Compositions and methods for ameliorating CNS inflammation, psychosis, delirium, PTSD or PTSS

Patent metadata

Field	Value
Publication number	US-10407374-B2
Application number	US-201815953083-A
Country	US
Kind code	B2
Filing date	Apr 13, 2018
Priority date	Oct 19, 2007
Publication date	Sep 10, 2019
Grant date	Sep 10, 2019

Abstract

The invention provides compositions and methods for ameliorating, treating, reversing or preventing pathology or inflammation in the central nervous system (CNS), or the brain, caused or mediated by NFkB, IL-6, IL-6-R, NADPH oxidase (Nox), and/or superoxide and/or hydrogen peroxide production by a NADPH oxidase, including for example ameliorating, treating, reversing or preventing schizophrenia, psychosis, delirium, e.g., post-operative delirium, drug-induced psychosis, psychotic features associated with frailty syndrome (FS), aging, depression, dementias; traumatic war neurosis, post traumatic stress disorder (PTSD) or post-traumatic stress syndrome (PTSS), Amyotrophic Lateral Sclerosis (ALS, or Lou Gehrig's Disease), and/or Multiple Sclerosis (MS). The invention also provides methods for purifying a C60 fullerene, C3 (tris malonic acid C60) or malonic acid derivatives.

First claim

What is claimed is:

1. A method of:
decreasing superoxide and/or hydrogen peroxide levels in a cell, or,
inhibiting or decreasing the level of activation or activity of an NFkB, an IL-6, an IL-6-R, or an NADPH oxidase, comprising
(a) providing a C60 malonic acid derivative; and
(b) administering the C60 malonic acid derivative to the cell, wherein optionally the administering is in vitro or in vivo.

2. The method of claim 1 , wherein administering the C60 malonic acid derivative in vivo to an individual in need thereof treats, ameliorates, slows the progress of or reverses: a schizophrenia; a psychosis; a delirium, optionally a post-operative delirium; a drug-induced psychosis or a psychotic feature; frailty syndrome (FS), a cognitive impairment, or a learning or memory impairment, resulting from or associated with frailty syndrome (FS), aging, depression, dementia; a traumatic war neurosis; a post traumatic stress disorder (PTSD) or a post-traumatic stress syndrome (PTSS); Amyotrophic Lateral Sclerosis (ALS, or Lou Gehrig's Disease); Multiple Sclerosis (MS); a cognitive, learning or memory impairment; a CNS inflammation, optionally a CNS inflammation resulting from a trauma or an inflammation, optionally an inflammation from a CNS infection; Alzheimer's disease; Lewy Body Disease; Parkinson's Disease; Huntington's Disease; a dementia, optionally a multi-infarct dementia (vascular dementia) or a senile dementia; or, Frontotemporal Dementia (Pick's Disease).

3. The method of claim 1 , wherein administering the C60 malonic acid derivative in vivo to an individual in need thereof: treats, ameliorates, slows the progress of, abates, prevents or reverses: neuron damage, CNS damage or brain damage in an individual having frailty syndrome (FS), aging, an injury, a pathology, a disease, an infection, a condition causing and/or associated with an increased amount of CNS inflammation and/or CNS oxidative stress; or accelerating the recovery of CNS neuron or brain damage in individuals having an injury, a pathology, an Amyotrophic Lateral Sclerosis (ALS, or Lou Gehrig's Disease), Multiple Sclerosis (MS)), and/or cognitive, learning or memory impairments resulting therefrom, a disease, an infection and/or a condition causing and/or associated with an increased amount of CNS inflammation and/or CNS oxidative stress, and/or cognitive, learning or memory impairments resulting therefrom.

4. The method of claim 1 , wherein the C60 malonic acid derivative is formulated as a pharmaceutical formulation, and optionally the pharmaceutical formulation is formulated for delivery to the CNS, or brain or a CNS neural cell, or for passing through the blood brain barrier (BBB).

5. The method of claim 1 , wherein the C60 malonic acid derivative is formulated for delivery to a parvalbum in-positive GABA-ergic interneuron.

6. The method of claim 1 , further comprising administration of a small molecule, wherein optionally the small molecule comprises an o-methoxycatechol, an apocynin, a diapocynin, 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF), 4-hydroxy-3′-methoxy-acetophenon, N-Vanillylnonanamide, staurosporine or a combination thereof.

