CA2166383A1 - Pharmaceutical compositions and use thereof for treatment of neurological diseases and etiologically related symptomology - Google Patents

Abstract

Pharmaceutical compositions for treatment of several neurological diseases and pathophysiologically related symptomology in other body tissues, 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, are dislcosed. Spurious pathological chemical crosslinking of normal intracellular structures is a fundamental aspect of these neurological diseases. Covalent bond crosslinking of protein and lipid subcellular elements appear to underlie the formation of polymerized aggregates of neurofilaments and other structural proteins, and lipo-fuscin. Pharmacological intervention in some neurological diseases using water soluble, small molecular weight primary amine agents and derivatives thereof, as oral therapeutic agents, may compete with cellular protein and lipid amine groups for reaction with disease-induced carbonyl-containing aliphatic and aromatic hydrocarbons. Primary pharmacological agents include 4-aminobenzoic acid and derivatives thereof to facilitate kidney recognition and removal. This invention also includes: (1) oral use of non-absorbable polyamine polymers and amine-related co-agents such as chitosan to covalently bind and sequester potentially toxic carbonyl compounds present in the diet, (2) oral use of known antioxidant co-agents and related nutritional factors and (3) use of the primary agent and co-agents in combination with known medicaments for treatment of these neurological diseases.

Description

WO95/0109~ PCT~S94/07277 21 66~83 PHARMACEUTICAL COMPOSITIONS AND USE THEREOF FOR TREATMENT
OF NEUROLOGICAL DISEASES AND ETIOLOGICALLY RELATED
SYMPTOMOLOGY

SUMMARY OF THE INVENTION

The present invention defines pharmaceutical compositions comprising (1) at least one amine or amine-related benzoic acid derivative primary agent capable of covalently binding carbonyl substances; (2) optionally at least one co-agent selected from the group consisting of nonabsorbable polyamine polymers or nonabsorbable polyamine-relat;ed polymers, anti-oxidants, vitamins, substances which facilitate glutathione biological activity, a hormone, chemical conjugating sub-stances which facilitate kidney drug elimination, metabolites at risk of depletion, sulfhydryl containing co-agents and derivatives thereof, and free radical trap~ping compounds; and (3) at least one previously recognized medicament for treat-ment of symptoms of several neurological diseases and for treatment of pathophysiologically related symptomology.
The invention relates to the use of a composition com-prising a therapeutically effective amount of at least one primary agent and a therapeutically effective amount of at least one co-agent, said primary agent comprising a water soluble primary amine or amine-related derivative of benzoic acid in the molecular weight range of from 100 to 1,400 Dal-tons, for use in the treatment of a mammal suffering from a neurological disease or pathophysiologically related symp-tomology, wherein said primary agent and co-agent combination serves to impede the progression of said neurological disease or pathophysiologically related symptomology.
In such a preferred embodiment of the use of a composi-tion comprising a primary agent and at least one co-agent for treatment of the symptomology of a neurological disease or WO95/01096 PCT~S94/07277 3~3 pathophysiologically related symptomology, the neurological disease or pathophysiologically related symptomology is char-acterized by the deterioration of intracellular and extracel-lular compartments and pathological chemical crosslinking of the intracellular and extracellular components thereof; said deterioration and said crosslinking resulting in part from reaction of the mammal's nerve cells, other cellular struc-tures and their intracellular and extracellular components with disease-induced carbonyl-containing aliphatic or aromatic hydrocarbons present in the mammal; said intracellular and extracellular components comprising proteins, lipids and deoxyribonucleic acid; and wherein said chemical crosslinking comprises covalent bond crosslinking of said nerve cells and intracellular and extracellular components.
In a preferred embodiment of the use of a composition disclosed herein, said use is directed towards treatment of the symptomology of a neurological disease or pathophysiologi-cally related symptomology wherein the disease-related cova-lent bond crosslinking of said nerve cells, other cellular structures and intracellular structures is characterized in part by the formation of at least one neuropathological structure selected from the group consisting of (a) polymer-ized aggregates of structural protein filaments such as excess neurofilament accumulation; (b) heterogeneous protein aggre-gates such as neurofibrillary tangles; (c) amorphous protein and lipid aggregates, such as senile plaques; and (d) lipofus-cin granules.
In a preferred embodiment of the use of a composition disclosed herein, said use is directed towards treatment of the symptomology of a neurological disease or pathophysiolog-ically related symptomology wherein the disease-related cova-lent bond crosslinking of said nerve cells, other cellular structures and extracellular structures is characterized in part the formation of at least one neuropathological structure or pathophysiologically related structure selected from the group consisting of (a) polymerized aggregates of blood serum WO95/01096 PCT~S94/07277 21~63~3 and structural proteins such as excess amyloid accumulation;
and (b) amorphous protein and lipid aggregates, such as senile plaques and atherosclerotic plaques.
In a preferred embodiment of the invention the primary agent has at least one primary amine group or amine-related group thereon for reaction with disease-induced carbonyl-con-taining aliphatic or aromatic hydrocarbons to decrease the deterioration of said nerve cells and intracellular and extra-cellular compartments and to decrease the pathological chemi-cal crosslinking of said nerve cells and intracellular and extracellular components by permitting said primary agent to effectively compete with and covalently bind to said disease-induced carbonyl-containing aliphatic or aromatic hydrocar-bons.
In a preferred embodiment, the use of the primary agent is additionally characterized in that it does not interact with noL-mal cell metabolism of the mammal or does so in a non-cytotoxic manner, is administered orally, and is capable of being tolerated by said mammal in dosages in the range of 15 mg/kg daily to 800 mg/kg daily for extended periods of time, the primary agent being readily absorbed by the kidney tissue of said mammal and excreted in the urine of said mammal with-out nephrotoxic consequences.
In a preferred embodiment, the use this invention in-cludes selection of a primary agent from the group consisting of the free acid forms, salts, benzene ring isomers, amide derivatives, carboxylic acid ester derivatives and analogous non-aromatic benzene ring derivatives of the group consisting of:

R = -NH2 -aminoalkyl group having R ~ COOH 1-10 carbons including hydrocarbon isomers and/or hydroxylated derivatives I thereof -WO95/01096 PCT~S94/07277

2~"6~3 -NHC(=NH)NH2 -(cHz)nNHc(=NH)NH2 where n = 1-10 -C(=NH)-NH2 -(CH2)n-cH=Nc(=NH)NH2 where n = 1-10 -NHC(=NH)NHNH2 -(CH2)nNHc(=NH)NHNH2 where n = 1-10 -(CH2)n-cH=Nc(=NH)NHNH2 where n = l-10 -NHNHC(=NH)NH2 -(cH2)n-NHNHc(=NH)NH2 where n = 1-10 -(cH2)n-cH=N-NHc(=NH)NH2 where n = l-10 R1 = -NH2 -aminoalkyl group (1-10 carbons) including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof COOH -(cH2)nNHc(=NH)NH2 ~ where n = 1-10 2 -C(=NH)-NH2 II -(CH2)n-cH=Nc(=NH)NH2 where n = 1-10 -NHC(=NH)NHNH2 -(CH2)nNHc(=NH)NHNH2 where n = 1-10 -(CH2)n-cH=Nc(=NH)NHNH2 where n = 1-10 -NHNHC(=NH)NHz -(CH2)n-NHNHc(=NH)NH2 where n = 1-10 WO95/01096 66~8~ PCT~594/~7277 -(cH2)n-cH=N-NHc(=NH)NH2 where n = 1-10 R2 = --NH2 -OH

-0-R' with alkyloxy group R' having 2-10 carbons including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof -aminoalkyl group (1-10 carbons) including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof -(CH2)1lCH3 where n = 1-10 inclu.ding hydrocarbon isomers and/or hydroxyl-ated derivatives thereof R1 = -(CH2)n-NH2 where n = 0-10 including isomers of the aminoalkyl group and R~ ~~~\ R~ hydroxylated derivatives ~-COOH thereof ~ R~ -C(=NH)-NH2 R2 -NHC(=NH)NH2 III -(CH2)r,NHC(=NH)NH2 where n = 1-10 -(CH2)r,-cH=Nc(=NH)NH2 where n = 1-10 -NHC(=NH)NHNH2 -(CH2)rNHC(=NH)NHNH2 where n = 1-10 ~,~.C~3~ ----(CH2) n--CH=NC (=NH) NHNH2 where n = 1-10 --NHNHC ( =NH ) NH2 - (CHz) n--NHNHC (=NH) NH2 where n = 1-10 --(CH2) n--CH=N--NHC (=NH) NH2 where n = 1-10 R2 = -NH2 -H
-OH

-O-R3 with alkyloxy group R3 has 2-10 carbons including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof -aminoalkyl group (1-10 carbons) including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof -(CH2)nCH3 where n = 1-10 including hydrocarbon - isomers and/or hydroxyl-ated derivatives thereof R' = -H

-OH
R" = -H

-OH

for controlling the symptoms of a human disorder featur-ing neurofilament associated pathology or pathophysiologically WO 95/0109C 6638~j~ PCT/US94/07277 related symptomology, wherein said disorder is selected from the group consisting of hereditary motcr and sensory neuro-pathies; diabetic polyneuropathy; Alzheimer's presenile demen-tia; 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 including symptoms of hypoperistalisis of the alimentary tract, hiatal hernia, partia]. food regurgitation, urinary incontinence, breathing insufficiency due to diaphram weakness and decreased autonomic sexual function; age-related atrophy of neurons of the central nervous system; age-onset pathophysiologically related changes in t;he kidney, optic lens and cardiovascular system including atherosclerosis and symptoms related thereto; alcoholic polyneuropathy; multiple sclerosis; olivopontocerebellar atrophy and Huntington's disease.
In a preferred embodiment, the one or more co-agent is selected from the group consisting of nonabsorbable polyamine polymers or nonabsorbable polyamine-related polymers, anti-oxidants, suspending reagents, vitamins, co-agents which fa-cilitate glutathione biological activity, a hormone, chemical conjugating co-agents which facilitate kidney drug elimina-tion, metabolites at risk of depletion, sulfhydryl containing co-agents and derivatives thereof, and free radical trapping compounds, for controlling the symptoms of a human disorder featur-ing neurofilament associated pathology or pathophysiologically related symptomology, wherein said disorder is selected from the group consisting of hereditary motor and sensory neuro-pathies; diabetic polyneuropathy; Alzheimer's presenile demen-tia; 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 including symptoms of hypoperistalisis of the alimentary tract, hiatal hernia, partial food regurgitation, urinary incontinence, breathing insuffic:iency due to diaphram WO95/01096 ~16 6 3 ~3 PCT~ss4lo7277 weakness and 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 including atherosclerosis and symptoms related thereto; alcoholic polyneuropathy; multiple sclerosis; olivopontocerebellar atrophy and Huntington's disease.
In a preferred embodiment, the one or more co-agent selected from the group consisting of nonabsorbable polyamine polymers or nonabsorbable polyamine-related polymers, anti-oxidants, suspending reagents, vitamins, co-agents which fa-cilitate glutathione biological activity, a hormone, chemical con~ugating co-agents which facilitate kidney drug elimina-tion, metabolites at risk of depletion, sulfhydryl containing co-agents and derivatives thereof, and free radical trapping compounds is administered orally.
In a preferred embodiment, the one or more co-agent selected from the group consisting of nonabsorbable polyamine polymers or nonabsorbable polyamine-related polymers, anti-oxidants, suspending reagents, vitamins, co-agents which fa-cilitate glutathione biological activity, a hormone, chemical conjugating co-agents which facilitate kidney drug elimina-tion, metabolites at risk of depletion, sulfhydryl containing co-agents and derivatives thereof, and free radical trapping compounds is administered intravenously, intramuscularly or subcutaneously.
In a preferred embodiment, the nonabsorbable polyamine polymer co-agent or nonabsorbable polyamine-related derivative thereof is in a microfibrillated form or microcrystalline form having enhanced surface area, increased porosity, increased water retention capacity and enhanced chemical accessibility.
In a preferred embodiment, the therapeutically effective amount of said nonabsorbable polyamine polymer co-agent or nonabsorbable polyamine-related derivative thereof is a dosage in the range of one gm/day to forty gm/day.
In a preferred embodiment, the one or more co-agent is WO95/01096 PCT~S94/07277 ~166~

additionally selected from the group co:nsisting of a neuro-active drug; an antihistaminic drug; a vasoactive drug; an immunoregulatory drug; an anti-oxidant drug recognized as having neuroprotective properties; an anti-diabetic drug; an antiulcerative drug; or a chemical selected from the group consisting of acetylhomocysteine thiolactone, alaproclate, aminooxyacetic acid, anfacine, arecoline, cimetidine, cisa-pride, cyclandelate, D-cycloserine optionally with a cholin-esterase inhibitor, famotidine, flavoxate, galanth~m;ne, ganglioside GM1, ifenprodil, isosorbide dinitrate, lazabemide, levodopa optionally with a peripheral decarboxylase inhibitor, linopirdine, metoclopramide, mixed cow brain gangliosides, nafronyl, omeprazole, ranitidine, 13-cis-retinoic acid, 13-trans-retinoic acid, serine, thiamine disulfide O,O-diiso-butyrate, L-threonine, thyrotropin releasing factor, tiapride, trinitroglycerin, and vasopressin analogues including desmo-pressln, for controlling the symptoms of a human disorder featur-ing neurofilament associated pathology or pathophysiologically related symptomology, wherein said disorder is selected from the group consisting of hereditary motor and sensory neuro-pathies; diabetic polyneuropathy; Alzheimer's presenile demen-tia: 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 including symptoms of hypoperistalisis of the alimentary tract, hiatal hernia, partial. food regurgitation, urinary incontinence, breathing insufficiency due to diaphram weakness and decreased autonomic sexual function; age-related atrophy of neurons of the central nervous system; age-onset pathophysiologically related changes in t.he kidney, optic lens and cardiovascular system including atherosclerosis and symptoms related thereto; alcoholic polyneuropathy; multiple sclerosis; olivopontocerebellar atrophy and Huntington's disease.
In another preferred embodiment, the invention relates to WO95/01096 PCT~S94/07277 2i 6~i3~ ~

