Method of treating neurological diseases and etiologically related symptomology using carbonyl trapping agents in combination with medicaments

• US 6,746,678 B1
• Filed: 04/06/2000
• Issued: 06/08/2004
• Est. Priority Date: 02/22/1991
• Status: Expired due to Fees

• Current Assignee: SECANT MEDICAL, LLC (Compagnie Generale DES Etablissements Michelin SCA)
• Original Assignee: Howard K. Shapiro
• Inventors: Shapiro, Howard K.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): FUBARA, BLESSING M
• Application Number:
  US09/545,870
• Time in Patent Office: 1,524 Days
• Field of Search: 424/78.08, 424/464, 424/451, 424/400, 514/150, 514/565, 514/561, 514/567
• US Class Current: 424/400
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 31/185 Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids hydroxamic acids A61K31/16; peroxy acids A61K31/327
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/455 Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
• CPC Class Codes: A61K 31/60 Salicylic acid; Derivatives thereof
• CPC Class Codes: A61K 31/621 having the hydroxy group in position 2 esterified, e.g. benorylate
• CPC Class Codes: A61K 31/63 Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
• CPC Class Codes: A61K 31/785 Polymers containing nitrogen
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: G01N 33/6896 Neurological disorders, e.g. Alzheimer's disease

Abstract

This invention defines a novel method for treatment of several neurological diseases and pathophysiologically related symptomology, said diseases including peripheral neuropathies, secondary symptomology of diabetes, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, alcoholic polyneuropathy and age-onset symptomology, as well as analogous veterinary disease states. An opportunity exists for pharmacological intervention in some neurological diseases by use of water soluble, small molecular weight primary amine agents and chemical derivatives thereof. Examples of such primary pharmacological agents include 4-aminobenzoic acid and derivatives thereof. The present invention also includes: (1) oral use of optional non-absorbable polyamine polymeric co-agents such as chitosan, (2) oral use of optional known antioxidant co-agents and nutritional factors related thereto, and (3) use of the primary agents and co-agents noted above in optional combination with medicaments recognized as effective for treatment of the diseases addressed herein or symptoms thereof.

Claims

1. A method of treating the underlying biochemical symptoms of neurological diseases in a mammal, said method comprising a systemic administration of a composition consisting essentially of (a) at least one required primary agent administered orally to said mammal in a therapeutically effective amount in a dosage range of from about 15 mg/kg/day to about 450 mg/kg/day, said required primary agent being a pharmaceutically acceptable salt, free acid or pharmaceutically acceptable ester of the phenyl, cyclohexadiene, cyclohexene or cyclohexane carboxylic acid chemical structure of the formula

wherein

R₁ is selected from the group consisting of —

NH₂;

ε

-aminoalkyl having 1-10 carbons linear or branched and hydroxylated derivatives of this structure;

—

NHC(═

NH)NH₂;

—

(CH₂)_nNHC(═

NH)NH₂ wherein n is 1-10 hydrocarbons linear or branched and hydroxylated derivatives of this structure;

—

C(═

NH)NH₂;

—

(CH₂)_n—

CH═

NH(═

NH)NH₂ wherein n is 1-10 hydrocarbons linear or branched and hydroxylated derivatives of this structure;

—

NHC(═

NH)NHNH₂;

—

(CH₂)_nNHC(═

NH)NHNH₂ wherein n is 1-10 hydrocarbons linear or branched and hydroxylated derivatives of this structure;

—

(CH₂)_n—

CH═

NC(═

NH)NHNH₂ wherein n is 1-10 hydrocarbons linear or branched and hydroxylated derivatives of this structure;

—

NHNHC(═

NH)NH₂;

—

(CH₂)_nNHNHC(═

NH)NH₂ wherein n is 1-10 hydrocarbons linear or branched and hydroxylated derivatives of this structure; and

—

(CH₂)_n—

CH═

N—

NHC(═

NH)NH₂ wherein n is 1-10 hydrocarbons linear or branched and hydroxylated derivatives of this structure;

R₂ is selected from the group consisting of H;

—

NH₂;

—

OH;

—

O—

CH₃;

—

OR′

wherein R′

is alkyl of 2-10 hydrocarbons linear or branched and hydroxylated derivatives of this structure;

ε

-aminoalkyl wherein the alkyl group is 1-10 hydrocarbons linear or branched and hydroxylated derivatives of this structure;

—

SO₃H;

—

CH₃; and

—

(CH₂)_nCH₃ wherein n is 1-10 hydrocarbons linear or branched and hydroxylated derivatives of this structure; and