7. A method of protecting the function of, or maintaining the level of activation or activity of cortical inhibitory inhibitory neurons, or parvalbum in-positive GABA-ergic interneurons comprising:
contacting the cortical inhibitory inhibitory neurons, or parvalbumin-positive GABA-ergic interneurons in vitro with a composition comprising a superoxide dismutase mimetic that is capable of decreasing superoxide and/or hydrogen peroxide levels,
wherein the superoxide dismutase mimetic comprises a C60 fullerene, C3 tris malonic acid C60 fullerene or a malonic acid derivative.

8. The method of claim 1 , wherein the C60 malonic acid (propanedioic acid) derivative is purified by a method comprising:
(i)
(a) dissolving an impure powder form of a C60 malonic acid derivative in a dilute sodium hydroxide (NaOH) solution at a concentration of between about 1 mM to 400 mM at about 4 degrees C. with stirring, wherein optionally the C60 malonic acid derivative is or comprises a C3 tris malonic acid C60 fullerene or a C60 macrocyclic malonate derivative, and optionally the malonate is functionalized with a halide atom, or malonate ester groups are replaced by alkyne groups, optionally as a dialkynylmethanofullerene;
(b) adding a second solution of NaOH more concentrated than the dilute NaOH solution in step (a) drop-wise to the solution of step (a) to achieve an approximately neutral pH;
(c) incubating the solution of step (b) at 4 degrees C. in the dark for approximately 0.5 to 3 hours;
(d) centrifuging the solution after the incubating of step
(c) to produce a clear dark red supernatant and a solid light pink pellet;
(e) removing the supernatant to a different container;
(f) incubating the supernatant removed in step (e) at 4 degrees C. for an additional about 3 to 4 hours; and
(g)
(1) re-centrifuging to remove substantially all or all undissolved material to generate a pellet and a solution comprising purified C3 tris malonic acid C60 fullerene, wherein the pellet comprises an insoluble waxy material containing contaminant and small amounts of residual C3 tris malonic acid C60 fullerene, or
(2) filtering the sample through a filter which allows only aqueous solutions to pass, thereby removing an insoluble waxy contaminant after solubilization in dilute NaOH, thereby generating a solution comprising purified C3 tris malonic acid C60 fullerene; or

(ii) the method of (i), wherein the purified C3 solution is further treated to remove a minor amount of volatile contaminant by vacuum distillation or by bubbling an inert gas through the solution.

9. The method of claim 1 , wherein the C60 malonic acid (propanedioic acid) derivative is purified by a method comprising:
(i)
(a) providing a solution comprising an impure powder form of a C60 malonic acid derivative, wherein optionally the C60 malonic acid derivative is or comprises a C 3 tris malonic acid C60 fullerene or a C60 macrocyclic malonate derivative, and optionally the malonate is functionalized with a halide atom, or malonate ester groups are replaced by alkyne groups, optionally as a dialkynylmethanofullerene;
(b) providing an antibody directed against a C60 fullerene or a C60 malonic acid derivative, wherein optionally the C60 malonic acid derivative is a C 3 tris malonic acid C60 fullerene; and
(c) isolating the C60 fullerene or the C60 malonic acid derivative by incubating the antibody with the C60 fullerene or the C60 malonic acid derivative under conditions wherein the antibody specifically binds to the C60 fullerene, or the C60 malonic acid derivative; or

(ii) the method of (i), wherein an antibody-C60 fullerene complex or an antibody-C 3 tris malonic acid C60 fullerene or antibody-malonic acid derivative complex is purified by gel electrophoresis purification, HPLC, immunoprecipitation, column chromatography, differential centrifugation or affinity column chromatography.

10. The method of claim 1 , wherein the C60 malonic acid derivative is or comprises a C3 tris malonic acid C60 fullerene or a C60 macrocyclic malonate derivative.

11. The method of claim 1 , wherein the malonate derivative is functionalized with a halide atom, or malonate ester groups are replaced by alkyne groups, and optionally the malonate derivative is dialkynylmethanofullerene.

12. The method of claim 7 , wherein the malonic acid derivative is or comprises a macrocyclic malonate compound.

13. The method of claim 7 , wherein the malonate is functionalized with a halide atom, or malonate ester groups are replaced

Assignees

• Univ California

Inventors

• Dugan Laura L
• Behrens Marie Margarita
• Ali Sameh

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07C51/47 Primary

  by solid-liquid treatment; by chemisorption · CPC title

• A61K31/194

  having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid · CPC title

• C07K16/2866

  against receptors for cytokines, lymphokines, interferons · CPC title