the use of a composition for treating a mammal suffering from a veterinary disorder featuring neurofilament associated path-ology or pathophysiologically related symptomology comprising orally administrating a therapeutically effective amount of a primary agent sufficient to treat said mammal; wherein said mammalian veterinary disorder is selected from the group con-sisting of diabetic polyneuropathy; metabolic symptomology related to diabetic polyneuropathy; amyotrophic lateral scler-osis; age-related atrophy of peripheral sensory and motor nerves and symptomology related thereto including tinnitus;
age-related atrophy of autonomic nerves and symptomology thereof including hypoperistalisis of the alimentary tract, hiatal hernia, partial food regurgitation, urinary incontin-ence, breathing insufficiency due to diaphram weakness and decreased autonomic sexual function; age-related atrophy of neurons of the central nervous system; and age-onset patho-physiologically related changes in the kidney, optic lens and cardiovascular system including atherosclerosis and symptoms related thereto; wherein the primary agent is selected so that it does not interact with the normal cell metabolism of the mammal or does so in a non-cytotoxic manner, is capable of being tolerated by said mammal in dosages in the range of 15 mg/kg daily to 800 mg/kg daily for extended periods of time, is readily absorbed by the kidney tissue of said mammal and excreted in the urine of said mammal without nephrotoxic consequences to said mammal and is selected from the group consisting of water soluble, small molecular weight, primary amine containing chemical agents or amine-related derivatives thereof as defined above.
In a preferred embodiment, the mammal is also treated with a therapeutically effective amount of at least one co-agent.
In a preferred emobiment, the mammal is treated with a therapeutically effective amount of one or more co-agent selected from the group consisting of nonabsorbable polyamine polymers or nonabsorbable polyamine-related polymers, anti-WO95/0109l6 16~3 PCT~S94107277 oxidants, suspending reagents, vitamins, co-agents which fa-cilitate glutathione biological activity, a hormone, chemical conjugating co-agents which facilitate kidney drug elimina-tion, metabolites at risk of depletion, sulfhydryl containing co-agents and derivatives thereof, and free radical trapping compounds.
In another aspect of the invention, the invention relates to a pharmaceutical composition for use in the treatment of the symptoms of disorders selected from t:he group consisting of:
hereditary motor and sensory neuropathies; diabetic polyneuropathy; Alzheimer's presenile dementia; Alzheimer's senile dementia; Down's syndrome; Parkinson's disease; amyo-trophic lateral sclerosis; age-related at:rophy of peripheral sensory and motor nerves; age-related atrophy of autonomic nerves including symptoms of hypoperista]isis of the alimen-tary tract, hiatal hernia, partial food regurgitation, urinary incontinence, breathing insufficiency due to diaphram weakness and decreased autonomic sexual function; age-related atrophy of neurons of the central nervous system; age-onset pathophys-iologically related changes in the kidney, optic lens and cardiovascular system including atherosc].erosis and symptoms related thereto; alcoholic polyneuropathy; multiple sclerosis;
olivopontocerebellar atrophy and Huntingt:on's disease, the composition comprising at least one primary agent having a molecular weight of from 100 to 1,400 Daltons select-ed from free acid forms, salts, benzene ring isomers, amide derivatives, carboxylic acid ester derivatives and analogous non-aromatic benzene ring derivatives of the group consisting of:

R = -NH
-aminoalkyl group having R ~ COOH 1-10 carbons including hydrocarbon isomersand/or I hydroxylated derivatives WO95/01096 PCT~S94/07277

3 ~3 thereof -NHC(=NH)NHz -(cH2)nNHc(=NH)NH2 where n = 1-10 -C(=NH)-NH2 -(CHz)n-cH=Nc(=NH)NH2 where n = 1-10 -NHC(=NH)NHNHz -(cH2)nNHc(=NH)NHNH2 -where n = 1-10 -(CH2)n-CH=NC(=NH)NHNH2 where n = 1-10 -NHNHC(=NH)NH2 -(CH2)n-NHNHc(=NH)NH2 where n = 1-10 ~(CH2)n-CH=N-NHC(=NH)NH2 where n = 1-10 Rl = -NHz -aminoalkyl group (1-10 carbons) including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof COOH -(CH2)nNHc(=NH)NHz ~ where n = 1-10 R2 -C(=NH)-NH2 II -(cH2)n-cH=Nc(=NH)NH2 where n = 1-10 -NHC(=NH)NHNH2 -(CH2)nNHc(=NH)NHNH2 where n = 1-10 -(CH2)n-CH=NC(=NH)NHNH2 where n = 1-10 -NHNHC(=NH)NH2 .
-(cH2)n-NHNHc(=NH)NH2 ~WO95/0109~ 13 6~383 PCT~S94/07277 where n = 1-10 --(CH2) n--CH=N--NHC (=NH) NH2 where n = 1-10 R2 = --NH2 -OH

-O-R' with alkyloxy group R' having 2-10 carbons including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof -aminoalkyl group (1-10 carbons) incl~lding hydrocarbon isomers and/or hydroxyl-ated derivatives thereof -(CH2)nCH3 where n = 1-10 including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof R1 = -(CH2)r,-NH2 where n = 0-10 including isomers of the aminoalkyl group and R1 ~ ~~~~\ R~ hydroxylated derivatives --C--COOH thereof ~ R" -C (=NE~) - NH2 R2 --NHC ( ==NH ) NH2 III --(CH2) nNHC (=NH) NH2 where n = 1-10 --(CH2) n--CH=NC (=NH) NH2 where n = 1-10 -NHC (--NH ) NHNH2 --(CH2) nNHC (=NH) NHNH2 WO95/01096 ~6~ PCT~S94/07277 where n = 1-10 --(CH2) n--CH=NC (=NH) NHNH2 where n = 1-10 --NHNHC ( =NH ) NH2 - (CH2) n--NHNHC (=NH) NH2 where n = 1-10 - ( CH2) n-CH=N-NHC ( =NH) NH2 where n = 1-10 R2 = -NH2 --H
-OH

-O-R3 with alkyloxy group ~, R3 has 2-lo carbons including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof -aminoalkyl group (1-10 carbons) including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof -(CH2)nCH3 where n = 1-10 including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof R' = -H

-OH
R" = -H

-OH

in a dosage range of from 15 mg/kg daily to 800 mg/kg ~ 095/01096 216 6 3 8 3 PCT~S94/07277 daily, in association with a pharmaceutically acceptable carrie~ thereof.
In another preferred embodiment, this composition com-prises at least one co-agent present in an effective amount.
In another aspect of this invention, the invention re-lates to a pharmaceutical composition additionally comprising one or more co-agent selected from the group consisting of non-absorbable polyamine polymers or nonabsorbable polyamine-related polymers, anti-oxidants, suspending reagents, vita-mins, co-agents which facilitate glutathione biological activ-ity, a hormone, chemical conjugating co--agents which facili-tate kidney drug elimination, metabolites at risk of deple-tion, sulfhydryl containing co-agents and derivatives thereof, and free radical trapping compounds.
In another aspect of this invention, the invention re-lates to a pharmaceutical composition additionally comprising one or more co-agent selected from the group consisting of a neuroactive drug; an antihistaminic drug; a vasoactive drug;
an immunoregulatory drug; an anti-oxidant drug recognized as having neuroprotective properties; an anti-diabetic drug; an antiulcerative drug; or a chemical selected from the group consisting of acetylhomocysteine thiolactone, alaproclate, aminooxyacetic acid, anfacine, arecoline, cimetidine, cisa-pride, cyclandelate, D-cycloserine optionally with a cholin-esterase inhibitor, famotidine, flavoxate, galanth~ine, ganglioside GM1, ifenprodil, isosorbide d:initrate, lazabemide, levodopa optionally with a peripheral decarboxylase inhibitor, linopirdine, metoclopramide, mixed cow brain gangliosides, nafronyl, omeprazole, ranitidine, 13-ci_-retinoic acid, 13-trans-retinoic acid, serine, thiamine disulfide O,O-diiso-butyrate, L-threonine, thyrotropin releasing factor, tiapride, trinitroglycerin, and vasopressin analogues including desmo-pressin .
In another aspect of the invention, the invention in-cludes a process for determining if the genomic contents of a human includes the presence of the gene which encodes for WO95/01096 PCT~S94/072 2~6~3 16 chromosome 17 hereditary motor and sensory neuropathy, also known as chromosome 17 Charcot-Marie-Tooth disease, the pro-cess comprising the steps of: (a) establishment of a cultured fibroblast strain derived from a skin biopsy or amneotic fluid sample obtained from said human; (b) homogenation of a sample of said fibroblast strain so as to obtain a solubilized sus-pension of proteins; (c) resolution of said proteins according to molecular charge by use of isoelectric focusing gel elec-trophoresis of said solubilized protein suspension; (d) and/or resolution of proteins according to molecular weight by use of sodium dodecyl sulfate gel electrophoresis; (e) visualization of resolved protein spots on said electrophoresis gel; (f) analysis of the electrophoretic pattern of the resolved cul-tured fibroblast proteins by visual ~m; nation or use of computer-assisted image processing technology, including reference to protein standards of known molecular weight and known isoelectric point, so as to determine the presence or absence of at least one chromosome 17 hereditary motor and sensory neuropathy-specific supernumerary protein.

BACKGROUND OF THE INVENTION

1. Field of the Invention This invention relates to the clinical treatment of neuro-degenerative diseases, including hereditary motor and sensory neuropathies (HMSN, also known as Charcot-Marie-Tooth dis-ease), diabetic polyneuropathy, Alzheimer's pre-senile and senile dementia, Down's syndrome, Parkinson's disease, olivo-pontocerebellar atrophy, Huntington's disease, amyotrophic lateral sclerosis, age-onset neurological deterioration, alcoholic polyneuropathy, tinnitus, multiple sclerosis, and pathophysiologically symptomology.

WO95/01096 PCT~S94/07277 ~16638 2. Description of Prior Art The logic and potential value, even synerqistic value, of using two or more therapeutic agents in combination has been recognized previously (Ghose and cowork:ers, 1983; Goldstein and coworkers, 1990, pg. 102; Rinne, 19'31). For example, in a study on two-drug combinations of memory enhancing agents Flood and coworkers (1988) noted that:

The potential for clinically desirable drug inter-actions has been emphasized for drugs in general (1) and for memory enhancing drugs in particular (2,3).
For example, individual cholinergic drugs which im-prove memory retention test scores (4,5,6) do so in two-drug combinations at substantially lower doses than would be predicted if the two drugs acted addi-tively (7,8,9)...
In prior studies of the effect of two-drug combin-ations on memory processing (8,9), we determined the effect of varying the dose of two clrugs while holding the ratio constant. The ratio was based on the optimal memory enhancing doses of each drug administered singly.
These studies showed that drugs administered in certain combinations require 67 to 96% less drug to improve re-tention, than when the same drugs were administered alone. This type of drug interaction was said to yield supra-additivity.

The present disclosure describes the inventive concept of using the therapeutic technology of US patent application 08/026,617 in combination with pharmaceutical agents previ-ously recognized as having, or possibly having some medicinal value for treatment of the disease entit:ies noted above. No pharmacological treatment of comprehensive effectiveness is currently available for any of the neurological disorders discussed herein. However, a variety of pharmaceutical agents WO95/01096 PCT~S94/072~
3~ 18 have been described which may offer at least some degree of symptomatic relief from the clinical effects of these diseases.

The 16th edition of the Merck Manual (Berkow, 1992, pp. 1497- r 1499) has defined symptomatic clinical treatment of Parkin-son's disease to consist of: (a) oral co-administration of levodopa, the metabolic precursor of dopamine, and carbidopa, a peripheral decarboxylase inhibitor [in compositions such as Sinemet CR]; (b) co-agent use of amantadine HCl [Symmetrel; 1-amino-adamantane, a rye ergot alkaloid and neuronal trans-mission enhancer]; (c) co-agent use of ergot alkaloids such as bromocriptine mesylate [Parlodel, which has a dopamine agonist activity for D2 receptors and antagonist activity at D1 recep-tors] and pergolide mesylate [Permax, a dopamine-receptor agonist active at both D1 and D2 receptor subtypes (Robin, 1991)]; (d) selegiline HCl [EldePryl, a selective inhibitor of monoamine oxidase B which prolongs the action of dopamine (Rinne, 1991)]; (e) co-agent use of anticholinergic medica-tions such as benztropine mesylate [Coqentin], trihexylphenid-yl [Artane], procyclidine [Kemadrin], biperiden and ethopropa-zine [Paridol]; (f) co-agent use of antihistamines such as diphenhydramine [Benadryl] and orphenadrine; (g) co-agent use of tricyclic antidepressants such as amitriptyline, imipra-mine, nortriptyline and doxepin; and (h) co-agent use of propranolol.

Other well established or experimental therapeutic approaches for clinical treatment of Parkinson's disease, which may or may not be used in conjunction with L-dopa, have been publicly disclosed. These include possible use of (a) selegiline in combination with tocopherol (Greenamyre and O'Brien, lg91);
(b) D-cycloserine with or without a cholinesterase inhibitor co-agent (Francis and coworkers, 1991); (c) other dopamine receptor agonists such as (+)-4-propyl-9-hydroxynaphthoxazine (Martin and coworkers, 1984), apomorphine and ciladopa (Koller WO95/OlO9~S ~ PCT~S94/07277 ~16638,~

and coworkers, 1986; Goldstein and coworkers, 1990); (d) neurotransmission enhancer drugs such as lisuride, a rye ergot alkaloid (Rinne, 1989; Rinne, 1991); (e) known antioxidants such as ascorbic acid, ~-tocopherol, ~-carotene (Mathews-Roth, 1987), N-acetylcysteine (Smilkstein a.nd coworkers, 1988), penicillamine or cysteamine (Harris, 1982), as increased levels of lipid peroxidation are apparent in parkinsonian tissue (Ceballos and coworkers, 1990; Fahn, 1989); (f) other peripheral decarboxylase inhibitors such as benserazide (MadoPar HBS) (Pinder and coworkers, 1976; Pletscher, 1990);
and (g) N-methyl-D-asparate (NMDA) glut:amate receptor antag-onists such as dizocilpine (Clineschmidt and coworkers, 1982;
Woodruff and coworkers, 1987) and milacemide (Youdim, 1988;
Ferris, 1990) or use of the possible antagonist 1-amino-3,5-dimethyl adamantane (Memantine) (Fischer and coworkers, 1977;
Schmidt and coworkers, l99O; Greenamyre and O'Brien, 1991);
(h) tacrine (Coqnex, an experimental ayent of Warner-Lambert Co.) and a hydroxy derivative thereof, (+/ )-9-amino-1,2,3,4-tetrahydroacridin-l-ol (Shutske and coworkers, 1988); and (i) tiapride (Price and coworkers, 1978).

