©ú¡A¨S­¹¤l»Ä³q¹L¨ä§Ü®ñ¤Æ©M²M°£¦Û¥Ñ°òªº¯S©Ê´î®z¤FCHI»¤¾Éªº¦æ¬°©M¹q¥Í²z¯Ê³´¡A¨Ã¹ï¸£²Ó­M¬¡¤O¨ã¦³ÅãµÛªº«OÅ@§@¥Î¡C

3.

¨S­¹¤l»Ä¹ï¤j¹«Ã¨§b«¬ªüº¸¯ý®üÀq¯fªº¼vÅT¡G¹q¥Í²z¾Ç©M²Õ´¾Ç¬ã¨s

www.ncbi.nlm.nih.gov/pmc/articles/PMC4892325/

Results:

Data showed that LTP amplitude and area under curve significantly impaired in AD rats (P<0.001), while significantly improved in AD rats treated with GA (P<0.05, P<0.01).

µ²½×¡G

¥Ø«eªº¬ã¨sµ²ªGªí©ú¡AGA¥i¥H´î¤Ö¯«¸g·l¶Ë©M¸£¾ý¯»¼Ë³J¥Õ¯«¸g¯f²z¾Ç¡A¨Ã³q¹L²M°£¦Û¥Ñ°ò©M§í¨îA£]ªº¹è»E¤Æ¨Ó§ïµ½»{ª¾¥\¯à¡A¦ý¹ï°·±d¤j¹«¨S¦³¼vÅT¡C

4.

¨S­¹¤l»Ä¯}ÃaA£]1-42»E¶°¨Ã®¾±ÏAPP / PS1Âà°ò¦]¤p¹«ªº»{ª¾°I°h

www.biorxiv.org/content/10.1101/258848v1

GA¤fªA¤£¶È§ïµ½¤F¦­´ÁAD¤p¹«(4­Ó¤ë¤j)ªºªÅ¶¡°Ñ¦Ò°O¾Ð©MªÅ¶¡¤u§@°O¾Ð,¦Ó¥BÅãµÛ´î¤Ö¤F±ß´ÁAD¤p¹«(9­Ó¤ë¤j)¦bªÅ¶¡¾Ç²ß¡B°Ñ¦Ò°O¾Ð¡Bµu´ÁÃѧO¡BªÅ¶¡ÃѧO©MªÅ¶¡¤u§@°O¾Ð¸û¬°ÄY­«ªº¯Ê³´¡C

Microsoft® ½Ķ

¦bGAªvÀøªº±ß´ÁAPP/PS1 AD¤p¹«¤¤,®ü°¨ªø´Á¼W±j (LTP)¤]ÅãµÛ¤É°ª¡C

¤ÀªRªí©ú,GA¯à´î¤ÖA£]1-42»E¦X©Ò§Î¦¨¦³¬r¹è»Eª«©MÅÖºû³J¥Õ¡C

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Gallic acid bioavailability in humans

www.researchgate.net/publication/287308102_Gallic_acid_bioavailability_in_humans

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Polyphenols journey through blood-brain barrier towards neuronal protection ( ¦h×ô³q¹L¦å¸£«Ì»ÙÁÚ¦V¯«¸g¤¸«OÅ@ )

www.nature.com/articles/s41598-017-11512-6

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ndltd.ncl.edu.tw/cgi-bin/gs32/gsweb.cgi?randomimg=via.pS_1563437909&validpath=%2Ftmp%2F%5Enclcdr__doschk%2Fvia.pS_1563437909__ZDJlODht&validinput=d2e88m&check=%E7%A2%BA%E5%AE%9A

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hhv-6foundation.org/alzheimers-disease/harvard-scientists-show-that-amyloid-plaques-are-an-antimicrobial-response-to-herpesvirus

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¤HÃþ¯p¯l¯f¬r6¡]HHV-6¡^: HHV-6A©MHHV-6B¬OBetaherpesvirinae¨È¬ì©MRoseolovirusÄݤ¤ªºÂùÃìDNA¯f¬r¡CHHV-6A©MHHV-6B·P¬V¤F´X¥G©Ò¦³¤w¸g´ú¸Õ¹Lªº¤H¸s¡CHHV-6A³Q´y­z¬°§ó¨ã¯«¸g¬r©Ê¡A¦]¦¹¦b±w¦³¦hµo©Êµw¤Æµ¥¯«¸gª¢¯g¯e¯fªº±wªÌ¤¤§ó±`¨£¡Cªüº¸¯ý®üÀq¯f±wªÌªº¤j¸£¤¤HHV-6¡]©MHHV-7¡^¤ô¥­¤]¤É°ª

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µM¦Ó¡A³Ì²×¡AA£]¥\¯à¥¢½Õªº¿n»E¥i¯à¾É­P´³¶ô©M¨ä¥L¯«¸g¯f²z¾Çªº¥[³tµo®i¡C

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www.ncbi.nlm.nih.gov/pubmed/30001512

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Anti-Herpes Simplex Virus Type 1 Activity of Specially Selected Groups of Tannins.