R′ and

R″

are H, —

OH or —

CH₃; and

m is 0 or 1;

(b) optionally in combination with a therapeutically effective amount of one or more additional co-agent selected from the group consisting of non-absorbable polyamine carbonyl trapping substances, antioxidants, vitamins, metabolites at risk of depletion, sulfhydryl substance co-agents and co-agents which may facilitate glutathione activity;

(c) optionally in combination with one or more co-agent medicament in an amount effective to treat the neurological disease;

said composition furthermore optionally including (d) a pharmaceutically acceptable carrier suitable for the orally administered component thereof wherein the carrier is selected from the group consisting of carboxymethyl cellulose, microcrystalline cellulose, cellulose, starch, dicalcium phosphate, tricalcium phosphate, stearic acid, magnesium stearate, silica, soy flour, watercress, yeast, alfalfa, parseley, lecithin, rice bran, gum tragacanth, gum guar, gum agar, gum arabic, gum carrageenan, gum ghatti, gum karaya, locust bean gum, gum mastic, gum mesquite and gum xanthan, which may include all of the ingredients of said composition; and

said composition furthermore optionally including (e) a pharmaceutically acceptable carrier suitable for systemic administration by the intravenous, intramuscular or subcutaneous route of one or more co-agent medicament.

2. The method of claim 1 for treating a human suffering from the symptomology of a neurodegenerative disease, wherein said disease is selected from the group consisting of hereditary motor and sensory neuropathies;

diabetic polyneuropathy;

Alzheimer'"'"'s presenile dementia;

Alzheimer'"'"'s senile dementia;

Down'"'"'s syndrome;

Parkinson'"'"'s disease;

amyotrophic lateral sclerosis;

age-related atrophy of peripheral sensory and motor nerves;

age-related atrophy of autonomic nerves resulting in symptoms of hypoperistalisis of the alimentary tract, hiatal hernia, partial food regurgitation, urinary incontinence, breathing insufficiency due to diaphram weakness or decreased autonomic sexual function;

age-related atrophy of neurons of the central nervous system;

age-onset pathophysiologically related changes in the kidney, optic lens and cardiovascular system, atherosclerosis and symptoms related thereto;

alcoholic polyneuropathy;

multiple sclerosis;

olivopontocerebellar atrophy and Huntington'"'"'s disease;

said method comprising administering to said human a therapeutically effective amount of a composition of claim 1 sufficient to treat said human for said symptomology.

3. The method according to claim 2 wherein the disease is Alzheimer'"'"'s senile dementia.

4. The method according to claim 2 wherein the disease is Alzheimer'"'"'s presenile dementia.

5. The method according to claim 2 wherein the disease is a hereditary motor and sensory neuropathy.

6. The method according to claim 2 wherein the disease is Down'"'"'s syndrome.

7. The method according to claim 2 wherein the disease is diabetic polyneuropathy.

8. The method according to claim 2 wherein the disease is Parkinson'"'"'s disease.

9. The method according to claim 2 wherein the disease is amyotrophic lateral sclerosis.

10. The method according to claim 2 wherein the disease is age-related atrophy of peripheral sensory and motor nerves.

11. The method according to claim 2 wherein the disease is age-related atrophy of autonomic nerves resulting in symptoms of hypoperistalisis of the alimentary tract, hiatal hernia, partial food regurgitation, urinary incontinence, breathing insufficiency due to diaphram weakness or decreased autonomic sexual function.

12. The method according to claim 2 wherein the disease is age-related atrophy of neurons of the central nervous system.

13. The method according to claim 2 wherein the disease is age-onset pathophysiologically related changes in the kidney, optic lens and cardiovascular system.

14. The method according to claim 2 wherein the disease is atherosclerosis.

15. The method according to claim 2 wherein the disease is alcoholic polyneuropathy.

16. The method according to claim 2 wherein the disease is multiple sclerosis.

17. The method according to claim 2 wherein the disease is olivopontocerebellar atrophy.

18. The method according to claim 2 wherein the disease is Huntington'"'"'s disease.

19. The method of claim 1 for treatment of a mammal, wherein said mammal is a human, said method comprising administering to said human a therapeutically effective amount of an optional non-absorbable polyamine carbonyl trapping substance co-agent sufficient to treat said human wherein said co-agent is selected from the group consisting of:

a. naturally occurring polysaccharides having β

-1,2, β

-1,3, β

-1,4 and/or β

-1,6 linkages containing aminosugars;

b. deacetylated. naturally occurring polysaccharides, having at least one N-acetylated residue;

c. chemically aminated polysaccharides selected from the group consisting of;

aminodeoxy polysaccharides;

aminoalkyl-, amino(hydroxyalkyl)-, aminoalkyl-ether-, and amino(hydroxyalkyl)-ether-derivatives of cellulose, chitin and other naturally occurring non-digestible carbohydrates selected from the group consisting of