Since activation of NMDA glutamate receptors has also been implicated in the etiologies of Huntington's disease, amyo-troph.ic lateral sclerosis, olivopontocerebellar atrophy and Alzheimer's disease, use of NMDA glutamate receptor antago-nists such as those listed above may be of clinical benefit for patients having these diseases (Woodfuff and coworkers, 1987; Greenamyre and O'Brien, 1991; G.iuffra and coworkers, 1992)~ as well as for patients sufferin.g from certain neuro-degenerative effects of aging (Ferris, l99O). Drugs which may enhance acetylcholine synthesis or release such as phospha-tidylcholine, 3,4-diaminopyridine (Ferris, l99O; Harvey and Rowanr l99O) and choline (Sitaram and coworkers, 1978a), as well as the muscarinic cholinergic agon.ist arecoline (Tariot and coworkers, 1988), have also been proposed for treatment of Huntington's disease.

WO95/01096 PCT~S94/07277 .

The use of L-dopa as the primary therapeutic agent for treat-ment of Parkinson's disease may serve as an example of the limitations of present technology. Citing earlier work, Robin (1991) has noted that "...chronic exposure to high dose L-dopa may accelerate the progression of Parkinson's disease."
Indeed, clinical benefits to be obtained from L-dopa therapy are predictably limited to perhaps three to five years. After that period, continued use of L-dopa will not provide clinical benefit. This situation exists because L-dopa therapy depends on conversion of this physiological precursor into dopamine within a population of substantia nigra neurons which is selectively deteriorating in this disease. Once the last of these nerve cells is gone, the therapeutic strategy has lost its physiological basis.

However, use of the invention originally disclosed in US pa-tent application 07/660,561 may serve to sequester and remove aldehyde and ketone products of the lipid peroxidation process known to exist in parkinsonian substantia nigra tissue (Fahn, 1989; Youdim, 1990). This may at least partially address the etiological basis of the disease. Use of the invention orig-inally disclosed in US patent application 07/660,561 in com-bination with, or originally prior to, present L-dopa thera-peutic technology should serve to further advance prior art technology for treatment of Parkinson's disease. Hence, the invention described herein may serve to delay the necessity of initiating L-dopa therapy and, once L-dopa therapy has begun, may serve to permit use of a smaller dosage of the dopamine precursor. This, in turn, may permit a decreased level of metabolic stress on substantia nigra nerve cells.

Similar reasoning applies in the case of prospective treatment of Alzheimer's disease and age-related neuron degeneration.
As noted by Ceballos and coworkers (1990):

...The development of clinical features in AD

WO95/0109l6 PCT~S94/07277 ~ 6~3~3 [Alzheimer's disease] is linked to the amount of deposition of amyloid in the limbic areas and cerebral cortex. Moreover, amyloid formation may arise as a consequence of membrane damage...
~ue to lipid peroxidation...About 6% of PHF
[paired helical filaments] is composed of the amino- acid, hydroxyproline. This amino- acid is not a constituent of cytoplasmic protein in normal brain and the abundance of hydroxyproline in cyto-plasmic PHF involves non-enzymatic hydroxylation of proline residues probably by hydroxyl free radicals. This free radical hypothesis of PHF
formation suggests that AD is an acceleration of the normal aging process in affected brain regions.

This background information, in addition to that provided in US patent application 08/026,617, provides the conceptual basis for use of the invention described herein for treatment of humans suffering from Alzheimer's disease and age-related neuron degeneration. Recently reported strategies for clini-cal treatment of Alzheimer's disease include possible use of (a) vasodilator or other nootropic direct brain metabolic enhancer drugs such as idebenone (Nagaoka and coworkers, 1984;
Shimizu, 1991), propentophylline (Hindmarch and Subhan, 1985;
Shimizu, 1991), pentoxifylline (Moos and Hershenson, 1989), citicoline (Moos and Hershenson, 1989), piracetam (Franklin and coworkers, 1986; Becker and Giacobini, 1988), oxiracetam (Spignoli and Pepeu, 1987; Villardita and coworkers, 1987), aniracetam (Cumin and coworkers, 1982; Spignoli and Pepeu, 1987), pramiracetam (Franklin and coworkers, 1986), pyroglu-tamic acid (Spignoli and coworkers, 1987; Porsolt and co-workers, 1988), tenilsetam (Moos and coworkers, 1988, pg. 362;
Pepeu and Spignoli, 1989), rolziracetam (Moos and Hershenson, 1989), etiracetam (Franklin and coworkers, 1986), dupracetam, vinpocetine (Groo and coworkers, 1987; Moos and Hershenson, 1989), ebiratide (Hock and coworkers, 1988), ~-carbolines WO95/01096 c PCT~S94107277 ?,~&~3~ --(Jensen and coworkers, 1987), naloxone (Jensen and coworkers, 1980; Reisberg and coworkers, 1983; Rush, 1986; Henderson and coworkers, 1989; Pepeu and Spignoli, l99O, pgs. 247-248;
Cooper, 1991; Whitehouse, 1991), ergoloid mesylates such as Hydergine (Moos and Hershenson, 1989; Cooper, JK, 1991), brom-vincamine (Moos and Hershenson, 1989), cyclandelate (Ananth and coworkers, 1985; Moos and Hershenson, 1989), isoxsuprene (Moos and Hershenson, 1989), nafronyl (Moos and Hershenson, 1989), papaverine (Moos and Hershenson, 1989), suloctidil (Moos and Hershenson, 1989), vinburnine (Moos and Hershenson, 1989), vincamine (Moos and Hershenson, 1989), vindeburnol (Moos and Hershenson, 1989), flunarizine (Holmes and cowork-ers, 1984; Moos and Hershenson, 1989; Cooper, 1991), nimodi-pine (Moos and Hershenson, 1989; Cooper, 1991; Whitehouse, 1991), nicergoline (sermion) (Battaglia and coworkers, 1989;
Moos and Hershenson, 1989), razobazam (Hock and McGaugh, 1985;
Moos and Hershenson, 1989), exifone (Moos and Hershenson, 1989), rolipram (Moos and Hershenson, 1989), sabeluzole (Clincke and coworkers, 1988; Moos and Hershenson, 1989), phosphatidylserine (Delwaide and coworkers, 1986; Zanotti and coworkers, 1986; Amaducci and coworkers, 1987; Moos and Hersh-enson, 1989; Ferris, 1990; Wurtman and coworkers, 1990, pg.
123; Cooper, 1991)), ifenprodil (Carron and coworkers, 1971) and fipexide (Budavari and coworkers, ~989, pg. 639); (b) neurotransmission enhancer drugs (Shimizu, 1991) such as amantadine, calcium hopantenate (Umeno and coworkers, 1981), lisuride, bifemelane (Kikumoto and coworkers, 1981; Egawa and coworkers, 1987; Tobe and coworkers, 1981) and indeloxazine (Tachikawa and coworkers, 1979; Hayes and Chang, 1983; Mizuno and coworkers, 1988); (c) tiapride, a selective D2 blocker (Peselow and Stanley, 1982; Shimizu, 1991); (d) antipsychotic drugs such as haloperidol, bromperidol (Niemegeers and Jans-sen, 1979: Woggon and coworkers, 1979), thioridazine, thio-thixene, fluphenazine, perphenazine and molindone (Shimizu, 1991; and Cooper, 1991): (e) anti-oxidants such as toco-pherols, ascorbic acid (Ceballos and coworkers, 1990) or W095/0109~ PCT~S94/07277 23 6~J

deferoxamine (Halliwell, 1991, pg. 593), as oxidant stress appears to be part of the cytopathology of Alzheimer's disease; (f) acetylcholinesterase inhibitors such as physo-stigmine (optionally with lecithin) (I'hal and Altman Fuid, 1983; Bartus and Dean, 1988; Becker and Giacobini, 1988; Bel-ler and coworkers, 1988; Stern and coworkers, 1988; Thal and coworkers, 1989), heptylphysostigmine (~3rufani and coworkers, 1987; Moos and Hershenson, 1989), tetrahydroaminoacridine (tacrine) (Summers and coworkers, 1986; ~artus and Dean, 1988;
Mesulam and Geula, 1990, pg. 235) and a hydroxy derivative thereof, ('/ )-9-amino-1,2,3,4-tetrahydroacridin-1-ol(Shutske and coworkers, 1988; Davies, 1991, pg. S-25), metrifonate (Becker and Giacobini, 1988), velnacrine maleate (Cooper, 1991; Cutler and coworkers, 1992), galanthamine (Nivalin) (Ferris, 1990; Sweeney and coworkers, 1990), sulfonyl fluor-ides such as methanesulfonyl fluoride (Moos and Hershenson, 1989) and phenylmethylsulfonyl fluoride (Ferris, 1990; Pope and Padilla, 1990), huperzines A and B (Tang and coworkers, 1989; Ferris, 1990), edrophonium (Flood and coworkers, 1988) and miotine and derivatives therof (]~oos and Hershenson, 1989); (g) calcium channel antagonist agents such as diltia-zem, verapamil, nifedipine, nicardipine, isradipine, amlodi-pine and felodipine; (h) biogenic amines and agents related thereto (Moos and Hershenson, 1989) such as clonidine, a nor-adrenergic ~2-receptor agonist (Ferris, 1990; Cooper, 1991), guanfacine, an adrenergic agonist (Cooper, 1991), alaproclate, zimeldine and citalopram; (i) anti-rage drugs such as pro-pranolol, carbamazepine and fluoxetine (Cooper, 1991); (j) anxiolytic agents such as benzodiazepine drugs (Cooper, 1991);
(k) angiotensin converting enzyme inhibitors such as captopril (Capoten, or in combination with hydrochlorothiazide, Capo-zide) (Ondetti, 1988; Ferris, 1990; Cooper, 1991; Whitehouse, 1991); (1) agents which may enhance acetylcholine synthesis, storage or release (Moos and Hershenson, 1989) such as phosph.atidylcholine, 4-aminopyridine (Sellin and Laakso, 1987;
Ferris, 1990; Harvey and Rowan, 1990, pg. 228; Wurtman and WO95/01096 21 ~ fi 3 ~ ~ PCT~S94/07277 coworkers, l99O, pg. 122), bifemelane, 3,4-diaminopyridine (Bartus and Dean, 1988), choline (Summers and coworkers, 1986;
Harvey and Rowan, 1990, pgs. 229-232; Sitaram and coworkers, 1978a; Sitaram and coworkers, 1978b), vesamicol (Moos and Hershenson, 1989), secoverine, bifemelane, tetraphenylurea (Moos and Hershenson, 1989) and nicotinamide (Moos and Hersh-enson, 1989); (m) postsynaptic receptor agonists such as arecoline (Sitaram and coworkers, 1978b; Tariot and cowork-ers, 1988), oxotremorine (Cho and coworkers, 1964; Baratti and coworkers, 1984; Flood and coworkers, 1988; Ferris, 1990), bethanechol (Chan-Palay, l99O, pg. 255; Ferris, l99O), ethyl nipecotate (Moos and Hershenson, 1989) and levacecarnine (Bonavita, 1986; Tempesta and coworkers, 1987; Parnetti and coworkers, 1992); (n) N-methyl-D-aspartate glutamate receptor antagonists such as milacemide (Ferris, l99O; Dysken and coworkers, 1992); (o) ganglioside GM1, as a factor which may potentiate the release of nerve growth factor (Ferris, l99O);
(p) mixed cow brain gangliosides (Cronassial) as a composition for induction of nerve axonal sprouting (Bradley, l99O); (q) specific monoamine oxidase-A inhibitors such as moclobemide (Larsen and coworkers, 1984; Wiesel and coworkers, 1985;
Burkard and coworkers, 1989; Anand and Wesnes, 1990, pgs. 261-268; Chan-Palay, 1992); (r) monoamine oxidase B inhibitors such as selegiline (Cooper, 1991); (s) thiamine (Cooper, 1991) and a derivative thereof, sulbutiamine (Micheau and coworkers, 1985); (t) D-cycloserine (Francis and coworkers, 1991); (u) anfacine (Ferris, 1990); (v) linopirdine; (w) nonsteroidal anti-inflammatory agents such as those recognized for treat-ment of rheumatoid arthritis, as well as deferoxamine (McGeer and Rogers, 1992); and (x) serotoneregic receptor antagonists such as ketanserin (Ketan) and mianserin (Mian) (Normile and Altman, 1988).

Some published work has reported that L-deprenyl (selegiline) may work in part by slowing the aging process (Sanchez-Ramos, 1991, pg. 400). Monoamine oxidase B (MAO-B) activity, which WO95/UI096 6~3~3 ~CT~S94/07277 is thought to increase with aging in some areas of the brain, generates H202, which in turn may generate neurocytotoxic hydroxyl free radicals (HO) and leads to subsequent lipid peroxidation. Hence, use of MAO-B inhibitors such as L-deprenyl may have an anti-aging clin.ical effect (Youdim, 1990). ~The use of L-deprenyl as a clinical agent for treat-ment of canine age-related dementia is an example of the potent.ial veterinary applications of the prior art drugs included in this invention (Milgram, 1992).