www.ncbi.nlm.nih.gov/pubmed/30134445

¤@¯ë¦Ó¨¥¡A¤@¨t¦CÂýªá³æ¹çÅã¥Ü¥X¹ï§ÜHSV-1½Æ»sªº¬¡©Ê©úÅã±j©ógall³æ¹ç¡C¤»ºØ´ú¸ÕªºÂýªá³æ¹çªí²{¥X©úÅ㪺¬¡©Ê¡Gepiacutissimin B¡]¿ï¾Ü©Ê«ü¼Æ¡ASI> 60.6¡^¡Aepiacutissimin A¡]SI> 55.5¡^¡Aacutissimin A¡]SI> 34.8¡^¡Amongolicain¡]SI> 32.5¡^¡AVgSBuSH¡]SI> 24.6¡^©MVgOMe¡]SI> 22.0¡^¡C¥|ºØgall³æ¹çÃþ¤Æ¦Xª«¦b¸û§C¦ý¤´µMÅãµÛªºµ{«×¤W§í¨îHSV-1ªº½Æ¨î¡GGal-04B¡]SI> 35.7¡^¡AGal-04A¡]SI> 28.5¡^¡AGal-11M¡]³æ¹ç»Ä¡^¡]SI> 25¡^©MGal-05M¡]SI = 15.6¡^¡C

2.

Anti-HSV-1 and anti-HIV-1 activity of gallic acid and pentyl gallate.

www.ncbi.nlm.nih.gov/pubmed/18797755

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Homology Modeling of DNA polymerases of Herpesviridae family and structure-based virtual screening for inhibitor identification

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www.japsonline.com/admin/php/uploads/1718_pdf.pdf

From the study it is found that alliin and gallic acid exhibit good binding affinity than acyclovir and other natural compounds. So, here we purpose that these two compounds can be potential candidates to inhibit Herpesviridae family.

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Therapeutic potential and underlying mechanism of sarcosine (N-methylglycine) in N-methyl-D-aspartate (NMDA) receptor hypofunction models of schizophrenia

journals.sagepub.com/doi/abs/10.1177/0269881119856558

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sponsors concluded that the potential benefit for participants taking

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COMPOSITIONS CONTAINING TANNIC ACIDS AND USES THEREOF

United States Patent Application 20190201427

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Tsai; Guochuan Emil ; et al. July 4, 2019

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1.

United States Patent 10,336,679

July 2, 2019

Polymorphic forms of sodium benzoate and uses thereof

2.

United States Patent 10,336,724

July 2, 2019

D-amino acid oxidase inhibitors and therapeutic uses thereof

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1.

United States Patent 10,328,041

Co-crystals of substituted glycine and uses thereof

June 25, 2019

2.

United States Patent 10,328,042

Co-crystals of substituted glycine and uses thereof

June 25, 2019

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Farnesyltransferase Haplodeficiency Reduces Neuropathology and Rescues Cognitive Function in a Mouse Model of Alzheimer Disease

www.ncbi.nlm.nih.gov/pmc/articles/PMC3861644/

These results document that farnesylation and geranylgeranylation play differential roles in AD pathogenesis and suggest that specific inhibition of protein farnesylation could be a potential strategy for effectively treating AD.

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Sodium Benzoate, a Metabolite of Cinnamon and a Food Additive, Reduces Microglial and Astroglial Inflammatory Responses

www.ncbi.nlm.nih.gov/pmc/articles/PMC2862570/

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NaB was found to inhibit LPS-induced expression of inducible NO synthase (iNOS), proinflammatory cytokines (TNF-£\ and IL-1£]) and surface markers (CD11b, CD11c, and CD68) in mouse microglia.

Similarly, NaB also inhibited fibrillar amyloid £] (A£])-, prion peptide-, double-stranded RNA (polyinosinic-polycytidylic acid)-, HIV-1 Tat-, 1-methyl-4-phenylpyridinium+-, IL-1£]-, and IL-12 p402-induced microglial expression of iNOS.

In addition to microglia, NaB also suppressed the expression of iNOS in mouse peritoneal macrophages and primary human astrocytes.

Inhibition of NF-£eB activation by NaB suggests that NaB exerts its anti-inflammatory effect through the inhibition of NF-£eB.

...

Furthermore, we demonstrate that an inhibitor of p21ras farnesyl protein transferase suppressed the expression of iNOS, that activation of p21ras alone was sufficient to induce the expression of iNOS, and that

NaB suppressed the activation of p21ras in microglia.

These results highlight a novel anti-inflammatory role of NaB via modulation of the mevalonate (¥Òßm¥³»Ä)pathway and p21ras.

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1.

Âűбµ¥¤H¦bNovember 2005 µoªíªº

Sarcosine or D-Serine Add-on Treatment for Acute Exacerbation of Schizophrenia

A Randomized, Double-blind, Placebo-Controlled Study

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jamanetwork.com/journals/jamapsychiatry/fullarticle/209027

Interventions

Six weeks of treatment with sarcosine (2 g/d), D-serine (2 g/d), or placebo and concomitant optimal risperidone therapy.