H₂N—

(CH₂)_n-[carbohydrate] where n=1-10;

H₂N—

(CH₂)_n—

CHOH—

(CH₂)_n-[carbohydrate], where m=0-10 and n=0-10;

H₂N—

(CH₂)_n—

O-[carbohydrate] where n=1-10;

H₂N—

(CH₂)_n—

CHOH—

(CH₂)_n—

O-[carbohydrate] where m=0-10 and n=0-10;

aminobenzyl-derivatives of cellulose, chitin or other naturally occurring non-digestible carbohydrates selected from the group consisting of

H₂N—

C₆H₄—

(CH₂)_n-[carbohydrate],

H₂N—

CH₂—

C₆H₄—

(CH₂)_n-[carbohydrate],

H₂N—

C₆H₄—

(CH₂)_n—

O-[carbohydrate] where n=0-10, and

H₂N—

C₆H₄—

(CH₂)_n—

CHOH—

(CH₂)_n—

O-[carbohydrate] where m=0-10 and n=0-10, including p-, o- and m-benzene ring amino- and aminomethyl-isomers, and alkyl group isomers;

guanidine and aminoguanidine derivatives of cellulose, chitin or other naturally occurring non-absorbable carbohydrates selected from the group consisting of;

H₂N—

C(═

NH )-[carbohydrate];

H₂N—

C(═

NH)—

(CH₂)_n-[carbohydrate], where n=1-10, including hydrocarbon isomers and hydroxylated derivatives thereof;

H₂N—

C(═

NH)—

O—

(CH₂)_n-[carbohydrate], where n=1-10, including hydrocarbon isomers, ether linkage isomers and hydroxylated derivatives thereof;

H₂N—

C(═

NH)—

NH-[carbohydrate];

H₂N—

C(═

NH)—

NH—

(CH₂)_n-[carbohydrate], where n=1-10, including hydrocarbon isomers and hydroxylated derivatives thereof;

H₂N—

C(═

NH)—

NH—

(CH₂)_n-O-[carbohydrate], where n=1-10, including hydrocarbon isomers, ether linkage isomers and hydroxylated derivatives thereof;

H₂N—

C(═

NH)—

N═

CH—

(CH₂)_n-[carbohydrate], where n=1-10, including hydrocarbon isomers and hydroxylated derivatives thereof;

H₂N—

C(═

NH)—

N═

CH—

(CH₂)_n—

O-[carbohydrate], where n=1-10, including hydrocarbon isomers and hydroxylated derivatives thereof;

H₂N—

NHC(═

NH)—

NH-[carbohydrate];

H₂N—

NHC(═

NH)—

NH—

(CH₂)_n-[carbohydrate], where n=1-10, including hydrocarbon isomers and hydroxylated derivatives thereof;

H₂N—

NHC(═

NH)—

NH—

(CH₂)_n—

O-[carbohydrate], where n=1-10, including hydrocarbon isomers, ether linkage isomers and hydroxylated derivatives thereof;

H₂N—

NHC(═

NH)—

N═

CH—

(CH₂)_n-[carbohydrate], where n=1-10, including hydrocarbon isomers and hydroxylated derivatives thereof;

H₂N—

NHC(═

NH)—

N═

CH—

(C₂)_n—

O-[carbohydrate], where n=1-10, including hydrocarbon isomers, ether linkage isomers and hydroxylated derivatives thereof;

H₂N—

C(═

NH)—

NH—

NH-[carbohydrate];

H₂N—

C(═

NH)—

NH—

NH—

(CH₂)_n-[carbohydrate], where n=1-10, including hydrocarbon isomers and hydroxylated derivatives thereof;

H₂N—

C(═

NH)—

NH—

NH—

(CH₂)_n—

O-[carbohydrate], where n=1-10, including hydrocarbon isomers, ether linkage isomers and hydroxylated derivatives thereof;

H₂N—

C(═

NH)—

NH—

N═

CH—

(CH₂)_n-[carbohydrate], where n=1-10, including hydrocarbon isomers and hydroxylated derivatives thereof;