Other recognized experimental anti-aging agents include (a) vasodilator and other nootropic direct brain metabolic en-hancer drugs such as ~-carbolines (Moos and Hershenson, 1989), sabeluzole (Clincke and coworkers, 1988; Moos and Hershenson, 1989; Crook, 1990), razobazam (Hock and McGaugh, 1985; Moos and Hershenson, 1989), exifone (Moos and Hershenson, 1989), idebenone (Moos and Hershenson, 1989), pentoxifylline (Moos and Hershenson, 1989), rolipram (Moos and Hershenson, 1989), vinpocetine (Moos and Hershenson, 1989), citicoline (Moos and Hershenson, 1989), bromvincamine (Moos and Hershenson, 1989), cyclandelate (Ananth and coworkers, 1985; Moos and Hershenson, 1989), ergoloid mesylates such as Hydergine (Moos and Hersh-enson, 1989), isoxsuprene (Moos and Hershenson, 1989), nafronyl (Moos and Hershenson, 1989), nicergoline (Moos and Hershenson, 1989), papaverine (Moos and Hershenson, 1989), suloctidil (Moos and Hershenson, 1989), vinburnine (Moos and Hershenson, 1989), vincamine (Moos and Hershenson, 1989), vindeburnol (Moos and Hershenson, 1989), nimodipine (Moos and Hershenson, 1989), naloxone (Jensen and coworkers, 1980; Rush, 1986), piracetam (Moos and Hershenson, 1989), pramiracetam (Moos and Hershenson, 1989), aniracetam (Cumin and coworkers, 1982; Moos and Hershenson, 1989), oxiracetam (Franklin and coworkers, 1986; Spignoli and Pepeu, 1987; Crook, 1990), rolziracetam (Moos and Hershenson, 198~), tenilsetam (Pepeu and Spignoli, 1989; Saletu and coworkers, 1989), flunarizine, phosphatidylserine (Delwaide and coworkers, 1986; Zanotti and WO95/01096 PCT~S94/07277 216~3~ 26 coworkers, 1986; Amaducci and coworkers, 1987; Crook and Larrabee, 1991), dupracetam (Ferris, l99O; Pepeu and Spignoli, l99O; Cooper, 1991; Whitehouse, 1991), propentophylline (Hind-march and Subhan, 1985), ebiratide, pyroglutamic acid and etiracetam; (b) acetylcholinesterase inhibitors such as miotine and derivatives thereof (Moos and Hershenson, 1989), physostigmine (Davis and coworkers, 1978; Bartus and Dean, 1988; Beller and coworkers, 1988; Stern and coworkers, 1988), heptylphysostigmine (Brufani and coworkers, 1987; Moos and Hershenson, 1989), tacrine (Bartus and Dean, 1988; Moos and Hershenson, 1989) and a hydroxy derivative thereof, (~ 9-amino-1,2,3,4-tetra-hydroacridin-1-ol (Shutske and coworkers, 1988), sulfonyl fluorides such as methanesulfonyl fluoride (Moos and Hershenson, 1989; Pope and Padilla, l99O), huperzine A (Moos and Hershenson, 1989), huperzine B (Tang and cowork-ers, 1989), edrophonium (Flood and coworkers, 1988), galan-th~;ne (Nivalin) (Sweeney and coworkers, l99O), metrifonate (Moos and Hershenson, 1989) and velnacrine (Cutler and co-workers, 1992); (c) cholinergic muscarinic agonists such as arecoline (Sitaram and coworkers, 1978b; Tariot and coworkers, 1988), oxotremorine (Cho and coworkers, 1964; Baratti and coworkers, 1984; Flood and coworkers, 1988), bethanechol (Moos and Hershenson, 1989), ethyl nipecotate (Moos and Hershenson, 1989) and levacecarnine (Bonavita, 1986; Tempesta and cowork-ers, 1987; Moos and Hershenson, 1989; Maccari and coworkers, 1990; Parnetti and coworkers, 1992); (d) biogenic amines and co-agents related thereto such as clonidine (Moos and Hersh-enson, 1989), alaproclate (Moos and Hershenson, 1989; Ferris, 1990), guanfacine (Moos and Hershenson, 1989; Crook, 1990, pg.
213), fipexide (Moos and Hershenson, 1989), zimeldine (Moos and Hershenson, 1989) and citalopram (Moos and Hershenson, 1989); (e) anfacine (Ferris, 1990); (f) acetylcholine syn-thesis, storage or release modulators such as choline (Sitaram and coworkers, 1978a; Sitaram and coworkers, 1978b; Franklin and coworkers, 1986), phosphatidylcholine (Crook, 1990, pg.
212), 4-aminopyridine (Sellin and Laakso, 1987; Wurtman and WO95/010916 PCT~S94/07277 coworkers, 1990), 3,4-diaminopyridine (Bartus and Dean, 1988;
Harvey and Rowan, 1990, pgs. 229-232), vesamicol (Moos and Hershenson, 1989), tetraphenylurea (Moos and Hershenson, 1989), secoverine (Moos and Hershenson, 1989), bifemelane (Moos and Hershenson, 1989) and nicotinamide (Moos and Hersh-enson~ 1989); (g) N-methyl-D-aspartate glutamate receptor antagonists (Clineschmidt and coworkers, 1982; Crook, 1990, pg. 214; Ferris, l99O) such as milacemide (Moos and Hershen-son, 1989), dizocilpine (Moos and Hershenson, 1989) and memantine (Moos and Hershenson, 1989); (h) ganglioside GM1 (Moos and Hershenson, 1989); (i) angiotensin converting enzyme inhibitors such as captopril (Ondetti, 1988; Moos and Hershen-son, 1989; Crook, 1990; Ferris, 1990) and quinapril (Moos and Hershenson, 1989); (j) prostaglandin B1 oligomers (PGBX, Fran-son and coworkers, 1991) and other antioxidants (Ceballos and coworkers, 1990); (k) the free radical scavenger agent acetyl-homocysteine thiolactone (Citiolase) (Totaro and coworkers, 1985); (1) sulbutiamine, a derivative of thiamine (Micheau and coworkers, 1985); and (m) serotoneregic receptor antagonists such as ketanserin (Ketan) and mianserin (Mian) (Normile and Altman, 1988).

Drugs recognized or suggested as experimental symptomatic agents for treatment of tinnitus (nerve deafness) include: (a) antidepressants or antianxiety medications such as amitrip-tyline HCl (Elavil), perphenazine/amitriptyline combinations (such as Triavil), alprazolam (Xanax) and triptolene; (b) anticonvulsants such as primidone (Mysoline), phenytoin (Dilantin) and carbamazepine (Tegreto:l); (c) intraveneous lidocaine (Schleuning, 1991); (d) tocainide and flecinide, derivatives of lidocaine which can be administered orally; (e) flunarizine; (f) nicotinamide; (g) amino-oxyacetic acid; (h) nafronyl; (i) aniracetam; and (j) piracetam (Brummett, 1989).
In addition in vitro evidence has been presented which indi-cates that retinoic acid has a stimulatory effect on differ-entiation of cochlear hair cells (Sporn and coworkers, 1977;

wo gS/01096 3~ 28 PCT~S94/07277 Ott and Lachance, 1979; Travis, 1992).

Presently recognized clinical therapeutic technology for treatment of diabetes, or experimental treatment of diabetes includes use of: (a) various insulin derivatives and composi-tions such as Humulin 70/30, Mixtard 70/30 or NOVQ1in 70/30;
(b) various oral sulfanilamide derivative hypoglycemic agents such as tolbutamide (Orinase), acetohexamide, tolazamide (Tolinase), chlorpropamide (Diabenese), glipizide (Glucotrol) and glyburide (Diabeta, Micronase) (Reed and Mooradian, 1991);
(c) vitamin supplements such as vitamin C, vitamin B1 and vitamin B6; (d) angiotensin converting enzyme inhibitors such as captopril, epi-captopril and zofenopril, which also have free radical scavenging properties (Westlin and Mullane, 1988); (e) anti-hyperlipidemia agents such as fibric acid derivatives, including gemfibrozil (LoPid) (Garg and Grundy, 1990), bezafibrate (Olsson and Lang, 1978a; Olsson and Lang, 1978b; Zimmermann and coworkers, 1978; Monk and Todd, 1987) and fenofibrate (Elsom and coworkers, 1976; Wulfert and co-workers, 1976); metformin (Hermann, 1979); guar gum (Lalor and coworkers, 1990); 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors such as lovastatin (Mevacor)(Garg and Grundy, 1990), pravastatin and simvastatin; acipimox, an analogue of nicotinic acid (Fuccella and coworkers, 1980; Lovisolo and coworkers, 1981); nicotinic acid (Fuccella and coworkers, 1980); or bile acid sequestrants such as cholestyramine (Garg and Grundy, 1990) and colestipol (Durrington, 1991; Stern and Haffner, 1991); (f) anti-oxidants such as probucol (Halliwell, 1991, pg. 583; Stern and Haffner, 1991) or PGBX, a polymerized derivative of prostaglandin B1 (Moss and coworkers, 1978;
Polis and Polis, 1979; Polis and Cope, 1980; Franson and co-workers, 1991) and, by inference, 2-aminomethyl-4-tert-butyl-6-iodophenol, 2-aminomethyl-4-tert-butyl-6-propionylphenol and 2,6-di-tert-butyl-4-[2'-thenoyl]phenol(Swingleandcoworkers, 1985; Halliwell, 1991, pg. 596); (g) immunosuppressive drugs such as cyclosporine (Sandimmune) or azathioprine/glucocorti-WO95/01096 PCT~S94/07277 ~16,638~

coids (Marks and Skyler, 1991; Skyler, 1991); (h) agents whichdecrease blood platelet aggregation such as salicylates and dipyridamole (Persantine) (Skyler, 1991); (i) agen~s which de-crease blood viscosity such as pentoxifylline (Trental) (Sky-ler, lg91); (j) purified cow brain mixed gangliosides (Cronas-sial) (Bradley, l99O); (k) various agents for treatment of diabetes-related nephrotic syndrome such as furosemide, metolazone, lovastatin, heparin, warfarin, and aminoguanidine (Brownlee and coworkers, 1986); (1) aldose reductase inhibi-tors (Skyler, 1991) such as sorbinil (Sima and coworkers, 1988), alrestatin (Kikkawa and cowor~ers, 1983); (E)-3-carboxymethyl-5-[(2E)-methyl-3-phenyl-propenylidene]rhodanine (Kikkawa and coworkers, 1983), statil (Daniels and Hostetter, 1989), and tolrestat (Dyck, 1989); and (m) analgesic agents such as acetaminophen for treatment of chronic pain (Weglicki and coworkers, l99O; Cooper, 1991; Guthrie, 1991; Skyler, 1991; Woodley and Whelan, 1992, pg. 224).

Various immunosuppressive agents have been proposed for the treatment of multiple sclerosis (Goodin, 1991). These in-clude: (a) azathioprine (Ellison and c~workers, 1988); (b) copolymer-l (Bornstein and coworkers, 1938); (c) cyclosporine (Dommasch, 1988); (d) interferons (Knobler, 1988); (e) corti-costeroids (Carter and coworkers, 1988); and (f) cyclophos-phamide (Carter and coworkers, 1988). Other experimental therapeutic agents for treatment of multiple sclerosis include the use of 4-aminopyridine (Sellin and Laakso, 1987), 3,4-di-aminopyridine (Bever and coworkers, l99O), which may be clas-sified as drugs which affect acetylcholine synthesis, storage or release, and baclofen, a skeletal muscle relaxant. In view of their diverse physiochemical activities, interferons may be regarded as examples of immunomodulator drugs. Within the context of the present invention, copolymer-l may also be regarded as an immunomodulator drug, and cyclophosphamide may be regarded as an example of a nonsteroidal anti-inflammatory drug.

-WO95/01096 PCT~S94/07277 Recent studies on amyotrophic lateral sclerosis have included experimental use of purified cow brain mixed gangliosides, and this agent has also been used in experimental clinical trials on alcoholic polyneuropathy and hereditary motor and sensory neuropathies (HMSN) (Bradley, 1990). Thyrotropin releasing factor (Bradley, 1990), serine, glycine and L-threonine (Roufs, 1991) have also been proposed as a possible therapeu-tic agents for treatment of amyotrophic lateral sclerosis.
Other agents which have been proposed as therapeutic agents for treatment of alcoholism include (a) tiapride, a substi-tuted benzamide (Shaw and coworkers, 1987); (b) 4-amino-pyridine (Sellin and Laakso, 1987); (c) physostigmine (Stojek and coworkers, 1986); (d) piracetam (Moos and coworkers, 1988, pg. 361); and (e) cyclandelate (Ananth and coworkers, 1985).
3,4-Diaminopyridine is another agent which has been proposed for the treatment of hereditary motor and sensory neuropathy (Windebank, AJ, Mayo Clinic, study in progress as of 1993).

Numerous prior art publications have disclosed that vitamin E
(~-tocopherol) functions physiologically as a lipid-soluble anti-oxidant free radical trapping agent. Prior art publi-cations have also described methionine as a water-soluble agent, an essential amino acid, an anti-oxidant and a free radical trapping agent. Many attempts have been made to clinically treat neuromuscular diseases with anti-oxidants, generally with little success. For example, Williams and coworkers (1990) reported that dietary supplementation with vitamin E had no significant effect on the clinical status of HMSN patients, while Gerster (1991) reported that dietary supplementation with a combination of vitamin C, vitamin E, ~-carotene, and selenium had the effect of halting or improving degenerative retinal changes in some patients having either age-related macular degeneration or diabetic retinopathy.
Additional work of this conceptual nature includes the work of Muller (1990), who reported that ~-tocopherol has a positive effect on the clinical status of patients suffering from W095l01~96 , 3~o~ PCT~594/07277 tardive dyskinesia. Yet none of these studies has disclosed the invention contained in copending US patent application 08/026,617, that is, treatment of neurodegenerative diseases by use of primary agents which are primary amine and amine-related substances to inhibit aldehyde-mediated protein and lipid crosslinking, said primary agents capable of being used in combination with known anti-oxidants and related substances as co-agents.

Vitamin C (ascorbic acid) is widely recognized as a water-soluble anti-oxidant vitamin. However, numerous published studies which have appeared since 1980 document that vitamin C also can act physiologically as a pro-oxidant (Gutteridge and Wilkins, 1982), an agent which stimulates lipid peroxida-tion (Chojkier and coworkers, 1989, pgs. 16957 and 16961), and that it is a strong protein glycosylating agent (Ortwerth and Olesen, 1988, pgs. 12, 14, 16, 18 and 20). Thus, for example, in vitro studies have documented the abi]ity of vitamin C to accelerate the process of cataract format:ion (Slight and co-workers, 1990, pgs. 369-373). In addition, some evidence sug-gests that ascorbic acid may act as a factor which stimulates - certain reactions which are characteristic of inflammatory diseases. For example, the presence of ascorbic acid in the synovial fluid of the arthritic joint may contribute to degradation of hyaluronic acid (Wong and coworkers, 1981;
Higson and coworkers, 1988). In light of such information, use of ascorbic acid has been withdrawn from the invention originally disclosed in US patent application 07/660,561.