Results

The sarcosine group revealed more reductions in PANSS total scores than the placebo (P = .04) and D-serine (P<.001) groups. Sarcosine adjunctive treatment was also superior to placebo in reducing SANS-20 (P = .007) and SANS-17 (P = .003) scores and to D-serine in decreasing SANS-20 (P = .006) and SANS-17 (P = .002) scores. The PANSS-general, PANSS-cognitive, and PANSS-depressive symptoms scores and SANS-alogia and SANS−blunted affect scores improved significantly more in sarcosine-cotreated patients than in risperidone monotherapy patients (P≤.02 for all). Sarcosine adjunctive therapy also surpassed D-serine in terms of PANSS-general, PANSS-positive, PANSS-negative, and PANSS-depressive symptoms scores (P≤.04 for all). D-Serine and risperidone cotreatment did not differ significantly from risperidone monotherapy in all efficacy domains.

( ½Ð¦Û¦æ°Ñ¦Ò ªí2 ©Mªí3 )

Conclusions

This first short-term treatment study on NMDA receptor−enhancing agents suggests that sarcosine, superior to D-serine, can benefit not only patients with long-term stable disease but also acutely ill persons with schizophrenia. This finding indicates that a glycine transporter 1 inhibitor may be more efficacious than NMDA-glycine site agonists for adjuvant treatment of schizophrenia, at least during the acute phase. Further studies are needed.

2.

High dose D-serine in the treatment of schizophrenia

°ª¾¯¶qD-µ·®ò»ÄªvÀøºë¯«¤Àµõ¯g

www.ncbi.nlm.nih.gov/pmc/articles/PMC3111070/

Background

Double-blind studies have been performed at 30 mg/kg/day (~2 g/day) with encouraging results, but no formal dose escalation studies have been performed. We describe the first evaluation of the efficacy and safety of D-serine at doses >30 mg/kg/day; a 4-week, open-label trial of adjunctive D-serine (30, 60 or 120 mg/kg/day).

Results

Significant improvement in symptoms and neuropsychological measures was noted across doses. On the PANSS, improvement was observed for positive (p=0.006;d=0.46), negative (p<0.001;d=0.68), general (p=0.001;d=0.53), and total (p<0.0001;d=0.74) symptoms. On MATRICS, while only non-significant improvement was noted at 30 mg/kg, highly significant, large effect size improvement was noted on the composite score (p<0.01;d=1.0) for doses ≥60 mg/kg, leading to a significant dose-by-time interaction (p<0.01).

Discussion

These findings support double-blind investigation of D-serine at doses ≥60 mg/kg/d, and suggest effectiveness in treatment of both persistent symptoms and neurocognitive dysfunction.

3.

D-Serine: Potential Therapeutic Agent and/or Biomarker in Schizophrenia and Depression?

D-µ·®ò»Ä¡Gºë¯«¤Àµõ¯g©M§íÆ{¯g¤¤¼ç¦bªºªvÀø¾¯©M/©Î¥Íª«¼Ð»xª«¡H

Published online 2019 Feb 6.

www.ncbi.nlm.nih.gov/pmc/articles/PMC6372501/

Clinical Studies With D-Serine in Schizophrenia

Several clinical studies with D-serine have used it as a potential adjunctive drug (30¡V120 mg/kg/day) to antipsychotics. When added to non-clozapine antipsychotics in schizophrenia patients, D-serine has been reported to improve negative, positive, and cognitive symptoms (90¡V94) and to be relatively free of side effects even at high doses.

It is interesting that D-serine addition to clozapine does not increase the efficacy of clozapine (99); this may be because clozapine releases D-serine and glutamate (100) and may have agonist or partial agonist activity at NMDA receptors (99¡V101). It is also possible that individuals on clozapine do not respond to D-serine since they are more often older and/or treatment-resistant (99).

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One of the problems of treating symptoms of schizophrenia with D-serine is the fact that it is metabolized rapidly by DAAO, reducing its bioavailability and requiring administration of high doses, which could lead to peripheral neuropathies.

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·|­û¡G²q·Q10136148  µoªí®É¶¡:2019/5/31 ¤U¤È 02:13:46²Ä 569 ½g¦^À³
³æ¹ç»Ä¬O§_¬° AD ªºA£] and tau prion-like activitiesªº§í¨î¾¯?