H₂N—

C(═

NH)—

NH—

N═

CH—

(CH₂)_n—

O-[carbohydrate], where n=1-10, including hydrocarbon isomers, ether linkage isomers and hydroxylated derivatives thereof;

d. primary amine, aminoguanidine and guanidine derivatives of sucrose polyesters having one or more carbonyl trapping functional group per molecule wherein each carbonyl trapping functional group is in the ω

-, ω

-1 or other isomeric position within the fatty acyl chains, wherein each fatty acyl chain may have from 3 to 26 carbons, from one to five nitrogen functional groups and from one to 24 hydroxyl groups;

e. synthetic polysaccharides consisting partly or entirely of aminosugars bound by β

-1,2, β

-1,3, β

-1,4 and/or β

-1,6 linkages;

f. mixed polysaccharide polymeric derivatives wherein primary amine, aminoalkyl (one to ten carbons per alkyl group), aminohydroxyalkyl (one to ten carbons per alkyl group and one to ten hydroxyl groups per alkyl group), aminoguanidine, aminoguanidinylalkyl (one to ten carbons per alkyl group), aminoalkylguanidinyl (one to ten carbons per alkyl group), guanidine, aminobenzene and/or aminoalkylbenzene (one to ten carbons per alkyl group) functional groups are covalently attached to matrices; and

g. non-polysaccharide polymeric derivatives wherein primary amine, aminoalkyl (one to ten carbons per alkyl group), aminohydroxyalkyl (one to ten carbons per alkyl group and one to ten hydroxyl groups per alkyl group), aminoguanidine, aminoguanidinylalkyl (one to ten carbons per alkyl group), aminoalkylguanidinyl (one to ten carbons per alkyl group), guanidine, aminobenzene and/or aminoalkylbenzene (one to ten carbons per alkyl group) functional groups are covalently attached to a synthetic non-digestible polymer selected from the group consisting of polystyrene, styrene-divinylbenzene copolymer, polyvinyl alcohol and crosslinked derivatives thereof, and wherein hydrocarbon spacer groups are selected from alkene and alkyl groups.

20. The method of claim 1 wherein said optional non-absorbable polyamine carbonyl trapping substance co-agent is in a micro-fibrillated form or microcrystalline form having enhanced surface area, increased porosity, increased water retention capacity and enhanced chemical accessibility.

21. The method of claim 1 wherein the antioxidant is selected from the group consisting of α

-tocopherol, β

-tocopherol, γ

-tocopherol, δ

-tocopherol, ε

-tocopherol, ζ

₁-tocopherol, ζ

₂-tocopherol, η

-tocopherol, pharmaceutically acceptable tocopherol derivatives, citric acid, coenzyme Q_n where n=1-12, glutathione, butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, dodecylgallate, tert-butylhydroquinone, dihydrolipoic acid, prostaglandin B₁ oligomers, 2-aminomethyl-4-tert-butyl-6-iodophenol,2-aminomethyl-4-tert-butyl-6-propionylphenol, 2,6-di-tert-butyl-4-[2′

-thenoyl]phenol, N,N′

-diphenyl-p-phenylenediamine, ethoxyquin, probucol, ebselen, 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-3-(dimethylamino)-4-thiazolidinone5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-3-(methylamino)-4-thiazolidinone, D-myoinositol-1.2.6-trisphosphate, nordihydroguaiaretic acid, deferoxamine mesylate, tirilazad mesylate, derivative of tirilazad in which the steroid portion of the chemical structure has been replaced with the tetramethyl chroman portion of d-α

-tocopherol, trimetazidine, N,N′

-dimethylthiourea, 2-(2-hydroxy-4-methylphenyl)aminothiazole hydrochloride, 2-L-oxothiazolidine, α

-lipoic acid, sodium α

-lipoate, ethylenediamine α

-lipoate, selenium, pharmaceutically acceptable salts of selenium, a seleno-containing amino acid, zinc, pharmaceutically acceptable salts of zinc, parthenolide, lycopene, daidzin, genistein, quercetin, morin, curcumin, apigenin, sesamol, chlorogenic acid, fisetin, ellagic acid, quillaia saponin, capsaicin, ginsenoside, silymarin, kaempferol, ginkgetin, bilobetin, isoginkgetin, isorhamnetin, herbimycin, rutin, bromelain, levendustin A and erbstatin.

