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" S-ketamine for the treatment of depression "

Kaija Järventausta, Olli Kampman, Arvi Yli-Hankala,Esa Leinonen

http://www.psykiatriantutkimussaatio.fi/uploads/files/PF_2015/PF2015_ART1.pdf

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Clinical efficacy of S-ketamine in major depression

In a recent preclinical study, S-ketamine was reported to have a poorer

and shorter antidepressant effect than R-ketamine in mice (42). The authors suggested

that R-ketamine may be a more potent antidepressant, relative to S-ketamine, and that

R-ketamine may also have less psychotomimetic side effects. In another clinical

report, however, S-ketamine caused less adverse psychotomimetic effects compared to

racemic ketamine in two patients having MDD, although showing a similar antidepressive

effect (43)

Adverse effects of S-ketamine

S-ketamine has been reported to induce more psychotic symptoms, loss of interest and

emotional withdrawal compared with R-ketamine in healthy volunteers (30). In a study of

ten healthy volunteers receiving R- or S-ketamine, the incidence of subjective side

effects was low, but more frequently associated with R- than S-ketamine (38). The most

common symptoms were drowsiness, dizziness, drunkenness, sensation of floating,

distorted body experience and distorted vision/hearing (38). In repeated S-ketamine

infusions in six TRD patient samples, two patients reported pronounced dissociative

symptoms (45). Contrarily, S-ketamine has been reported to be better tolerated

with fewer adverse psychotomimetic effects than R-ketamine in two depressive patients

(43).

...

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" Glia-Derived d-Serine Controls NMDA Receptor Activity and Synaptic Memory "

http://www.cell.com/cell/fulltext/S0092-8674(06)00506-X

As d-serine is released exclusively by astrocytes, we studied the physiological impact of the glial environment on NMDA receptor-dependent activity and plasticity.

¥t¤@½g¥ÑHerman Wolosker, Darrick T. Balu , Joseph T. Coyle ©Ò¼¶¼gªº

" The Rise and Fall of the d-Serine-Mediated Gliotransmission Hypothesis " (¥u¦³ºK­n)

http://www.sciencedirect.com/science/article/pii/S0166223616301187

«oªí©ú d-Serine Is Not a Gliotransmitter

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Evaluation of cytotoxic, apoptotic, mutagenic, and chemopreventive activities of semi-synthetic esters of gallic acid

http://www.sciencedirect.com/science/article/pii/S0278691517302107

In conclusion, our results suggest that alkyl gallates are non-genotoxic, non-mutagenic, and pro-apoptotic agents, which may serve as suitable and promising candidates for preventing chemically-induced chromosomal damage.

Gallic acid, one of the components in many plant tissues, is a potential inhibitor for insulin amyloid fibril formation

http://www.sciencedirect.com/science/article/pii/S0223523414007260

Gallic acid interacts with £\-synuclein to prevent the structural collapse necessary for its aggregation

http://www.sciencedirect.com/science/article/pii/S1570963914001058

Gallic acid is the major component of grape seed extract that inhibits amyloid fibril formation

http://www.sciencedirect.com/science/article/pii/S0960894X13011451

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371 subjects were randomized. In the ITT population (n=357), linear trend analysis at Week 24 suggested a dose response for CIBIC+ with a mean slope of -0.05 points/5-mg dose increase (95% confidence interval [CI]: -0.09, -0.01; p=0.016). The dose response slope for change from baseline in ADAS-Cog was -0.22 points/5-mg dose increase (95% CI: -0.45, 0.01; p=0.059). The adjusted mean treatment difference from placebo at Week 24 for SB-742457 35 mg (-0.31) was significant on CIBIC+ (95% CI: -0.62, -0.00; p=0.047) but non-significant on ADAS-Cog (-1.28 [95% CI: -2.96, 0.40]; p=0.135). Adverse events occurred in 24-37% in the SB-742457 groups vs 29% for placebo; 11-16% discontinued SB-742457 vs 15% for placebo.

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Outcome Measures

[0059] The mean.+-.SD scores of both primary and secondary outcomes--including ADAS-cog, additional cognition composite, and CIBIC-plus--of the two groups of patients are shown in FIG. 3, Table 2. At week 0 (baseline), there were no significant differences between the two groups in ADAS-cog and additional cognition composite (p=.75 and p=.2.7, respectively).

[0060] For the primary outcome, sodium benzoate produced greater improvement in ADAS-cog score than the placebo therapy throughout the study (mean differences from baseline were 3.8, 5.4, 5.9, and 5.9 in the benzoate group and 2.4, 1.7, 2.7, and 1.7 in the placebo group, at weeks 8, 16, 24, and endpoint; p=.3730, p=.0021, p=.0116, and p=.0031, respectively), with effect size of .86 at the end of the study (FIG. 3, Table 2). The results were similar when the baseline ADAS-cog score was controlled in the GEE model (FIG. 7, Table 6).

[0061] For the secondary outcomes, sodium benzoate was better than placebo in the additional cognition composite at endpoint (p=.007, effect size=.78). Benzoate treatment also produced greater improvement m CIBC-plus score than placebo therapy at week 16 (p=.015), week 24 (p=.016), and endpoint (p=.012, effect size=.73 at endpoint) (FIG. 3, Table 2).

[0062] The dropout rate (3.3%) of the sodium benzoate group tended to be lower than that (16.7%) of the placebo group, yet insignificantly (p=.195).

[0063] For subgroup analysis, we further examined efficacy of sodium benzoate versus placebo in CDR .5 and CDR 1 subgroups. For ADAS-cog, sodium benzoate produced greater improvement than placebo therapy at weeks 16 and 24 and endpoint (p=0151, p=.0387, and p=.0092, respectively) in the CDR 1 subgroup. However, sodium benzoate was not superior to the placebo therapy in the CDR .5 subgroup throughout the study (p>.05) (FIG. 4, Table 3).

[0064] Sodium benzoate showed better efficacy in the CDR 1 subgroup (p=.041) and borderline significance in the CDR .5 subgroup (p=.063) in improving the additional cognition composite (FIG. 5, Table 4). For CIBIC-plus, sodium benzoate produced greater improvement than placebo therapy at week 24 and endpoint (p=.040 and p=.018, respectively) in the CDR 1 subgroup but not in the CDR .5 subgroup (FIG. 6, Table 5).

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Inventors: Shieh; Dar-Bin (Tainan, TW)

Assignee: SYNEURX INTERNATIONAL CORP. (Taipei, TW)

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