ªüº¸¯ý®üÀq¯f¨ä¹ê¬O¤@ºØÂùÌÒ(£§£¹£³£¾)¯f¬r¯e¯f

¨Ó·½¡G ¥Íª«¨¦¡@2019-05-31

med.sina.com/article_detail_103_1_66640.html

¦b¤@¶µ·sªº¬ã¨s¤¤¡A¨Ó¦Û¬ü°ê¥[¦{¤j¾Çª÷¤s¤À®Õµ¥¬ã¨s¾÷ºcªº¬ã¨s¤H­ûµo²{¹ïªüº¸¯ý®üÀq¯f¯f²z¾Ç¦ÜÃö­«­nªº¨âºØ³J¥Õ§@¬°ÌÒ¯f¬r¡]prion¡^---µ²ºc²§±`ªº³J¥Õ³q¹L­¢¨Ï¥¿±`³J¥Õ§e²{¬Û¦Pªº¿ù»~§éÅ|§Îª¬¦Ó¹³¶Ç¬V¯f¤@¼Ë¦b²Õ´¤¤¶Ç¼½---µo´§§@¥Î¡C

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¤Þ­zªº½×¤å :

A£] and tau prion-like activities decline with longevity in the Alzheimer¡¦s disease human brain.

stm.sciencemag.org/content/11/490/eaat8462

]

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Inhibition of Amyloid Fibril Formation by Polyphenols: Structural Similarity and Aromatic Interactions as a Common Inhibition Mechanism

www.tau.ac.il/lifesci/departments/biotech/members/gazit/documents/52.pdf

»¡

Tannic acid inhibits b-amyloid and prion PrPsc

Yamada and coworkers (48) characterized tannic acid as a potential inhibitor of b-amyloid fibrillization and showed a dose¡Vresponse inhibition of b-amyloid assembly from monomeric b-amyloid into well-ordered fibrils. Tannic acid is a water-soluble polymeric polyphenol composed of phenolcarboxylic and gallic acids. Tannic acid did not extend the length of the lag phase, but decreased the rate of polymerization (48). Tannic acid was also described as the most potent polyphenol inhibitor of prion PrPsc (the infectious form of prion protein) by Caughey and coworkers (49).

Microsoft® ½Ķ

³æ¹ç»Ä§í¨î b-¾ý¯»¼Ë³J¥Õ©MPrion PrPsc (PrPSc¦³¦Û°Ê»E¶°ªº¶É¦V¡APrPSc·|»E¶°¦¨¾ý¯»¼Ë³J¥ÕÅÖºû)

¤s¥Ð©M¦P¨Æ (48) ±N³æ¹ç»Ä´y­z¬° b-¾ý¯»¼Ë³J¥Õ¦³Ãzµo¤Oªº¼ç¦b§í¨î¾¯, ¨ÃÅã¥Ü¥X¾¯¶q-¤ÏÀ³§í¨îb-¾ý¯»¼Ë³J¥Õ»E¶° , ±q³æÅé b-¾ý¯»¼Ë³J¥Õ¨ì¦³§ÇÅÖºû¡C³æ¹ç»Ä¬O¥Ñ×ôßn»Ä©M¨S­¹¤l»Ä²Õ¦¨ªº¤ô·»©Ê»E¦Xª«¦h×ô¡C³æ¹ç»Ä¨S¦³©µªø¿ðº¢´Áªº®É¶¡ªø«×, ¦ý­°§C¤F»E¦X³t²v (48)¡C³æ¹ç»Ä¤]³Q Caughey ©M¦P¨Æ (49) ´y­z¬° prion PrPsc (prion ³J¥Õªº¶Ç¬V©Ê§Î¦¡) ³Ì¦³®Äªº¦h×ô§í¨î¾¯¡C

Tannic acid ( IC50 Åé¥~ , ³æ¦ì:£gM (ref))

[ Prion PrPsc ] 0.1

[ b-Amyloid 1-40 ] 0.012

[ b-Amyloid 1-42 ] 0.022

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

ªüº¸¯ý®üÀq¯f¤¤³æ¹ç»Äªº¤À¤l¹vÂI¡C

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

TAÁÙ¦bÅé¥~¨Ï¯«¸g¬r©Ê¾ý¯»¼Ë³J¥Õ£]¡]A£]¡^­ìÅÖºû¤£Ã­©w¡C°£¤F¹ïA£]¯ÅÁpªº¼vÅT¥~¡ATAÁÙ¥i¥H§í¨îÅé¥~»E¶°tau肽---²Ó­M¤º¯«¸g­ìÅÖºûÄñµ²¡]NFTs¡^ªº®Ö¤ß¦¨¤À¡C

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SND-13¬O­nÀË©w ES >= 0.5 , power >= 85%

n1=n2=45

Pooled Åܲ§¼Æ : 65.71162 ¼Ð·Ç®t : 8.11

¨â²Õ¥­§¡¼Æ®ttÀË©w­È ------------ p ­È ( Âù§À )-------------------- ES ( ®ÄªG¶q )

3.000000000 1.75546 0.082660169801354500000000000000 0.37

4.000000000 2.34062 0.021512925122610300000000000000 0.49

5.000000000 2.92577 0.004370623525694480000000000000 0.62

5.200000000 3.04280 0.003089584121625170000000000000 0.64 <<<===

6.000000000 3.51092 0.000706669865842774000000000000 0.74

7.000000000 4.09608 0.000093147279703390700000000000 0.86

8.000000000 4.68123 0.000010278514398513600000000000 0.99

9.000000000 5.26639 0.000000975728888560859000000000 1.11

10.00000000 5.85154 0.000000081834052970207700000000 1.23

11.00000000 6.43669 0.000000006218013185253850000000 1.36

12.00000000 7.02185 0.000000000438003964185354000000 1.48

12.70000000 7.43146 0.000000000066103483698304400000 1.57

13.00000000 7.60700 0.000000000029198896305605100000 1.60

14.00000000 8.19216 0.000000000001875784299218310000 1.73

15.00000000 8.77731 0.000000000000117957344926712000 1.85

n1=n2=45 °t¦Xªº power­È

n1=n2=45 , £\=0.05 ( Âù§À )(¦¬®×174®Éªº±¡ªp)(174*0.75*0.7¨ú90)