As discussed in US patent application 08/026,617, a consider-able body of prior art publications has provided evidence suggesting that the etiologies of certain neurodegenerative diseases include evidence of chemical crosslinking of neuro-filaments. Such studies include work on hereditary motor and sensory neuropathies (Hughes and Brownell, 1972; Brimijoin and coworkers, 1973; van Weerden and coworkers, 1982; and Goebel WO9~/01096 PCT~S94/07277 21~G~-3 and coworkers, 1986), giant axon neuropathy (Prineas and co-workers, 1976), diabetic polyneuropathy (Yamamura and cowork-ers, 1982; Sidenius and Jakobsen, 1982; and Tomlinson and Mayer, 1984), Alzheimer's disease (Wisniewski and coworkers, 1970; Iqbal and coworkers, 1978, and Wisniewski and coworkers, 1982, pp. 110-112), Down's syndrome (Goodison and coworkers, 1989), Pick's disease (Yoshimura, 1989), Parkinson's disease (Oppenheimer, 1976, pp. 612-614; and Cohan, 1989, pg. 167), amyotrophic lateral sclerosis (Carpenter, 1968), infantile spinal muscular atrophy (Lee and coworkers, 1989), Fried-reich's ataxia (Lamarche and coworkers, 1982) and alcoholic polyneuropathy (Appenzeller and Richardson, 1966).

Likewise, evidence of increased deposition of lipofuscin in various neurodegenerative diseases has been presented. This observation has been documented in studies on amyotrophic lateral sclerosis (Carpenter, 1968), Guam Parkinsonism-de-mentia (Tan and coworkers, 1981), Alzheimer's disease (Tsuch-ida and coworkers, 1~987; Moran and Gomez-Ramos, 1989), Hunt-ington's disease (Tellez-Nagel and coworkers, 1974), Meniere's disease (Ylikoski and coworkers, 1980), and juvenile ceroid-lipofuscinosis (Schwendemann, 1982). Heart lipofuscin has been shown to have the following general composition: lipids, 20-50%; protein, 30-60%; and strongly pigmented resin-like hydrolysis-resistant material, 9-20%. Although the exact nature of the hydrolysis-resistant chemical bonds remains to be unequivically defined, the similarity between lipofuscin fluorescence and that of Schiff bases formed between malon-aldehyde and primary amines suggests that similar chemical crosslinks may be part of lipofuscin structure (Tsuchida and coworkers, 1987).

The results of several published research studies suggest that dysfunctional lipid peroxidation may be a contributing factor in the etiology of Parkinson's disease (Fahn, 1989), multiple sclerosis (Hunter and coworkers, 1985) and Duchenne muscular WO95/01096 PCT~S94/07277 dystrophy (Kar and Pearson, 1979; Jackson and coworkers, 1984;
Hunter.and Mohamed, 1986).
., Age-related changes share much in common with other disease entities discussed in this invention. At the biochemical level, the two most clearly defined patho.logical events within aging m~m~l ian cells appear to be (1) the progressive accumu-lation of lipofuscin and (2) concomitant appearance of high molecular weight protein aggregates and/or polymeric lipid-protein complexes (Shimasaki and coworkers, 1984). Age-onset peripheral nerve damage has been recognized in both man and experimental animals. Such polyneuropathy is extremely common in the elderly (Cohan, 1989). ~m; na.tion of human sural nerve biopsies has revealed age-related degeneration of both myelinated and non-myelinated fibers. This process includes the occurrence of unusual inclusions wit.hin axons consisting of filament bundles which appear more dense than those of normal neurofilaments (Ochoa and Mair, 1969). As peripheral, autonomic and central nervous system neu.rons lose functional ability as part of the aging process a variety of body functions under their control are adversely affected.

Autonomic nervous system functions include urinary continence, peristaltic movement of the digestive tract, sexual response and breathing. Forms of neurological dysfunction lying within the scope of this invention which may cause urinary inconti-nence include: Alzheimer's senile dementia, demyelinating diseases such as multiple sclerosis, peripheral nerve lesions, diabetes mellitus and alcoholic polyneuropathy (Palmer, 1985, pg. 27). Causes of urinary incontinence which may be classi-fied as urological/gynecological, psychological or environ-mental (Palmer, 1985, pg.22) do not fall within the scope of this invention. Drugs which are present].y recognized for use in treatment include cholinergics such as bethanechol, anti-cholinergics such as belladonna and ~-adrenergic agonists such as ephedrine (Palmer, 1985, pg. 58). None of these therapeu-WO95/01096 PCT~S94/07277 216638~ --tic agents have been heretofore recognized as drugs fallingwithin the pharmacological scope of US patent application 08/Q26,617, although this inventor regards the ~-adrenergic agonists ephedrine, which contains a secondary amine group, and phenylpropanolamine, which contains a primary amine group, as potential carbonyl-trapping agents.

Peristaltic movement of the digestive tract, which is con-trolled by the autonomic nervous system, may be adversely affected due to aging, diabetes (Bergmann and coworkers, 1992) or other clinical disorders. Drugs presently recognized for the treatment of gastroesophageal reflux disease, hypoperi-stalsis and/or delayed gastric emptying include (a) metoclo-pramide (Reglan); (b) cisapride (PrePulsid) (Bergmann and coworkers, 1992); (c) famotidine (PePcid); (d) cimetidine (Tagamet); (e) ranitidine (Zantac); (f) omeprazole (Prilosec);
and galan~h~m;ne (Sweeney and coworkers, 1990).

In their study on human senile and diabetic cataracts, Rao and Cotlier (1986) noted evidence that crosslinking of lens pro-teins via nonenzymatic glycosylation appears to be an under-lying pathological mechanism for both cataract types. In their analysis of senile cataracts these investigators ob-served statistically significant decreases in soluble protein content, increases in insoluble proteins, decreases in free ~-amino groups of insoluble proteins and increases in observed 5-hydroxymethyl furfural levels (that is, reducible Maillard products) in insoluble proteins. Similar data were obtained from diabetic cataracts. Earlier studies showed the appear-ance of covalently crosslinked protein polymers during senile cataract formation (Selkoe and coworkers, 1982). Evidence of increased lipid peroxidation in the aged human lens has also been presented (Bhuyan and coworkers, 1986).

In addition, several published studies have presented evidence which implicates lipid peroxidation products in the etiology WO951~1~96 66383 ~CT~S94/U7277 of atherosclerosis (Halliwell, 1991, pg. ';83). 4-Hydroxy-2,3-trans-nonenal covalently binds to lysine and other peptide residues of low-density lipoprotein much more readily than malondialdehyde. Hence, it (as well as other aldehydes) may play a role in the etiology of atherosclerotic lesions (Jur-gens and coworkers, 1986; and Esterbauer and coworkers, 1987).
As summarized by Steinbrecher (1987), there is reason to believe that reactive lipid peroxidation agents form Schiff base adducts with the lysine ~-amino groups of low density lipoproteins (LDL). Such modified LDL's are recognized by high-affinity acetyl-LDL receptors located on macrophages, which results in lipid accumulation. Lipid-laden macrophages appear to be precursors of the foam cells which populate early atherosclerotic lesions (Steinbrecher, 1987). Use of the invention of US patent application 08/026,617 in combination with previously recognized medicaments for treatment of atherosclerosis, hypertension and ischemic heart disease, as defined herein, may provide additional clinical benefit for patients suffering from these chronic, age-related diseases.
Previously recognized drugs for treatment of atherosclerosis include hypolipidemic agents such as fenofibrate (Elsom and coworkers, 1976; Wulfert and coworkers, 1976), bezafibrate (Olsson and Lang, 1978a; Olsson and Lang, 1978b; Zimmermann and coworkers, 1978; Monk and Todd, 1987), metformin (Hermann, 1979), nicotinic acid (Fuccella and coworX:ers, 1980), acipimox (Fuccella and coworkers, 1980; Lovisolo and coworkers, 1981) and guar gum (Lalor and coworkers, 1990), as well as anti-oxidants such as probucol (Halliwell, 199:L, pg. 583; Stern and Haffner, 1991) and prostaglandin B1 oligomers (PGBX) (Moss and coworkers, 1978; Polis and Cope, 1980) Previously known medicaments for treatment of hypertension (Woodley and Whelan, 1992, pp. 64-75) include diuretics, ~-adrenergic antagonists, calcium antagonists, angiotensin converting enzyme inhibitors, centrally acting ~-adrenergic agonists, direct-acting vaso-dilators, ~-adrenergic antagonists and peripherally acting anti-adrenergic agents. At least one peptide-based renin WO95/01096 PCT~S94/07277 ~Ga3s3 inhibitor (A-725517, Abbott Laboratories) has also been men-tioned as a prospective anti-hypertensive agent (Kleinert and coworkers, 1992). Previously known medicaments for treatment of ischemic heart disease include nitroglycerin, ~-adrenergic antagonists, calcium channel antagonists and aspirin (Woodley and Whelan, 1992, pp. 81-84). Recognized ventricular anti-arrhythmic drugs include sotalol, mexilitene, propafenone, quinidine gluconate, procainamide and pirmenol (Toivonen and coworkers, 1986). Some published information indicates that at least part of the physiological activity of some cardio-protective drugs may be due to their possessing certain free radical scavenging and/or anti-oxidant properties. This appears to be the case for (a) ~-blocker agents such as propranolol, pindolol, metoprolol, atenolol and sotalol; (b) calcium channel blockers such as nifedipine, verapamil and diltiazem; (c) probucol; and (d) angiotensin converting enzyme inhibitors such as captopril, epi-captopril and zofenopril (van Gilst and coworkers, 1986; Ondetti, 1988; Weglicki and coworkers, 1990).

This inventor has published the findings of a study which may describe part of the physiological basis of one of the heredi-tary motor and sensory neuropathies (Shapiro and coworkers, 1986; Shapiro and Kahn, 1990). In this study urine samples from five autosomal dominant chromosome 17 HMSN patients of the same family and five urine samples from age- and sex-matched normal control subjects were examined. By use of gas chromatography/mass spectrometry the urine concentrations of approximately 150 organic acids could be estimated in each sample. Average HMSN organic acid values differed most not-ably from normal values in a set of three physiologically related metabolites, 5-hydroxymethyl-2-furoic acid, 2,5-furandicarboxylic acid and 5-carboxy-2-furoylglycine. Average patient urine concentrations of these three organic acids were 29%, 50% and 37% of controls, respectively.

WO95/01096 6r383 PCT~594/07~77 5-Carboxy-2-furoylglycine is a mono-glycine conjugate of 2,5-furandicarboxylic acid. Hence 2,5-furandicarboxylic acid was measured directly as the dicarboxylic acid and indirectly as its mono-glycine conjugate. Glycine conjugation is a well recognized liver detoxication/excretion reaction, applied broadly to the carboxylic acid products of many endogenous HO H2C~o~,COOH HOOC~,COOH HOOC~ NH-CH2-COOH

5-hydr~xymethyl- 2,5-furandicar- 5-carboxy-2-2-furoic acid boxylic acid furoylglycine metabolites, dietary components and drugs (Williams, 1959, pp.
349-353).

Previous research studies have determined that 5-hydroxy-methyl-2-furoic acid and 2,5-furandicarboxylic acid are oxida-tion products of an aldehyde precursor, 5-hydroxymethyl-2-furfural (Jellum and coworkers, 1973). Decreased levels of furancarboxylic acid excretion suggest that this metabolite, and possibly other aldehyde precursors such as 2,5-furandi-aldehyde, is not being detoxicated and cleared in a normal manner. Several enzymes may be involved in the normal detox-ication of furanaldehydes. Oxidation of furanaldehydes to carboxylic acid products is known to occur in mammalian tissues (Williams, 1959, pp. 550-551), but: a specific furan-aldehyde dehydrogenase has not been characterized.

Prior art studies have demonstrated the existance of several mammalian aldehyde dehydrogenases which possess wide substrate specificities (Hjelle and Petersen, 1983; Lindahl and Evces, 1984). These are NAD(P)-dependent enzymes. Normal detoxi-cation of furanaldehydes may involve roles for one or more of these enzymes, or their flavin-dependent counterpart, and the HMSN pat:ients studied by this inventor and coworkers may have WO95/01096 PCT~S94/07277 2~663~

a genetic defect in this process.

5-Hydroxymethyl-2-furfural should be regarded as a potential protein crosslinking agent (Jellum and coworkers, 1973, pg.
200). 2,5-Furandialdehyde is even more suspect as a potential crosslinking agent, as it bears two highly reactive aldehyde groups. It is a close structural analogue of 2,5-hexanedione, a potent chemical peripheral neurotoxin implicated in the covalent crosslinking of neurofilaments.

H~ ~ CH CH2-CH2 2,5-furandialdehyde 2,5-hexanedione Hence 2,5-furandialdehyde appears to be a particularly inter-esting metabolite. It is cleared from the body only with difficulty in patients having a genetic peripheral neuropathy;
and its size, three dimensional shape and analogous bicarbonyl structure make it structurally related to a chemical known to induce peripheral neuropathy in mammals after relatively trace levels of exposure (Krasavage and coworkers, 1980). Covalent chemical crosslinking of neurofilaments has been shown to be the basis of 2,5-hexanedione neurotoxicity (Carden and cowork-ers, 1986).

There is reason to believe that 5-hydroxymethyl-2-furfural and 2,5-furandialdehyde can originate as by-products of either of two general areas of metabolism, that of sugars and lipids.
The thought that secondary products of lipid peroxidation might include metabolites such as 5-hydroxymethyl-furanalde-hyde and 2,5-furandialdehyde has attracted little, if any, attention within the biomedical research community prior to submission of US patent application 07/660,561. As described in that disclosure, 2,5-dimethyl furan appears to be a key intermediate in the process leading to the appearance of these WO95/01096 383 PCT~S94/07277 aldehydes.

