Purpose
TAK-831 is a highly selective and potent inhibitor of D-amino acid oxidase (DAAO) currently under clinical development for schizophrenia. In this study, a mechanistic multilayer quantitative ...model that parsimoniously connects pharmacokinetics (PK), target occupancy (TO) and D-serine concentrations as a pharmacodynamic (PD) readout was established in mice.
Methods
PK, TO and PD time-profiles were obtained in mice and analyzed by mechanistic binding kinetics model connected with an indirect response model in a step wise fashion. Brain distribution was investigated to elucidate a possible mechanism driving the hysteresis between PK and TO.
Results
The observed nonlinear PK/TO/PD relationship was well captured by mechanistic modeling framework within a wide dose range of TAK-831 in mice. Remarkably different brain distribution was observed between target and reference regions, suggesting that the target-mediated slow binding kinetics rather than slow penetration through the blood brain barrier caused the observed distinct kinetics between PK and TO.
Conclusion
A quantitative mechanistic model for concentration- and time-dependent nonlinear PK/TO/PD relationship was established for TAK-831 in mice with accounting for possible rate-determining process. The established mechanistic modeling framework will provide a quantitative means for multilayer biomarker-assisted clinical development in multiple central nervous system indications.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
N-methyl-
d
-aspartate (NMDA) receptor hypofunctionality is a well-studied hypothesis for schizophrenia pathophysiology, and daily dosing of the NMDA receptor co-agonist,
d
-serine, in clinical ...trials has shown positive effects in patients. Therefore, inhibition of
d
-amino acid oxidase (DAAO) has the potential to be a new therapeutic approach for the treatment of schizophrenia. TAK-831 (luvadaxistat), a novel, highly potent inhibitor of DAAO, significantly increases
d
-serine levels in the rodent brain, plasma, and cerebrospinal fluid. This study shows luvadaxistat to be efficacious in animal tests of cognition and in a translational animal model for cognitive impairment in schizophrenia. This is demonstrated when luvadaxistat is dosed alone and in conjunction with a typical antipsychotic. When dosed chronically, there is a suggestion of change in synaptic plasticity as seen by a leftward shift in the maximum efficacious dose in several studies. This is suggestive of enhanced activation of NMDA receptors in the brain and confirmed by modulation of long-term potentiation after chronic dosing. DAAO is highly expressed in the cerebellum, an area of increasing interest for schizophrenia, and luvadaxistat was shown to be efficacious in a cerebellar-dependent associative learning task. While luvadaxistat ameliorated the deficit seen in sociability in two different negative symptom tests of social interaction, it failed to show an effect in endpoints of negative symptoms in clinical trials. These results suggest that luvadaxistat potentially could be used to improve cognitive impairment in patients with schizophrenia, which is not well addressed with current antipsychotic medications.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Irregular
N
-methyl-
d
-aspartate receptor (NMDAR) function is one of the main hypotheses employed to facilitate understanding of the underlying disease state of schizophrenia. Although direct ...agonism of the NMDAR has not yielded promising therapeutics, advances have been made by modulating the NMDAR co-agonist site which is activated by glycine and
d
-serine. One approach to activate the co-agonist site is to increase synaptic
d
-serine levels through inhibition of
d
-amino acid oxidase (DAO), the major catabolic clearance pathway for this and other
d
-amino acids. A number of DAO inhibitors have been developed but most have not entered clinical trials. One exception to this is sodium benzoate which has demonstrated efficacy in small trials of schizophrenia and Alzheimer’s disease. Herein we provide data on the effect of sodium benzoate and an optimised Takeda compound, PGM030756 on ex vivo DAO enzyme occupancy and cerebellar
d
-serine levels in mice. Both compounds achieve high levels of enzyme occupancy; although lower doses of PGM030756 (1, 3 and 10 mg/kg) were required to achieve this compared to sodium benzoate (300, 1000 mg/kg). Cerebellar
d
-serine levels were increased by both agents with a delay of approximately 6 h after dosing before the peak effect was achieved. Our data and methods may be useful in understanding the effects of sodium benzoate that have been seen in clinical trials of schizophrenia and Alzheimer’s disease and to support the potential clinical assessment of other DAO inhibitors, such as PGM030756, which demonstrate good enzyme occupancy and
d