---ES----power

0.30----29.07%

0.40----46.69%

0.50----65.02%

0.60----80.37%

0.64----85.14% <<<===

0.65----86.20%

0.70----90.73%

0.75----94.04%

0.80----96.35%

n1=n2=90

Pooled Åܲ§¼Æ : 65.68115 ¼Ð·Ç®t : 8.10

¨â²Õ¥­§¡¼Æ®ttÀË©w­È ------------ p ­È ( Âù§À )-------------------- ES ( ®ÄªG¶q )

3.000000000 2.48317 0.013947312271187300000000000000 0.37

3.700000000 3.06258 0.002535067705165960000000000000 0.46 <<<===

4.000000000 3.31090 0.001125957057843460000000000000 0.49

5.000000000 4.13862 0.000053838561586147200000000000 0.62

6.000000000 4.96635 0.000001590975952698780000000000 0.74

7.000000000 5.79407 0.000000030593163101535700000000 0.86

8.000000000 6.62180 0.000000000404832963041950000000 0.99

9.000000000 7.44952 0.000000000003902286289489770000 1.11

10.00000000 8.27725 0.000000000000028957435730735100 1.23

11.00000000 9.10497 0.000000000000000174243271532627 1.36

12.00000000 9.93270 0.000000000000000000891548306913 1.48

13.00000000 10.7604 0.000000000000000000004047625352 1.60

14.00000000 11.5881 0.000000000000000000000016926096 1.73

15.00000000 12.4158 0.000000000000000000000000067337 1.85

n1=n2=90 °t¦Xªº power­È

n1=n2=90 , £\=0.05 ( Âù§À ) (¦¬®×348®Éªº±¡ªp)(348*0.75*0.7¨ú180)

---ES----power

0.30----51.66%

0.40----76.08%

0.45----85.14%<<<===

0.50----91.56%

0.55----95.63%

0.60----97.95%

©Î³\¤j®a¤w¸g¹îı

¦b¼Ð·Ç®t¤@¼Ëªº±¡ªp¤U

ES(®ÄªG¶q)¥u©M¨â²Õ¥­§¡®t(ÃÄ®Ä)¦³Ãö , ¦ý©M¼Ë¥»¼ÆµLÃö

µM P ­È«o¦]¼Ë¥»¼Æªº¤£¦P¦Ó¤Ñ®t¦a»·(ÁöµMÃÄ®Ä(¨â²Õ¥­§¡®t)¤@¼Ë)

³o§Ú­Ì´N©ú¥Õ , ¦³ªº°]¤j®ð²Ê¼t®a¥Î¤H®ü¾Ô³N(¤j¼W¼Ë¥»¼Æ)¨Ó¼W¥[P ­È¤p©ó0.05ªº¾÷·| , ¦ý¬OESÁÙ¬O¤£¤j

¤£¹LÁÙ¬O¥i¥H¼W¥[ power ­È

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Pooled Åܲ§¼Æ 65.71162 ¼Ð·Ç®t : 8.11 ( n1=n2=45 )

¨â²Õ¥­§¡®t t ÀË©w­È --------- p ­È ( Âù§À ) ----- ES ( ®ÄªG¶q )

3.000000000 1.75546 0.082660169801354500 0.37

3.400000000 1.98952 0.049748591299121400 0.42

4.000000000 2.34062 0.021512925122610300 0.49

5.000000000 2.92577 0.004370623525694480 0.62

6.000000000 3.51092 0.000706669865842774 0.74

7.000000000 4.09608 0.000093147279703391 0.86

8.000000000 4.68123 0.000010278514398514 0.99

9.000000000 5.26639 0.000000975728888561 1.11

10.00000000 5.85154 0.000000081834052970 1.23

11.00000000 6.43669 0.000000006218013185 1.36

12.00000000 7.02185 0.000000000438003964 1.48

12.70000000 7.43146 0.000000000066103484 1.57

13.00000000 7.60700 0.000000000029198896 1.60

14.00000000 8.19216 0.000000000001875784 1.73

15.00000000 8.77731 0.000000000000117957 1.85

n1=n2=45 , £\=0.05 ( Âù§À )(¤j¬ù¦¬®×150®Éªº±¡ªp)(150*0.9*0.7¨ú90)

---ES----power

0.30----29.07%

0.40----46.69%

0.50----65.02%

0.60----80.37%

0.64----85.14% <<<===

0.65----86.20%

0.70----90.73%

0.75----94.04%

0.80----96.35%

0.85---- > 97%

n1=n2=68 , £\=0.05 ( Âù§À )