5-Hydroxymethyl-2-furfural and 2,5-furandialdehyde can also form spontaneously from glucose or fructose under mildly acidic aqueous conditions and, as they are readily generated during food cooking, they are part of the human diet. There is reason to believe that these aldehydes, among others, may play a significant role in the etiology of diabetic poly-neuropathy. As discussed in US patent application 08/026,617, it is the understanding of this inventor that conversion of fructose to 5-hydroxymethyl furfural and possibly 2,5-furandi-aldehyde may in fact be the basis of neurotoxic consequences resulting from activation of the polyol pathway seen in dia-betic polyneuropathy.

Studies during the past decade have clearly established that long-term hyperglycemia associated with diabetes leads to generalized non-enzymatic addition of reducing sugar residues to proteins via covalent addition to amine functional groups located on amino acid sidechains. Following initial addition, several structural rearrangements occur which can result in intra- and intermolecular crosslinking of proteins (Brownlee, 1990). This is a complex series of non-enzymatic reactions which are not completely defined at this`time. Yet, as dis-cussed in US patent application 08/026,617, there is reason to believe that this phenomenon is involved in diabetic vascular changes, diabetic nephropathy, cataracts, diabetic retinopathy and other secondary diabetic symptomology. Such reactions may also underlie much of the biochemistry of aging (Pongor and coworkers, 1984).

The nature of the chemical bonds responsible for holding to-gether the neurofibrillary tangles of Alzheimer's disease (AD) and other neurodegenerative diseases is still poorly under-stood. What limited information is publicly available on this question is compatable with the overall inventive concept of WO95/01096 PCT~S94/07277 ` 2~3~3 US patent application 08/026,617; that cytotoxic consequences result from various forms of spurious covalent bond protein crosslinking, at least some forms of which may be clinically treated by the pharmacological procedures described therein.

Both AD senile plaques and neurofibrillary tangles consist largely of networks of intermediate size protein filaments helically wound in pairs having a periodicity of 80 nm (Selkoe and coworkers, 1982). Isolated paired helical filament (PHF) has proven to have remarkable properties of chemical stabil-ity. PHF chemical crosslinking bonds are not broken by sodium dodecyl sulfate, ~-mercaptoethanol, 9.5 M urea, two percent Triton X-100, one percent NP-40, 6 M guanidine hydrochloride, 0.2 N HCl or 0.2 N NaOH. As heating of PHF in the presence of either reducing agents such as ~-mercaptoethanol or detergents such as Triton X-100 or NP-40 did not solubilize PHF, bonds other than disulfide are implicated in amino acid crosslinking of this type of rigid intracellular polymer. This unusual chemical stability has seriously impeded PHF analysis by gel electrophoresis (Selkoe and coworkers, 1982). As a postulated mechanism for such unusual crosslinking Selkoe and coworkers (1982) noted that "different protein polymers in senile cata-racts, terminally differentiated epidermal cells, and red blood cells are covalently crosslinked by y-glutamyl-~-lysine sidechain bridges." Like PHF, these other protein complexes are insoluble in sodium dodecyl sulfate and not solubilized by reducing agents. Selkoe and coworkers (1982) speculated that such y-glutamyl-~-lysine crosslinks may also form pathologi-cally in nerve cells, as human brain contains a transglutamin-ase capable of acting on normal neurofilament to form an in-soluble high molecular weight filamentous polymer.

The clinical neurology literature includes many descriptions of patients having an incipient form of a disease, patients showing the recognized symptoms of a disease and additional symptomology, and patients demonstrating concurrent clinical 95/0109l6 ~ PCT~S94/07277 ~1 symptomology of two or more recognized disease entities. Such clinical disorders are frequently excluded from biochemical studies due to inherent problems of classification and their happenstance occurrence. Hence comparatively little research information is available on such clinical phenomena. Yet it is the understanding of this inventor that information avail-able on the etiologies of well recognized neurological dis-orders, as summarized herein, can also be extrapolated to infer that the drug therapies described in this invention may also be applied with success to the incipient and more complex forms of the diseases mentioned above.

OBJECTS OF THE INVENTION

Accordingly, it is a general object of this invention to treat neurological diseases and etiologically related symptomology by use of carbonyl trapping agents in combination with known antioxidant free radical trapping co-agents, and in combina-tion with various additional known medicaments which have been shown to or may contribute to the alleviation of symptomology of the diseases addressed herein, so as to overcome the dis-advantages of the prior art.

In particular, it is an object of the present invention that the drug compositions originally described in US patent ap-plication 07/660,561 may be combined with known medicaments so as to ~rovide increased clinical value in the treatment of disease symptomology for disorders featuring well defined neurofilament associated pathology, lipofuscin accumulation and/or aberrant lipid peroxidation, including: diabetic poly-neuropathy and related metabolic symptomology; Alzheimer's presenile/senile dementia; Down's syndrome; Parkinson's dis-ease; amyotrophic lateral sclerosis; age-related atrophy of peripheral sensory and motor nerves, autonomic nerves, and neurons of the central nervous system, and pathophysiologi-cally related changes in the cardiovascular system, kidney, WO95/01096 PCT~S94/07277 2~ 8~ --and optic lens; alcoholic polyneuropathy; multiple sclerosis;
olivopontocerebellar atrophy; Huntington's disease and dis-orders clinically related thereto.

It is another object of the present invention that in so far as the therapeutic procedures described herein may serve to delay the necessity of initiating the use of known medica-ments or to decrease the dosages of known medicaments required to achieve beneficial effects, the period of prior art drug therapeutic value may be extended and detrimental clinical side effects resulting from use of known medicaments may be decreased, so that overall patient treatment may be improved.

It is another object of the present invention that in so far as the therapeutic procedures described herein may be of bene-fit for improvements in autonomic nervous system function, it is claimed that such procedures may better ameliorate symp-tomology of urinary incontinence.

It is yet another object of the present invention that in so far as the therapeutic procedures described herein may serve to covalently bind and sequester agents which may underlie, in part, the etiology of atherosclerosis, it is believed that such procedures may be of benefit in treatment of this age-related disorder.

It is a further object of this invention that the absorbable amine and amine-related substances and derivatives thereof described herein when used in combination with specified co-agents may be clinically applied to treat veterinary disorders comparable to those human disorders described above.

It is a further object of this invention to draw attention to and originally recognize that the appearance of one or more chromosome 17 HMSN-specific cultured fibroblast proteins may be used as a clinical diagnostic procedure for defining the W095/010g6 PCT~S94/07277 43 ~3~
presence of this genetic disease.

Use of absorbable amine and amine-related primary agents, non-absorbable amine and amine-related co-agents, co-agents which inhibit lipid peroxidation, human growth hormone co-agent, vitamin co-agents which may be inadvertently depleted, co-agent metabolites such as glycine which may be depleted within the body, and sulfhydryl co-agents as defined in US patent ap-plication 08/026,617 is included in the present invention, in combination with use of various additional known medicament co-agents which have been shown to or may contribute to the alleviation of symptomology of the diseases addressed herein.
In addition, the present invention includes use of various co-agents which may facilitate glutathione activity, such as N-acetylcysteine, oxothiazolidinecarboxylate, timonacic acid, cysteamine, lipoamide derivatives such as malotilate (Kantec), sulfarlem (ADT), and oltipraz (Dansette and coworkers, 1990), as these co-agents may further serve to improve the invention described in US patent application 08/026,617.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

l. Physiological Basis of the Invention These and other objects of this invention are achieved by pro-viding a novel method for clinical treatment of neurological diseases and etiologically related clinical symptomology.
While the causes of these diseases are diverse and largely undefined at present, these disorders nevertheless share many common characteristics at the cellular level.

For any one neurological disease certain nerve cells, usually with a characteristic anatomical distribution, will undergo a process of intracellular deterioration, eventually leading to cell death. In this process certain normal intracellular structures are progressively altered in terms of structure, as WO95/01096 PCT~S94/07277 ~&6~

apparent by electron microscopy, and function, as indicated by enzyme activities. In addition, certain pathological struc-tures, not normally present, will appear and usually develop in terms of number and size until they come to dominate the intracellular environment. These neuropathological changes end in cell death.

Biomedical information now publicly available indicates or suggests that spurious, pathological chemical crosslinking of normal intracellular structures is a fundamental aspect of the neurological diseases addressed herein. Such covalent bond crosslinking of protein and lipid subcellular elements appears to underlie the formation of at least four common neuropatho-logical structures: (1) polymerized aggregates of structural protein filaments (e.g., excess neurofilament accumulation), (2) heterogeneous protein aggregates (e.g., neurofibrillary tangles), (3) amorphous protein and lipid aggregates (e.g., senile plaques), and (4) lipofuscin granules, which are amor-phous aggregates rich in lipid chemical complexes. Spurious, excess protein chemical crosslinking is also apparent in the extracellular compartment in some of these diseases, for ex-ample, blood capillary basement membrane thickening in long term diabetes mellitis. In addition, analogous pathological chemical crosslinking of DNA can also occur under certain cir-cumstances, thus further damaging cells prone to such attack.
Based on the presence of one~or more of the neuropathological events noted above, the drug treatment protocols falling with-in the scope of this invention may be of benefit to patients having one of the diseases addressed herein.

Moving to the chemical level, considerable biomedical litera-ture indicates that certain sites on normal proteins and lipids are specific targets for spurious chemical crosslink-ing, most notably the ~-amino groups of lysine residues in proteins and the amine groups of phosphatidylethanolamine molecules in cell lipid membrane bilayers. These primary WO95/010916 PCT~S94/07277 2~ 6g3~3 amine groups are especially prone to attack by small molecular weight carbonyl-containing hydrocarbons Such carbonyl-con-taining molecules may originate by many pathological mechan-isms still only partly defined, but, in general, they origin-ate from peroxidation of fatty acids or as by-products of sugar metabolism. A monocarbonyl specie can bind to a protein or amino-lipid, alter its three dimension,al structure and pos-sibly affect its chemical activity. A d:icarbonyl hydrocarbon can react with two amine groups, thus making a covalent chemi-cal crosslink. The specific primary pathological changes which underlie this type of deterioration remain largely unde-fined, but their structural products have been characterized in many respects.

Kikugawa and Beppu (1987) noted that lipid radicals, hydro-peroxides and their secondary products react with neighboring protein molecules, damaging protein structure and function.
Such damage includes formation of fluorescent chromophores, lipid-protein adducts, and protein-protein crosslinks. Using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, these investigators demonstrated that malonaldehyde (also known as malondialdehyde), a bifunctional molecule having two aldehyde groups, can covalently crosslink proteins. This re-action primarily involves Schiff base formation with protein ~-amino groups on the sidechains of lysine residues. Kikugawa and Beppu (1987) also reported that monofunctional aldehydes such as acetaldehyde, l-hexanal, l-heptanal and 2,4-decadienal can also crosslink proteins, generating fluorescent products.
This biochemical curiosity still not well understood. Some form of self-condensation may be involved.

The generation of water soluble, carbonyl-containing products of lipid peroxidation can be readily demonstrated under simple in vitro conditions. Schauenstein (1967~ incubated suspended polyunsaturated fatty acid esters with water at 40C in the presense of air and demonstrated the generation of numerous WO95/01096 PCT~S94107277 2~ 3~ --such products. These included oct-2-trans-en-1-al, 4-hydro-peroxynon-2-en-l-al, 1-hydroxyheptan-2-one, 4-hydroxy-2-trans-octen-1-al, as well as numerous other water soluble products not characterized in Schauenstein's investigation. Other in-vestigators have also documented the generation of numerous carbonyl-containing products of lipid peroxidation, however the exact identities of many of these agents remains undefined (Esterbauer and coworkers, 1982).

The conceptual similarities between lipid peroxidation-induced protein crosslinking and protein crosslinking associated with non-enzymatic glycosylation has been noted in the research literature (Kikugawa and Beppu, 1987). Some evidence has been presented which suggests that a slow, age-dependent deteriora-tion of biological systems which counteract lipid peroxida-tion may be a fundamental part of the aging process (Harman, 1971). This concept is sometimes referred to as the free radical theory of aging.

A variety of furans, aldehydes and ketones have been identi-fied in normal human urine (Zlatkis and Liebich, 1971; Matsu-moto and coworkers, 1973). These include 2,5-dimethyl furan, 2-methyl furan, other alkyl furans, and a variety of five- to eight-carbon alkyl aldehydes and ketones. Yancey and cowork-ers (1986) induced lipid peroxidation in rats by use of a defined diet deficient in both vitamin E and selenium, and then studied volatile urine metabolites. The results showed that urine of vitamin E deficient animals contained 16 carbon-yl compounds which were present at elevated levels of statis-tical significance. The greatest increases observed were for hydroxyacetylaldehyde (676%), benzaldehyde (538%) and furfural (487%). In discussing their findings, Yancey and coworkers concluded, in part:

Both capillary GC and LC results appear to im-plicate aldehydes (both normal and unsaturated) WO95/01096 PCT~S94/07277 63b~

and related compounds, furan derivatives, as characteristic products of lipid peroxidation.
Elevated aldehyde levels were also noticed in our -earlier investigations of urinary metabolites of both long-term diabetic rats and genetically diabetic mice. Since an increased lipid peroxid-ation process has been associated with the diabetic condition, it is not surprising that known peroxid-ation metabolites should be more abundant in diabetic than normal urine samples...
Increased lipid peroxidation clearly results in a greater production of metabolites t:hat are either proven or suspected neurotoxins.

Non-enzymatic in vitro autoxidation of furfural has been described, which yields a mixture of products which includes 2-furoic acid (Dunlop and Peters, 1953, pg. 385). Likewise, Williams (1959, pp. 550-551) has described the mammalian in vivo oxidation of 2,5-dimethyl furan to 5--methyl-2-furoic acid and of 5-hydroxymethyl-furfural to 5-hydroxymethyl-2-furoic acid. In principle, the process of enzymatically converting hydrocarbon functional groups such as a methyl group of 2,5-dimethyl furan to a carboxylic acid group involves three con-secutive oxidation reactions.

