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Combination of gaboxadol and lithium for treatment of psychiatric disorders

A technology of gaboxadol and composition, which is applied in the field of composition for treating mental disorders, and can solve problems such as acute toxicity of infants

Pending Publication Date: 2022-02-18
CERTEGO THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, close monitoring of serum lithium levels is essential because, as the patient's renal function returns to a lower glomerular filtration rate postpartum, an associated increase in serum lithium levels can lead to acute toxicity in both the mother and infant ( Horton et al., 2012; Wesseloo et al., 2017)

Method used

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  • Combination of gaboxadol and lithium for treatment of psychiatric disorders
  • Combination of gaboxadol and lithium for treatment of psychiatric disorders
  • Combination of gaboxadol and lithium for treatment of psychiatric disorders

Examples

Experimental program
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Effect test

Embodiment 1

[0305] Example 1: Whole Brain Drug Screening Platform

[0306]Many preclinical trials are currently being used to try to elucidate or predict the clinical effects of new drugs on the brain. These include in vitro high-content screening (HCS) assays that measure the pharmacokinetics of drugs against specific molecular targets and their effects in simple cellular assays, at relatively low resolution (PET / CT, PET / MRI, fMRI) or at high cellular Resolution (electrophysiological or two-photon imaging) in vivo assays that measure local responses, and behavioral assays that measure animal performance in various tasks (Jain and Heutink, 2010; Judenhofer et al., 2008; Markou et al., 2009). Despite the considerable effort invested in preclinical research, the clinical effects of drugs remain unpredictable, plaguing the drug development pipeline and resulting in clinical trial failure rates exceeding 90% (Pammolli et al., 2011).

[0307] To assess neuronal activity in regions that are di...

Embodiment 2

[0312] Example 2: Mapping Brain Activation Under Therapeutic Effects of Lithium in Psychiatry

[0313] To understand the mechanism of action of lithium in the whole brain, the pharmacodynamic mapping technique described above was used to map lithium-induced brain activation in response to the following doses (mg / kg) in mice: 120, 150, 200, and 300, which are approximately equivalent to Human equivalent dose (mg): 600, 750, 1000 and 1500. These experiments revealed dose-dependent increases in brain activation patterns, including modest activation of some structures at 120 and 150 mg / kg and fairly widespread activation at 200 and 400 mg / kg ( figure 2 ). The activation pattern observed with lithium doses of 120 and 150 mg / kg included the anterior portion of the bed nucleus of the stria terminalis (BSTa), the central amygdala (CEA), and the anterior portion of the locus coeruleus (LC) ( figure 2 , top row). In addition to the anterior limbic (PL) and inferior limbic (ILA) cor...

Embodiment 3

[0314] Example 3: Lithium-induced c-fos activation pattern closely matches that of the GABA-A agonist gaboxadol

[0315] The effects of lithium on the mouse brain mapped using the pharmacodynamic mapping platform described above can be directly compared to lithium-induced brain activation patterns and those of other test compounds. Strikingly, the pharmacodynamic pattern evoked by the high dose of 300mg / kg lithium closely matched that of 20mg / kg gaboxadol, including the following c-fos activation: 1) broad cortical activation including exercise (MO), Gustatory (GU), associated visceral (VISC), agranular insula (AI), somatosensory (SS), auditory, visual (VIS), auditory (AUD), anterior (PL) and inferior (ILA), postpressor (RSP), parietal lobe (PTL), temporal association (TEa), extorhinal (ECT), entorhinal (ENT), perirhinal (PERI), piriform (PIR) and anterior cingulate (ACA) cortices, claustrum (CLA), and 2) subcortical activation, including the CA1 region of the hippocampus, th...

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Abstract

The disclosure reports on the discovery that low dose lithium can act in synergy with gaboxadol to enhance lithium's action on brain signaling activity. The combination of lithium and gaboxadol may greatly reduce the amount of lithium needed to treat many debilitating psychiatric disorders, such as bipolar disorder, depression, treatment resistant depression and suicidality, while reducing the often-serious side effects associated with high dose and chronic lithium treatment, especially ephrotoxicity, nephrogenic diabetes insipidus and chronic kidney disease. Co-administration of gaboxadol and lithium may also be useful for the treatment of refractory bipolar disorder, i.e. bipolar disorder which cannot be treated appropriately by administration of lithium alone. Gaboxadol may also prove useful as add-on therapy for the augmentation of the response to lithium in patients that do not respond to conventional lithium monotherapy.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to Provisional Patent Application No. 62 / 770,287, filed November 21, 2018, and Provisional Patent Application No. 62 / 879,921, filed July 29, 2019, the contents of which are hereby incorporated by reference in their entirety . technical field [0003] The present invention relates to compositions and methods for the treatment of psychiatric disorders utilizing the synergistic combination of lithium and gaboxadol. Background technique [0004] Lithium has been a first-line treatment for mood stabilization and reduction of suicidality in bipolar disorder (BD) since the 1960s according to clinical practice guidelines, providing acute antimanic remission and prevention of BD relapse in countless BD patients (Baldessarini et al, 2006 ; Cipriani et al., 2013; Kessi ng et al., 2018; Roberts et al., 2017; Sani et al., 2017; Severus et al., 2014). However, despite lithium's widespread use, it ...

Claims

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Application Information

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IPC IPC(8): A61K33/00A61K31/437A61P25/24A61P25/00A61P13/12A61P13/00A61P1/08A61P25/28A61P21/00A61P17/14A61P17/10A61P43/00
CPCA61K31/437A61K33/24A61P25/24A61P25/18A61K2300/00A61K33/00A61K31/407
Inventor 帕维尔·奥斯滕克里斯廷·鲍德温罗伯特·德维塔
Owner CERTEGO THERAPEUTICS
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