---ES----power

0.30----41.18%

0.40----63.90%

0.50----82.50%

0.52----85.32% <<<===

0.60----93.49%

0.65----96.43%

0.70----98.18%

n1=n2=90 , £\=0.05 ( Âù§À ) (¤j¬ù¦¬®×300®Éªº±¡ªp)(300*0.9*0.7¨ú180)

---ES----power

0.30----51.66%

0.40----76.08%

0.45----85.14%

0.50----91.56% <<<===

0.55----95.63%

0.60----97.95%

SND-13¬O­nÀË©w ES >= 0.5 , power >= 85%

·q½Ð«ü±Ð

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·|­û¡G²q·Q10136148  µoªí®É¶¡:2019/5/30 ¤U¤È 03:52:43²Ä 566 ½g¦^À³
³o¨Çªí®æ´£½Ð¤j®a«ü¾É«ü¥¿ ( ¥H¨â²Õ¼Ë¥»¼Æ¦U¬° 45 ¼ÒÀÀ )

Pooled Åܲ§¼Æ : 169.63182 ¼Ð·Ç®t : 13.02

¨â²Õ¥­§¡®t t ÀË©w­È --------- p ­È ( Âù§À ) ----- ES ( ®ÄªG¶q )

3.000000000 1.09259 0.277554153105974000 0.23

4.000000000 1.45679 0.148732774988454000 0.31

5.000000000 1.82099 0.072006844630945500 0.38

6.000000000 2.18519 0.031531843163060000 0.46

7.000000000 2.54939 0.012523230152946300 0.54

8.000000000 2.91358 0.004528996279133220 0.61

9.000000000 3.27778 0.001498832221455010 0.69

10.00000000 3.64198 0.000456484198698783 0.77

11.00000000 4.00618 0.000128732787002188 0.84

12.00000000 4.37038 0.000033833095199926 0.92

13.00000000 4.73457 0.000008341427671365 1.00

14.00000000 5.09877 0.000001941965420996 1.07

15.00000000 5.46297 0.000000429687373374 1.15

Pooled Åܲ§¼Æ : 141.13182 ¼Ð·Ç®t : 11.88

¨â²Õ¥­§¡®t t ÀË©w­È --------- p ­È ( Âù§À ) ----- ES ( ®ÄªG¶q )

3.000000000 1.19784 0.234194351543827000 0.25

4.000000000 1.59712 0.113822856807283000 0.34

5.000000000 1.99641 0.048980790232679700 0.42

6.000000000 2.39569 0.018708250691597500 0.51

7.000000000 2.79497 0.006371000291012050 0.59

8.000000000 3.19425 0.001946191151473640 0.67

9.000000000 3.59353 0.000537156014378807 0.76

10.00000000 3.99281 0.000135028202671890 0.84

11.00000000 4.39209 0.000031176846295564 0.93

12.00000000 4.79137 0.000006669398242214 1.01

13.00000000 5.19065 0.000001333355872936 1.09

14.00000000 5.58994 0.000000251240192027 1.18

15.00000000 5.98922 0.000000044983934661 1.26

Pooled Åܲ§¼Æ : 100.68889 ¼Ð·Ç®t : 10.03

¨â²Õ¥­§¡®t t ÀË©w­È --------- p ­È ( Âù§À ) ----- ES ( ®ÄªG¶q )

3.000000000 1.41815 0.159678976227872000 0.30

4.000000000 1.89086 0.061932714425177900 0.40

5.000000000 2.36358 0.020300974494559300 0.50

6.000000000 2.83630 0.005662886873305900 0.60

7.000000000 3.30901 0.001357856929235800 0.70

8.000000000 3.78173 0.000283323001402368 0.80

9.000000000 4.25445 0.000052146411811305 0.90

10.00000000 4.72716 0.000008587660476277 1.00

11.00000000 5.19988 0.000001283742846248 1.10

12.00000000 5.67259 0.000000176663194754 1.20

13.00000000 6.14531 0.000000022684111455 1.30

14.00000000 6.61803 0.000000002752223132 1.40

15.00000000 7.09074 0.000000000319217089 1.49

Pooled Åܲ§¼Æ : 74.91616 ¼Ð·Ç®t : 8.66

¨â²Õ¥­§¡®t t ÀË©w­È --------- p ­È ( Âù§À ) ----- ES ( ®ÄªG¶q )

3.000000000 1.64409 0.103726346095153000 0.35

4.000000000 2.19212 0.031010737203899700 0.46

5.000000000 2.74014 0.007435372372944750 0.58

6.000000000 3.28817 0.001450470245801010 0.69

7.000000000 3.83620 0.000234552393031191 0.81

8.000000000 4.38423 0.000032114227229400 0.92

9.000000000 4.93226 0.000003806784513076 1.04

10.00000000 5.48029 0.000000399482000624 1.16

11.00000000 6.02832 0.000000037917261013 1.27

12.00000000 6.57635 0.000000003321295922 1.39

13.00000000 7.12438 0.000000000273462435 1.50

14.00000000 7.67241 0.000000000021516850 1.62

15.00000000 8.22043 0.000000000001641664 1.73

Pooled Åܲ§¼Æ : 50.14343 ¼Ð·Ç®t : 7.08

¨â²Õ¥­§¡®t t ÀË©w­È --------- p ­È ( Âù§À ) ----- ES ( ®ÄªG¶q )

