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Methods of using (2r, 6r)-hydroxynorketamine and (2s, 6s)-hydroxynorketamine in treatment of depression, anxiety, anhedonia, suicidal ideation, and post traumatic stress disorders

A depressive disorder, anxiety disorder technique for use with (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, fatigue, suicidal ideation and post-traumatic stress In the field of arousal disorders, it can solve problems such as no response, response to antidepressant effects, etc.

Inactive Publication Date: 2019-03-15
US DEPT OF HEALTH & HUMAN SERVICES +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Also, some patients respond to the antidepressant effects of ketamine but not to SSRIs or other antidepressants

Method used

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  • Methods of using (2r, 6r)-hydroxynorketamine and (2s, 6s)-hydroxynorketamine in treatment of depression, anxiety, anhedonia, suicidal ideation, and post traumatic stress disorders
  • Methods of using (2r, 6r)-hydroxynorketamine and (2s, 6s)-hydroxynorketamine in treatment of depression, anxiety, anhedonia, suicidal ideation, and post traumatic stress disorders
  • Methods of using (2r, 6r)-hydroxynorketamine and (2s, 6s)-hydroxynorketamine in treatment of depression, anxiety, anhedonia, suicidal ideation, and post traumatic stress disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0253] Example 1. Ketamine, ketamine enantiomers and desipramine in an antidepressant model.

[0254] Comparison of ketamine and the classic tricyclic antidepressant dexime in male CD-1 mice in the forced swim test at 1 hour (acute) and 24 hour (sustained) time points (forced swim test (FST); Figure 1a) Antidepressant effects of Parmin. Administration of ketamine at a dose of 10 mg / kg resulted in an acute and long-lasting dose-dependent antidepressant effect in the FST, whereas desipramine reduced immobility time only 1 h after injection.

[0255] To elucidate whether NMDA inhibition is the main mechanism for the antidepressant effect of ketamine, the effects of ketamine and the noncompetitive NMDA receptor antagonist MK-801 in FST were compared, and acute antidepressant responses of ketamine and MK-801 were observed. Only ketamine showed a sustained effect after 24 hours (Fig. 1e). In addition, the effects of the ketamine enantiomers (S)- and (R)-ketamine on the FST (Fig. 1...

Embodiment 2

[0258] Example 2. Metabolism and autonomic movement experiments of ketamine

[0259] Ketamine is stereoselectively metabolized to a broad series of metabolites, including norketamine, hydroxyketamine (HK), HNK, and dehydronorketamine (DHNK) (Fig. 1f, Fig. 5). After ketamine administration, (2S,6S; 2R,6R)-HNK was the major metabolite found in mouse plasma and brain and human plasma (Fig. 6a, 6b).

[0260] To directly determine whether ketamine's metabolism of (2S,6S;2R,6R)-HNK is required for its antidepressant effects, ketamine was deuterated at the C6 position (6,6-dideuterioketamine). Deuteration blocks the metabolism of ketamine to the metabolites, 2S,6S-HNK and 2R,6R-HNK.

[0261] Indeed, 6,6-dideuterioketamine did not alter or NMDA-mediated hypermobility (Fig. 8c, 8d), but strongly hindered its metabolism to (2S,6S; 2R,6R)-HNK without altering ketamine in Levels in the brain (Fig. 2a-2c). Unlike ketamine, administration of 6,6-dideuterioketamine did not induce antidepr...

Embodiment 3

[0262] Example 3. Ketamine, Ketamine Enantiomers, and (2S,6S; 2R,6R)-HNK in Antidepressant Models

[0263] To investigate whether these sex-dependent antidepressant differences are explained by different pharmacokinetic profiles of ketamine in males versus females, the levels of ketamine and its metabolites were measured in the brain and plasma of ketamine-injected mice. (2S,6S; 2R,6R)-HNK was the major HNK metabolite found in mouse plasma and brain and in human plasma (Fig. 6a, 6b). Figure 1g shows that ketamine has higher antidepressant potency in female mice, similar to previous evidence showing enhanced ketamine antidepressant responses in female rats compared with male rats. These differences were not associated with sex differences in ketamine-induced hyperlocomotion, which may be mediated by NMDAR inhibition (Fig. 8a, 8b).

[0264] To investigate whether these sex-dependent antidepressant differences were predicted by different pharmacokinetic profiles of ketamine in mal...

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Abstract

Disclosed is a method of treating Psychotic Depression, Suicidal Ideation, Disruptive Mood Dysregulation Disorder, Persistent Depressive Disorder (Dysthymia), Premenstrual Dysphoric Disorder, Substance / Medication-Induced Depressive Disorder, Depressive Disorder Due to Another Medical Condition, Other Specified Depressive Disorder, Unspecified Depressive Disorder, Separation Anxiety Disorder, Selective Mutism, Specific Phobia, Social Anxiety Disorder (Social Phobia), Panic Disorder, Panic Attack (Specifier), Agoraphobia, Generalized Anxiety Disorder, Substance / Medication-Induced Anxiety Disorder, Anxiety Disorder Due to Another Medical, Other Specified Anxiety Disorder, Unspecified Anxiety Disorder, or fatigue, the method including administering a pharmaceutical composition containing an effective amount of an active agent, wherein the active agent is purified (2R,6R)-hydroxynorketamine, purified (2S,6S)-hydroxynorketamine, or a combination thereof, or a pharmaceutically acceptable saltthereof, together with a pharmaceutically acceptable carrier to a patient in need of such treatment.

Description

[0001] Citations to related applications [0002] This application claims priority to, and all benefits derived from, U.S. Provisional Patent Application No. 62 / 313,317, filed March 25, 2016, in the U.S. Patent and Trademark Office, the contents of which are incorporated by reference in their entirety under 35 U.S.C. §119 Incorporated into this article. [0003] Statement of Government Support [0004] This invention was made with Government support under Grant No. NH099345 awarded by the National Institutes of Health. The US Government has certain rights in this invention. Background technique [0005] Ketamine, a drug currently used in human anesthesia and veterinary medicine, has been shown in clinical studies to be effective in the treatment of a variety of conditions, including treatment-resistant bipolar depression, major depressive disorder, anhedonia, fatigue, and suicidal ideation. [0006] However, ketamine is only approved for use as an anesthetic. Use of drugs ...

Claims

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Application Information

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IPC IPC(8): A61K31/135A61P25/28A61P25/24
CPCA61K31/135A61P25/24
Inventor 欧文·魏纳卡洛斯·萨拉特鲁因·莫阿德尔托德·古尔德帕诺斯·萨诺斯克雷格·托马斯帕特里克·莫里斯
Owner US DEPT OF HEALTH & HUMAN SERVICES
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