As summarized above, and discussed at greater length in US
patent application 08/026,617, 2,5-dimethyl furan is a recog-nized secondary product of lipid peroxidation and there is reason to believe that it may be oxidize~ in vivo to products such as 5-hydroxymethyl-2-furancarboxylic acid and 2,5-furan-dicarboxylic acid. This, in turn, suggests that 5-hydroxy-methyl furfural and 2,5-furandialdehyde may be metabolic intermediates in this process.

It is the unique belief and understand:ing of this inventor that the long term generation of furan aldehyde agents as by-WO95/01096 2 ~6~ PCT~S94/0727 products of lipid peroxidation can serve as a metabolic basisor underlying contributing factor in the etiology of diabetic symptomology, the etiology of other neurological diseases featuring evidence of Schiff base type chemical crosslinking phenomena, and in the etiology of age-related symptomology.
It seems reasonable to this inventor that the chromosome 17 HMSN patients discussed above were experiencing toxic long term consequences of furanaldehyde exposure as a consequence of defective ability to oxidize furanaldehydes which are nor-mal products of lipid metabolism. Failure to dispose of these reactive metabolites efficiently may predispose the patients to pathological events initiated by spurious protein cross-linking. For diabetic patients, on the other hand, excess levels of furanaldehyde metabolites seem to appear as a conse-quence of chronic hyperglycemia. It appears that in the dia-betic state in vivo capacity to oxidize or otherwise detoxify furanaldehydes is simply exceeded by endogenous generation of these toxic metabolites. Thus there does appear to be a de-gree of similarity between these two disease states, reflected in similar peripheral neuropathies, yet their metabolic ori-gins appear to be different.

The present invention discloses protocols of drug therapy for treatment of the medical disorders addressed herein. As ori-ginally described in US patent application 07/660,561, these pharmacological reactions are based on the ability of primary amine and amine-related agents to react with aldehyde func-tional groups of potentially toxic agents, yielding covalently bound Schiff base products, and one may add to the beneficial effects of said treatment by compounding the primary agent with various co-agents.

US patent application 08/026,617 sets forth that absorbable pharmaceutical agents such as p-aminobenzoic acid when admin-istered to humans in oral dosages of from one gram/day to 40 grams/day may be used as therapeutic agents for treatment of WO95/01096 PCT~S94/07277 21.663 certain neurological diseases and for treatment of other pathophysiologically related clinical phenomena. US patent application 08/026,617 also comprises use of orally adminis-tered, nonabsorbable polyamine polymeric co-agents such as chitosan for use in treatment of the di;ease entities noted above. Such nonabsorbable pharmacological co-agents may act to covalently bind and sequester potentially toxic carbonyl compounds present in the diet. In addition, US patent appli-cation 08/026,617 comprises the use of ;uch chemical agents and co--agents in combination with antioxidants such as ~-tocopherol, suspending reagents such as carboxymethyl cellu-lose for the compounding of oral tablets, other vitamins, and chemical conjugating co-agents which may facilitate kidney drug elimination, such as glycine. The present disclosure describes the inventive concept of using the therapeutic tech-nology of US patent application 08/026,617 in combination with pharmaceutical agents previously recognized as having, or pos-sibly having some medicinal value for treatment of the disease entities noted above.

2. Examples of Orally Administered Absorbable Drug Products Useful in the Present Invention It is the central premise of US patent application 08/026,617 that an opportunity exists, heretofore unrecognized, for phar-macological intervention in some neurological diseases by use of watex soluble, small molecular weight primary amine agents and chemical derivatives thereof. Such pharmacological agents, administered orally, can compete with cellular protein and lipid amine groups for reaction with disease-induced car-bonyl-containing hydrocarbons. Such derivatized pharmacolog-ical agents can then be excreted by the kidneys. This pro-cess, while not necessarily addressing the primary etiology of a neuropathy, may be of practical clinical benefit to signifi-cantly delay the onset of a disease, stop disease progression for an extended period, or lead to observable improvement in WO95/01096 PCT~S94/07277 2~ ~3~3 patient status.

Ideally, such an absorbable pharmacological agent should have several characteristics. It should be water soluble and of small molecular weight so that it can passively and readily diffuse throughout the body, including within cells. It should have at least one chemically active trapping group, such as a primary amine group (R-NH2), for reaction with car-bonyl groups (R-CHO or R1 -CO-R2) to yield covalent bonded products. It should otherwise not interact with normal cell metabolism or do so in ways which are not cytotoxic. It should be tolerated by the body in relatively high dosages (range of grams per day) and for extended periods. In addi-tion, such an absorbable pharmacological agent and its meta-bolic derivatives should be readily absorbed by kidney tissue and excreted in urine without nephrotoxic consequences.

4-Aminobenzoic acid (also known as p-aminobenzoic acid or PABA) is an example of the absorbable primary agent of this invention. PABA has a small molecular weight (137, free acid) and is water soluble. It has a primary amine group which should readily react with carbonyl-containing metabolites under physiological conditions. PABA has already been commer-cially marketed for other health applications and it has been used effectively and safely by millions of people. It has been used as a popular sun screen topical cream additive and it has also been used as an antifibrotic prescription drug for treatment of dermatomyositis, scleroderma and several clini-cally related skin disorders. On a prescription basis PABA is recognized for use in a dosage of 12 gm/day for up to two years.

The metabolic fate of PABA in humans has been actively inves-tigated and well reported in the biomedical literature. It is so actively metabolized via several mechanisms and quantita-tively removed in urine that PABA excretion has become a wide-WO95/01096 PCT~S94/07277 2~ ~3~

ly recognized standard for measuring urinary clearance. Smallamounts of PABA are normally present in the human diet. It is recognized as being a vitamin for many organisms and is clas-sified as a member of the vitamin B complex. As a vitamin for human use PABA is commercially marketed in the dosage range of

5 to 550 mg/day.

For any of the chemical derivatives of PABA listed herein as useful in the present invention, it is believed that the salt forms, free acid form, ester derivatives, amide derivatives and analogous non-aromatic benzene ring derivative (i.e., cyclohexane carboxylic acid derivative) thereof will also be useful. Examples of the class of primary agents (molecular weight range 100 to 1,400) of the present invention may be summarized as noted below in chemical structures I, II and III.
R = -NH2 -aminoalkyl group having 1-10 carbons including Q hydrocarbon isomers and/or R~COOH hydroxylated derivatives thereof I -NHC(=NH)NH2 -(CH2)nNHc(=NH)NH2 where n = 1-10 -C(=NH)-NH2 -(CH2)n-cH=Nc(=NH)NH2 where n = 1-10 -NHC(=NH)NHNH2 -(cH2)nNHc(=NH)NHNH2 where n = 1-10 -(cH2)n-cH=Nc(=NH)NHNH2 where n = 1-10 -NHNHC(=NH)NH2 -(cH2)n-NHNHc(=NH)NH2 where n = 1-10

6 PCT~S94/07277 2~6~8~ ~

-(cHz)n-cH=N-NHc(=NH)NH2 where n = l-l0 R1 = -NH2 -aminoalkyl group (l-l0 carbons) including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof COOH -(CHz)nNHc(=NH)NH2 ~ where n = l-l0 R2 -C(=NH)-NH2 II -(CHz)n-cH=Nc(=NH)NH2 where n = l-l0 -NHC(=NH)NHNH2 -(cH2)nNHc(=NH)NHNH2 where n = l-l0 -(CH2)n-CH=NC(=NH)NHNH2 where n = l-l0 -NHNHC(=NH)NH2 -(cH2)n-NHNHc(=NH)NH2 where n = l-l0 -(cH2)n-cH=N-NHc(=NH)NH2 where n = l-l0 R2 = --NH2 -OH

-O-R' with alkyloxy group R' having 2-l0 carbons including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof -aminoalkyl group (l-l0 carbons) including hydrocarbon isomers and/or hydroxyl-WO95/0109~6 PCT~S94/07277 53 ~3 ated derivatives thereof -(CH2)nCH3 where n = l-lO
including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof R1 = -(CH2)r,-NH2 where n = 0-l0 including isomers of the aminoalkyl group and R~ ~~~\ R~ hydroxylated derivatives -COOH thereof ~ R" -C(=NH)-NH2 R2 -NHC(=NH)NH2 III -(CH2)nNHc(=NH)NH2 where n = l-lO
-(cH2)n-cH=Nc(=NH)NH2 where n = l-l0 -NHC(=-NH)NHNH2 -(CH2)nNHc(=NH)NHNH2 where n = l-l0 -(CH2)n-CH=NC(=NH)NHNH2 where n = l-lO
-NHNHC(=NH)NH2 -- -(cH2)n-NHNHc(=NH)NH2 where n = l-lO
-(CH2)n-CH=N-NHC(=NH)NH2 where n = l-l0 R2 = --NH2 --H
-OH

-O-R3 with alkyloxy group R3 has 2-lO carbons including hydrocarbon WO95/01096 PCT~S94/07277 isomers and/or hydroxyl-ated derivatives thereof -aminoalkyl group (1-10 carbons) including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof -(CH2)nCH3 where n = 1-10 including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof R' = -H

-OH
R" = -H

-OH

3. Examples of Orally A~m; n; stered Nonabsorbable Co-Agents Useful in the Present Invention As discussed in US patent application 08/026,617, the diet is a significant source of carbonyl agents. These agents may be contributing factors in the aging process, may predispose hu-mans for other neurodegenerative disorders, may be contribut-ing factors in atherosclerosis, may be contributing factors in inflammatory diseases and may also be contributing factors in the initiation of carcinogenesis. Such carbonyl agents, while contributing positively in some instances to the flavor of foods or beverages (for example, cheeses or wines), have no recognized nutritional value. It was proposed in US patent application 08/026,617 that certain dietary supplements can be of public health benefit by their ability to covalently trap dietary aldehydes and ketones. The co-agents described in WO95/01096 ~¦ PCT~S94/07277 this subsection can accomplish this function because they bear primary amine groups or derivatives thereof. As large molec-ular weight molecules which are non-digestible they have the capacity to pass through the digestive tract, acting in effect as another form of dietary fiber. As defined in the original filing of US patent application 07/660,5~1, examples of these nonabsorbable polyamine trapping substances may be divided into three classes; naturally occurring polyamine polysac-charides, chemical derivatives of naturally occurring poly-saccharides, and synthetic polyamine polymers.

(a). Naturally Occurring Amine-Containing Polysaccharides Any naturally occurring polysaccharide featuring ~-1,2, ~-1,3, ~-1,4 and/or ~-1,6 linkages which contains aminosugars may be regarded as a non-digestible, potentially active carbonyl trapping agent. The chitin class of biopolymers may be cited as an example of such an agent, having the general structure of poly-~-(1 4)-N-acetyl-D-glucosamine. A form of micro-crystalline chitin has been described in which some of the acetyl groups have been removed, revealing free amine groups (Austin and coworkers, 1981, pg. 750). C`hitins obtained from different sources feature different degrees of amine deacetyl-ation ~Austin and coworkers, 1981, pg. 752).

(b). Chemical Derivatives of Naturally Occurring Polysac-charides Various pretreatment procedures may be applied to naturally occurring polysaccharides prior to generation of chemical derivatives. Generation of microcrystalline polysaccharides is one example of such a pretreatment procedure. As applied to cel]ulose or chitin (Yalpani, 1988, pg. 389), this yields a colloidal processed form of polysaccharide featuring high porosity and enhanced susceptibility to chemical reactions.
Generat:ion of "microfibrillated" cellulose or chitin is an-WO95/01096 PCT~S94/072 ~
~16~ 56 other example of a pretreatment procedure which produces en-hanced surface area, increased water retention capacity and enhanced chemical accessibility (Yalpani, 1988, pg. 390). Use of strong (> 18%) sodium hydroxide is still another recognized pretreatment, or activation, procedure found to be helpful as a starting point for preparing chemical derivatives of poly-saccharides (Yalpani, 1988, pg. 214).

(b)(l). Deacetylation of Naturally Occurring Polysaccharides A variety of polysaccharides have been identified which are rich in N-acetylated residues. Upon chemical deacetylation these carbohydrates yield high molecular weight derivatives bearing primary amine groups directly linked to sugar carbons, that is, no sidearm spacer units present.

(i) Chitosan. This is the deacylated form of chitin. As des-cribed in the Merck Index (1989, pg. 316) chitin is a cellu-lose-like biopolymer the composition of which consists mostly of N-acetyl-D-glucosamine residues covalvently linked by ~-1,4 bonds. Chemical deacylation removes acetate, generating pri-mary amine groups still covalently bound to the polysacchar-ide. Chitosan has recognized uses in water treatment, in photographic emulsions, and in improving the dyability of synthetic fabrics and fibers. The free amine groups in this substance also give it chelating properties (Austin and coworkers, 1981).

(ii) Chondroitin sulfate. This is a mucopolysaccharide found commonly in mammalian tissue. It consists of repeating disaccharide units, each of which has a D-glucuronic acid residue ~-1,4 linked to an N-acetylchondrosine residue (Merck Index, 1989, pg. 344).

(iii) Hyaluronic acid. This mucopolysaccharide is also found commonly in mammalian tissues. It consists of glucuronic acid _WO95/0109~ ~ PCT~S94/07277 ~ .. ~6~'38,,3 and glucosamine residues bound by ~ 3 and ~-1,4 linkages (Merck Index, 1989, pp. 751-752).

(iv) Keratan sulfate. This mammalian glycosaminoglycan con-sists of a repeating disaccharide unit of a C-6 sulfated C-2 N-acetylated sugar residue and a galactose residue linked by ~-1,4 honds (Yalpani, 1988, pp. 27-28).

(b)(2). Chemical Amination of Polysaccharides (i) 2-Amino-2-deoxy-cellulose. Cellulose can be aminated by a process of selective oxidation, oximation and subsequent reduction with lithium aluminum hydride (Yalpani, 1988, pp.
281-282).

(ii) Alternative amination procedures. Aminodeoxy polysac-charides can also be prepared via azide or hydrazide inter-mediates or by reductive amination using sodium cyanoboro-hydride (Yalpani, 1988, pg. 281). Besides being applied to cellulose, other non-digestible polysaccharides such as curdlan (Yalpani, 1988, pg. 22) may be aminated by such chemical procedures.