3.000000000 2.00958 0.047539091895395900 0.42

4.000000000 2.67944 0.008801295607126630 0.56

5.000000000 3.34930 0.001194331886986870 0.71

6.000000000 4.01916 0.000122888088936599 0.85

7.000000000 4.68902 0.000009970573298117 0.99

8.000000000 5.35888 0.000000664464717355 1.13

9.000000000 6.02874 0.000000037846973092 1.27

10.0000000 6.69860 0.000000001911869736 1.41

11.00000000 7.36846 0.000000000088546639 1.55

12.00000000 8.03832 0.000000000003870410 1.69

13.00000000 8.70818 0.000000000000163660 1.84

14.00000000 9.37804 0.000000000000006834 1.98

15.00000000 10.0479 0.000000000000000287 2.12

2a´Á¸ÕÅçµ²ªG

cdn.jamanetwork.com/ama/content_public/journal/psych/929317/yoi130025t2.png?Expires=2147483647&Signature=gb89lKsXurBF28iTlYNC-tTtiqpI7H6vCwgZaLPDBgqfLZEuO~8rYT3b5BL0Z0HDegQytqtFI7ft-N6FT2wso8boRtMaCWQMCVdmk3EVbtheoYRjV98N~-kQKTTsFnnoZrZE73-Sc5GKqOQv0F8eNRZsEJhffWUmUQgOWi2f8~8ZEkrQOoJ46kQgmCRrmwH65ry149Pql659SZC0eMJN4dOyvTXgh6p09KIYHYqfg2UpP6kmDlT7Xc9d7eWY276nemvqED3xAFw~z3hGzwCBKGgWH5NOqTM3wUAN~RC8f-cBJIYtDlzCSR9lqzVadCHtZWEpSqbcUNO4PfQg7n1SVw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA

¨â²Õ§¡®t = 12.7 ( PANSS Á`¤À )

t ÀË©w­È = 7.6

===>>> ¼Ð·Ç»~ ( SE ) = 12.7 / 7.6 = 1.671

¼Ë¥»¼Ð·Ç®t ( SD ) ¬ù = ( 1.671 ) * (23.5)^0.5 = 8.101 ( 23.5 ¬°¨â²Õ¼Ë¥»¥­§¡(·§ºâ) )

®ÄªG¶qES = 12.7 / 8.101 = 1.57 ( ¸ÕÅç³ø§iªº¼Æ­È = 1.53 )

¤S¥ÎG*power³nÅé¨Ó¦ôºâ ÀË©w¤Opower

¥Î°Ñ¼Æ ES=0.7 , alpha=0.05 (Âù§À) , ¼Ë¥»¼Æn1=n2=45

­pºâªºÀË©w¤Opower = 90.75 %

¬ù¸¨¦b Pooled Åܲ§¼Æ : 100.68889 ¼Ð·Ç®t : 10.03 ³o²Õ

¨â²Õ¥­§¡®t(¬Û·í¨â²ÕÃÄ®ÄPANSSÁ`¤À®t¶Z)=7.0

©Î³\¤j®a¥iÀH¦Û¤v·Q­nªº°Ñ¼Æ , ¬Ý¬Ý¬d¬d·Q·Q , ±zªº¤ß¸Ì©Î·|¦³­Ó¦Û¤v·Q­nªºÃÐ

Pooled Åܲ§¼Æ 65.71162 ¼Ð·Ç®t : 8.11

¨â²Õ¥­§¡®t t ÀË©w­È --------- p ­È ( Âù§À ) ----- ES ( ®ÄªG¶q )

3.000000000 1.75546 0.082660169801354500 0.37

3.400000000 1.98952 0.049748591299121400 0.42 <<<=== p ­È¹LÃö(¼Ë¥»¼Æ¤£¦P ·|¦³¥X¤J)

4.000000000 2.34062 0.021512925122610300 0.49

5.000000000 2.92577 0.004370623525694480 0.62

6.000000000 3.51092 0.000706669865842774 0.74

7.000000000 4.09608 0.000093147279703391 0.86

8.000000000 4.68123 0.000010278514398514 0.99

9.000000000 5.26639 0.000000975728888561 1.11

10.00000000 5.85154 0.000000081834052970 1.23

11.00000000 6.43669 0.000000006218013185 1.36

12.00000000 7.02185 0.000000000438003964 1.48

12.70000000 7.43146 0.000000000066103484 1.57 <<<===2a¸ÕÅçµ²ªG

13.00000000 7.60700 0.000000000029198896 1.60

14.00000000 8.19216 0.000000000001875784 1.73

15.00000000 8.77731 0.000000000000117957 1.85

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ªLÂÅÂå®vµ¥¬ã¨s¹Î¶¤108¦~5¤ëµoªíNaB¥¢´¼¯g+BPSD¬ã¨s³ø§i

liawbf.pixnet.net/blog/post/48947012

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Pahan ±Ð±Â¬ã¨s¹Î¶¤«Ü«÷©Rµoªí NaB ¹ï¹B°Ê¯«¸g¯e¯f PD ªº¬ã¨s

liawbf.pixnet.net/blog/post/48945804

Pahan ±Ð±Âªº¬ã¨s¥i»¡¬OµY·ãº¡¥Ø , °w¹ïNaBªÌ¦p¤U :