22. The method of claim 1 wherein the vitamin is selected from the group consisting of retinol, vitamin A aldehyde, vitamin A acid, retinyl acetate, vitamin B₁, thiamine propyl disulfide, thiamine disulfide, thiamine disulfide O,O-diisobutyrate, thiamine disulfide hydrochloride, thiamine disulfide phosphate, thiamine mononitrate, thiamine 1,5-salt, thiamine phosphoric acid ester chloride, thiamine phosphoric acid ester phosphate salt, thiamine triphosphoric acid ester, vitamin B₂, riboflavin tetrabutyrate, riboflavine 5′

-phosphate ester monosodium salt, pantothenic acid, pantothenic acid sodium salt, pantothenic acid calcium salt, vitamin B₆, pyridoxal, pyridoxal HCl, pyridoxal 5-phosphate, pyridoxal 5-phosphate calcium salt, pyridoxamine, pyridoxamine dihydrochloride, pyridoxamine phosphate, vitamin B₁₂, methyl vitamin B₁₂, vitamin D₂, vitamin D₃, vitamin D₄, vitamin H, vitamin K₁, diacetyl dihydro vitamin K₁, vitamin K₁ oxide, vitamin(s) K₂, vitamin K₂₍₃₅₎, vitamin K₂₍₃₅₎ dihydrodiacetate, vitamin K₂₍₃₀₎, vitamin K₂₍₃₀₎ dihydrodiacetate, vitamin K₅, vitamin K₅ hydrochloride, N-acetyl vitamin K₅, vitamin K₆, vitamin K₆ dihydrochloride, vitamin K₇, vitamin K₇ hydrochloride, vitamin K-S(II), vitamin L₁, vitamin L₂, vitamin U, methylmethioninesulfonium bromide, α

-carotene, β

-carotene, γ

-carotine, ω

-carotene, Ψ

-,Ψ

-carotene, 7,7′

,8,8′

,11,12-hexahydro-Ψ

-,Ψ

-carotene, L-carnitine, acetyl-L-carnitine, folic acid, folinic acid, folinic acid calcium salt pentahydrate, niacinamide, nicotinic acid, nicotinic acid sodium salt sesquihydrate and nicotinic acid monoethanolamine salt.

23. The method of claim 1 wherein the co-agent which facilitates glutathione biological activity is selected from the group consisting of N-acetylcysteine, oxothiazolidine-carboxylate, timonacic acid, cysteamine and lipoamide derivatives.

24. The method of claim 1 wherein the metabolite at risk of depletion is selected from the group consisting of glycine and pharmaceutically acceptable salts thereof.

25. The method of claim 1 wherein the sulfhydryl substance co-agent is a sulfhydryl containing substance or derivative thereof selected from the group consisting of cysteine, homocysteine and methionine.

26. The method of claim 1 wherein the co-agent selected from the group consisting of non-absorbable polyamine carbonyl trapping substances, antioxidants, vitamins, metabolites at risk of depletion, sulfhydryl substance co-agents and co-agents which may facilitate glutathione activity is administered orally.

27. The method of claim 1 wherein the co-agent selected from the group consisting of antioxidants, vitamins, metabolites at risk of depletion, sulfhydryl substance co-agents and co-agents which may facilitate glutathione activity is administered intravenously, intramuscularly or subcutaneously.

28. A method of treating the underlying biochemical symptoms of neurological diseases in a human comprising the method of claim 1 and the added administration of a co-agent medicament effective to treat the disease or a symptom thereof.

29. A method of treating the underlying biochemical symptoms of veterinary neurological diseases in a mammal, said method comprising administering to the mammal a therapeutically effective amount of at least one orally administered required primary agent of claim 1 wherein the orally administered required primary agent is in a dosage in the range of 15 mg/kg daily to 450 mg/kg daily and may be administered for extended periods of time.

30. The method of claim 29 wherein the mammal is also treated with a therapeutically effective amount of at least one optional co-agent from the group consisting of non-absorbable polyamine carbonyl trapping substances, antioxidants, vitamins, metabolites at risk of depletion, sulfhydryl substance co-agents and co-agents which may facilitate glutathione activity as defined in claim 1.

31. The method according to claim 29, said method additionally comprising the added administration of a co-agent medicament effective to treat the disease or a symptom thereof.

32. The method of claim 1 wherein the category (c) medicament co-agent effective to treat the disease or a symptom thereof is administered orally.

33. The method of claim 1 wherein the category (c) medicament co-agent effective to treat the disease or a symptom thereof is administered intravenously, intramuscularly or sub-cutaneously.