-serine increases following administration of low oral doses.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract Serotonin-1A receptors may play a role in the pathophysiology of depression and suicide. In postmortem brain tissue, agonist binding to serotonin-1A receptors is reportedly increased or ...unchanged in depression or suicide, while neuroimaging studies report a decrease in antagonist binding to these receptors in subjects with depression. In this study, both agonist and antagonist radioligand binding to serotonin-1A receptors were examined in postmortem orbitofrontal cortex from subjects with major depressive disorder (MDD). Brain tissue was collected at autopsy from 11 subjects with MDD and 11 age- and gender-matched normal control subjects. Two depressed subjects had a recent psychoactive substance use disorder. Six subjects with MDD had a prescription for an antidepressant drug in the last month of life, and, of these six, postmortem bloods from only two subjects tested positive for an antidepressant drug. There was no significant difference between cohorts for age, postmortem interval or tissue pH. The receptor agonist 3 H8-OH-DPAT or the antagonist 3 HMPPF were used to autoradiographically label serotonin-1A receptors in frozen sections from cytoarchitectonically-defined left rostral orbitofrontal cortex (area 47). There was no significant difference between depressed and control subjects in agonist binding to serotonin-1A receptors. However, antagonist binding was significantly decreased in outer layers of orbitofrontal cortex in MDD. This observation in postmortem tissue confirms reports using an antagonist radioligand in living subjects with depression. Decreased antagonist binding to serotonin-1A receptors in outer layers of orbitofrontal cortex suggests diminished receptor signaling and may be linked to corresponding neuronal changes detected previously in these depressed subjects.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Display omitted
Herein we describe a series of tetrahydrobenzotriazoles as novel, potent metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of the ...SAR surrounding the tetrahydrobenzotriazole core ultimately led to the identification of 29 as a potent mGlu5 PAM with a low maximal glutamate potency fold shift, acceptable in vitro DMPK parameters and in vivo PK profile and efficacy in the rat novel object recognition (NOR) assay. As a result 29 was identified as a suitable compound for progression to in vivo safety evaluation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Key Summary Points
Aim
To examine changing trends in presentation of older people to the emergency department during the COVID-19 pandemic compared to 2018/2019.
Findings
On average 4 fewer people ...aged ≥70 years presented to the ED in the first 6 months of the COVID-19 pandemic (March-August 2020). There was a 20% reduction in presentations of stroke and cardiac complaints but a 25% increase in falls/injuries following easing of lockdown restrictions.
Message
It is imperative that we consider enabling strategies to ensure older people access unscheduled care in a timely manner when necessary.
Purpose
Reports suggest that many older people deferred seeking healthcare during the COVID-19 pandemic due to fear of contracting COVID-19. The aim of this study was to examine trends of emergency department (ED) use by older people during the first wave of the COVID-19 pandemic compared to previous years.
Methods
The study site is a 1000-bed university teaching hospital with annual ED new-patient attendance of > 50,000. All ED presentations of patients aged ≥ 70 years from March to August 2020, 2019 and 2018 inclusive (
n
= 13,989) were reviewed and compared for presenting complaint, Manchester Triage Score, and admission/discharge decision.
Results
There was a 16% reduction in presentations across the 6 months in 2020 compared to the average of 2018/2019. On average, 4 fewer people aged ≥ 70 years presented to the ED per day in 2020. Much of this was concentrated in March (33% fewer presentations) and April (31% fewer presentations), when the country was in ‘lockdown’, i.e. non-essential journeys were banned. There was a 20% reduction in patients presenting with stroke and cardiac complaints. In the 3 months following easing of restrictions, there was a 25% increase in falls and orthopaedic injuries when compared to 2018/2019.
Conclusion
This study demonstrates a significant decline in the number of older people presenting to the ED for unscheduled care, including for potentially time-dependent illnesses such as stroke or cardiac complaints. Given the possibility of further lockdowns, it is imperative that we consider enabling strategies to ensure older people access unscheduled care in a timely manner when necessary.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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