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DOI: 10.1007/s11064-017-2367-9

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. TAK-831 was synthesized and provided to us by Takeda Cambridge Limited. The drug was supplied in a solid form and stored at ¹s¤U20«×C until required to use.

. Therapeutic testing of TAK-831

.. Weight analysis

.. Beam-walk assessment

.. Rotarod assessment

.. Beam-breaker locomotor activity assessment

.. Quantification of FXN mRNA levels following TAK-831 treatment Investigation of FXN mRNA

µ²ªG :

. Throughout the dosing regime, no apparent toxicity was observed in any of the mice, indicating a safe administration of compound.

. However, a significant reduction was seen in male YG8sR mice average body weight with TAK-831 treatment, which were generally overweight as compared to the female YG8sR mice. Therefore, TAK-831 may have a specific effect on obese FRDA mice by increasing body metabolism.

. This indicates that TAK-831 significantly improved the balance and motor coordination ability of YG8sR mice at 8 months of age when the disease effect was prominent.

. Therefore, taking together the beam walk and the rotarod results, treatment with TAK-831 may prove beneficial to improve ataxia motor coordination deficits, which are associated with FRDA.

. Furthermore, the qRT-PCR results revealed no significant changes in FXN gene expression levels in the cerebellum and heart samples of TAK-831-treated YG8sR mice ,indicating that the beneficial effect of the TAK-831 was not due to increased FXN gene expression levels.

µ²½× :

Overall, our preliminary findings support the use of TAK-831, as a small molecule DAO inhibitor, in clinical development as a novel therapeutic approach for FRDA.

³o­Ó³ø§i¤]´£¤Î D-cycloserine ( SNA-1 ªº¥D¦¨¥÷ )

Previous studies have reported that systemic administration of D-cycloserine diminishes ataxia in mice carrying inherited or chemically induced cerebellar degeneration. Subsequently, D-cycloserine was then given to patients and ataxia was reduced after 14-day treatment (Ogawa et al., 2003).

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D-cycloserine for the treatment of ataxia in spinocerebellar degeneration.

( D-Àôµ·®ò»Ä¥Î©óªvÀø¯áÅè¤p¸£Åܩʤ¤ªº¦@ÀÙ¥¢½Õ¡C )

www.ncbi.nlm.nih.gov/pubmed/12736088

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Tannic acid inhibits the Jak2/STAT3 pathway and induces G1/S arrest and mitochondrial apoptosis in YD-38 gingival cancer cells.

www.ncbi.nlm.nih.gov/pubmed/26202061

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2.

³q¹LEGCG¡A³æ¹ç»Ä©MÁ¤¶À¯À½Õ¸`Àù²Ó­M¤¤ªº¦hÃÄ­@ÃÄ©Ê¡C

www.ncbi.nlm.nih.gov/pubmed/30466981

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3.

Effect of Green Tea Catechins and Hydrolyzable Tannins on Benzo[a]pyrene-Induced DNA ( BP-DNA ) Adducts and Structure¡VActivity Relationship

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www.ncbi.nlm.nih.gov/pmc/articles/PMC5087322/

µo²{ÅãµÛ§í¨îDNA¥[¦Xª«§Î¦¨¡]³æ¹ç»Ä>¤­¸²¿}¸²µå¿}>ªí¨S­¹¤l¨à¯ù¯À¨S­¹¤l»Äà­>ªí¨à¯ù¯À¨S­¹¤l»Äà­¡^

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4.

³q¹L³æ¹ç»Ä¹ï¤p¹«¤¤¹ï¤A酰®ò°ò×ô»¤¾Éªº¨x¬r©Ê¶i¦æ¦h¹vÂI«OÅ@¡C

www.ncbi.nlm.nih.gov/pubmed/28376392

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5.

³æ¹ç»Ä¹ï¥|´â¤ÆºÒ»¤¾ÉªºÅ餺¥~¨xÅÖºû¤Æªº§ïµ½§@¥Î¡C

www.ncbi.nlm.nih.gov/pubmed/26810570

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6.

he Effective Solubilization of Hydrophobic Drugs Using Epigallocatechin Gallate or Tannic Acid-Based Formulations.

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www.ncbi.nlm.nih.gov/pubmed/27522526

7.

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www.sciencedirect.com/science/article/pii/S2212877818309347

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