(iii) 3-Aminopropylcellulose. Reaction of cyanoethylcellulose with borane-tetrahydrofuran or borane-dimethyl sulfide com-plexes in tetrahydrofuran generates 3-aminopropylcellulose (Yalpani, 1988, pgs. 250 and 255). In this derivative each primary amine group is at the end of a three carbon sidearm.

(iv) Aminoethylcellulose. This chemical has been previously marketed as an anion exchange column chromatography resin (Sigma Chemical Co. catalog, Feb. 1981) and used as such in protein purification studies (Fasold, 1975, pp 481-482).

(v) Other aminoalkyl-, amino(hydroxyalkyl)-, aminoalkyl-ether-, and amino(hydroxyalkyl)-ether- derivatives of cellu-WO95/01096 PCT~S94/07277 2~ ~63~3 ~

lose, chitin and other naturally occurring non-digestible carbohydrates. Noting that the chemical methodology for producing such derivatives is documented in public domain literature, the biomedical application of such derivatives for therapeutic purposes described herein is also claimed. This would include:

aminoalkyl derivatives of the formula H2 N-~CH2)n-~carbohydrate] where n = 1 - 30, including alkyl isomers;
amino(hydroxyalkyl)- derivatives derivatives of the formula H2 N- (CHz) m-CHOH- ~CH2) n~ [carbohydrate]~ where m = 0 - 15 and n = 0 - 15;
aminoalkyl-ether- derivatives of the formula H2 N-(cHz)n-o-[carbohydrate]~ where n = 1 - 30; and amino(hydroxyaklyl)-ether- der-ivatives of the formula H2N-(CH2)m-CHOH-~CH2)n-O-[carbohydrate], where m = 0 - 15 and n = 0 - 15.

(vi) Aminobenzyl- derivatives of cellulose, chitin or other naturally occurring non-digestible carbohydrates. As the aro-matic amine group is a weaker base than its aliphatic counter-part, this class of nonabsorbable amines should be less chem-ically active than amino- and aminoalkyl- derivatives des-cribed above. These derivatives are of the following general structures:

H2N-C6H4-(CH2) n~ [carbohydrate];
H2N~CH2~C6H4-(CH2) n~ ~carbohydrate] ~
H2N-C6H4-(CH2) n~~ [carbohydrate] where n = 0 - 30; and H2N-C6H4- (CH2) m-CHOH- (CH2) n~~ tcarbohydrate] where m = 0 -15 and n = 0-15.

This includes p-, o- and m-benzene ring amino- and amino-methyl- isomers, and alkyl group isomers.

WO95/01096 ~ PCT~S94/07277 66'3~3 (vii) guanidine and aminoguanidine derivatives of cellulose, chitin or other naturally occurring no:nabsorbable carbohy-drates selected from the group consisting of:
H~-C~=NH)-tcarbohydrate];
H~N-C(=NH)-(CH2)n-[carbohydrate], where n = l-lO, includ-ing hydrocarbon isomers and hydroxylated derivatives thereof;
HzN-C(=NH)-O-(CHz)n-[carbohydrate], where n = l-lO, in-cluding hydrocarbon isomers, ether linkage isomers and hydroxylated derivatives thereof;
H2N-C(=NH)-NH-[carbohydrate];
H2N-C(=NH)-NH-(CH2) n~ tcarbohydrate], where n = 1-10, in-cluding hydrocarbon isomers and hydroxylated derivatives thereof;
H2N-C(=NH)-NH-(CH2) n~~ ~carbohydratel, where n = l-lO, in-cluding hydrocarbon isomers, ether linkage isomers and hydroxylated derivatives thereof;
HzN-C(=NH)-N=CH-(CH2)n-[carbohydrate~, where n = l-lO, in-cluding hydrocarbon isomers and hydroxylated derivatives thereof;
H2N-C(=NH)-N=CH-tCH2) n~~ [carbohydra1:e], where n = l-lO, including hydrocarbon isomers and hydroxylated deriva-tives thereof;
H2N-NHC(=NH)-NH-[carbohydrate];
H2N-NHC(=NH)-NH-(CH2) n~ tcarbohydrate], where n = l-lO, in-cluding hydrocarbon isomers and hydroxylated derivatives thereof;
H2N-NHC(=NH)-NH-(CHz) n~~ [carbohydrat,e], where n = l-lO, including hydrocarbon isomers, ether linkage isomers and hydroxylated derivatives thereof;
H2N-NHC(=NH)-N=CH-(CH2)n-tcarbohydrate], where n = l-lO, including hydrocarbon isomers and h.ydroxylated deriva-tives thereof;
H2N-NHC(=NH)-N=CH-(CH2) n~~ [carbohydrate], where n = 1-10, including hydrocarbon isomers, ether linkage isomers and hydroxylated derivatives thereof;

WO95/01096 PCT~S94/07277 2 ~

H~-Ct=NHI-NH-NH-[carbohydrate];
H2N-C(=NH)-NH-NH-(CHz)n-~carbohydrate], where n = 1-10, including hydrocarbon isomers and hydroxylated deriva-tives thereof;
H~N-C(=NH)-NH-NH-(CH2)n-0-[carbohydrate], where n = 1-10, including hydrocarbon isomers, ether linkage isomers and hydroxylated derivatives thereof;
H~N-C (=NH) -NH-N=CH- (CH2) n~ [carbohydrate], where n = 1-10, including hydrocarbon isomers and hydroxylated deriva-tives thereof; and H2N-C (=NH) -NH-N=CH- (CH2) n~~ [carbohydrate], where n = 1-10, including hydrocarbon isomers, ether linkage isomers and hydroxylated derivatives thereof.

(b)(3). Aminated Sucrose Polyesters Mixtures of fatty acid hexa-, hepta- and octaesters of su-crose, known as sucrose polyester, are not hydrolyzed by pan-creatic lipase enzymes and are not absorbed in the intestine (Jandacek, 1984). It is proposed and claimed herein that primary amine, aminoguanidine and guanidine derivatives of sucrose polyesters may be of benefit in reduction of dietary carbonyl substances, analogous to the proposed action of other nonabsorbable agents described herein. Such derivatives of sucrose polyesters would include structures in which the car-bonyl trapping functional group is in the ~ -1 or other isomeric position(s) within the fatty acyl chains, fatty acyl chains having more than one nitrogen functional group and fatty acyl chains having hydroxyl groups. Such aminated su-crose polyesters may be used in pure form as a dietary supple-ment, or may be prepared as a coating on a particulate carrier such as cellulose or styrene divinylbenzene copolymer resin.

(c). Synthetic Polyamine Polymers (c)(1). Synthetic polysaccharides consisting partly or en-WO95/01096 ~ PCT~S94/07277 ~383 tirely of aminosugars bound by ~-l,2, ~-1,3, ~-l,4 and/or ~-1,6 linkages may be regarded as nonabsorbable potential car-bonyl trapping agents.

(c)(2). Mixed polysaccharide polymeric derivatives. Primary amine, aminoalkyl (one to ten carbons per alkyl group), amino-hydroxyalkyl (one to ten carbons per alkyl group and one to ten hydroxyl groups per alkyl group), aminoguanidine, amino-guanidinylalkyl (one to ten carbons per alkyl group), amino-alkylguanidinyl (one to ten carbons per alkyl group), guan-idine, aminobenzene and aminoalkylbenzene (one to ten carbons per alkyl group) functional groups may be covalently attached to matrices such as epi-chlorohydrin copolymers of cellulose or chitin. Functional group spacer groups may include alkene as well as alkyl groups.

(c)(3). Non-polysaccharide polymeric derivatives. Primary amine, aminoalkyl (one to ten carbons per alkyl group), amino-hydroxyalkyl (one to ten carbons per alkyl group and one to ten hydroxyl groups per alkyl group), aminoguanidine, amino-guanidinylalkyl (one to ten carbons per alkyl group), amino-alkylguanidinyl (one to ten carbons per alkyl group), guan-idine, aminobenzene and aminoalkylbenzene (one to ten carbons per alkyl group) functional groups may be covalently attached to a wide variety of synthetic non-digestible polymers.
Functional group spacer groups may include alkene as well as alkyl groups. Like their sugar-based counterparts, these agents should be capable of reacting with dietary carbonyl compounds. Nitrogen-containing functional groups may be covalently attached to synthetic supports such as polystyrene, styrene-divinylbenzene copolymer, polyvinyl alcohol and cross-linked derivatives thereof.

WO95/01096 PCT~S94107277 ~63~ --4. Example of the Invention of US Patent Application 08/026,617 Used in a Clinical Trial .
Therapeutic Protocol:

Subject 1 is a male individual born in 1948 and having hereditary motor and sensory neuropathy. Family history indicates that this subject's family has the X-linked subvariety of the disease.

On September 1, 1990 Subject 1 began taking three 100 mg tablets of p-aminobenzoic acid per day. This daily dosage consisted of single 100 mg tablets (Schiff Products, Moonachie, NJ) taken one at a time approximately every eight hours. Also initiated at this time and taken three times per day: DL-methionine, 500 mg and vitamin E (as mix tocopherols in oil-based capsules), 200 I.U. His weight at the time was approximately 165 lbs. The daily dosage times were approxi-mately 8:00 AM, 4:00 PM and 11:30 PM. This original low dosage of PABA was selected in part as a check to ensure no adverse immunologic reaction. Symptoms of allergic reaction such as bronchial constriction or skin rash were not observed.
Actually, no clinical reaction to PABA was observed.

On October 1, 1990 Subject 1 began taking a total of 600 mg PABA per day by doubling the original dosage noted above; 200 mg taken three times per day. Also taken with PABA: DL-methionine, 500 mg and vitamin E, 200 I.U..

On January 1, 1991 Subject 1 began taking three 550 mg cap-sules of PABA (Solgar Co., Lynbrook, NY) per day, one approxi-mately every eight hours. DL-Methionine use was doubled to 1,000 mg every eight hours. Likewise, vitamin E dosage was doubled to 400 I.U. every eight hours. In addition, the following dietary supplements were initiated and taken once per day (4:00 PM):

WO9S/01096 PCT~S94/07277 3~3 pantothenic acid, 250 mg;
~-carotene, 25,000 I.U.;
selenium (Osco, Oak Brook, IL), 50 ug;
vitamin B1, l00 mg;
and one Osco brand "balanced B complex 50" tablet, each tablet consisting of:

folic acidl00 ~g vitamin B150 mg vitamin B2 50 mg niacin 50 mg vitamin B6 50 mg vitamin B1250 ug biotin 50 ~g pantot:henic acid 50 mg The ingredients as listed on the label are: "dicalcium phos-phate, d-calcium pantothenate, pyrido~ine hydrochloride, hydrogenated cottonseed oil, cellulose, niacinamide, rifo-flavin, thiamine mono-nitrtate, stearic acid, modified cellu-lose gum, magnesium stearate, silica, resin, gum acacia, hydroxypropylcellulose, rice bran, yeast, para-aminobenzoic acid, alfalfa, watercress, parsley, lecithin, cyanocobalamin, folic acid, biotin." Except as noted above, the amounts of ingredients (such as PABA) were not state.d.

On February 24, l99l Subject l began taking six 550 mg cap-sules of PABA per day, two every eight hours plus the dietary supplement combination initiated January 1st. DL-Methionine and vitamin E dosage were continued as initiated January lst;
3,000 mg and l,200 I.U. total daily, respectively. Dosage of additional dietary supplements was also continued as initiated January 1st, with the addition of l00 mg vitamin B1 per day.
Also, selenium daily dosage was reduced to 12 ~g per day.
r As of May 1st, l99l consumption of pantothenic acid and vita-min B1 were tripled to 250 mg 3X daily and l00 mg 3X daily, respectively, taken with PABA. Also initiated now, vitamin B6, l00 mg taken 3X daily with PABA.

WO95/01096 PCT~S94/07277 2~383 As of July 1st, 1991 the methionine product was switched to "L-Methionine 500 mg Caps with Vitamin B6" (Nature's Plus, Farmingdale, NY). Each capsule has the free form of the L-amino acid and 50 mg vitamin B6. This dose of vitamin B6 is in addition to the 300 mg/day noted in the preceding para-graph.

As of July 26, 1991 the vitamin E product was switched to "Natural Dry All E, 400 I.U." (Schiff Products, Moonachie, NJ). One of these dry powder capsules is taken 3X daily with PABA, as before.

As of August 7, 1991 daily doses of PABA, methionine and vitamin E were increased by 50%. Thus starting at this time, three 550 mg PA8A capsules, three 500 mg methionine capsules, one 400 I.U. dry vitamin E and a 200 I.U. dry vitamin E cap-sule were taken at a time, three times per day. Daily totals of these agents were now: PABA, 4.95 gm; methionine, 4.5 gm;
and vitamin E, 1,800 I.U. Other agents were taken as before.

As of November 22, 1991 the daily dose of PABA was increased.
Thus starting at this time, four 550 mg PABA capsules were taken at a time, three times per day. Daily total of PABA was now 6.6 gm. Other agents were taken as before.

Nerve Conduction Studies on Subject 1:

On June 20, 1988 Subject 1 participated in a nerve conduction research study at the National Institutes of Health. Nerve conduction data was recorded from the left median and ulnar nerves, which included conduction velocity, amplitude and distal latency for each nerve. On May 6, 1992 Subject 1 was tested again at the office of a neurologist in Bryn Mawr, Pennsylvania. The results of these studies may be summarized as follows.

WO95/01096 PCT~S94/07277 21 ~ 6383 Conduction velocity Amplitude Latency meters/sec mV msec Median Nerve 6/20/88 study 28 0.4 12.4 5/6/92 study 28.2 0.4 13.1 Ulnar Nerve 6/20/88 study 29 1.3 13.8 5/6/92 studY 31.8 2.4 13.1 These data indicate that there was little change in the neuro-physiological status of the left median nerve during the course of the experimental therapeutic drug trial; conduction velocity and amplitude remained unchanged, while the distal latency increased (that is, worsened) b~ six percent. How-ever, data on the left ulnar nerve document an improvement in neurophysiological status; conduction velocity improved by ten percent, amplitude improved by eighty-five percent and distal latency improved by five percent.

This experimental drug trial involved a step-by-step increase in dosages over an extended period. Dosages of PABA, the primary agent were slowly increased from September, 1990 to November, 1991. The final PABA dosage level (6.6 gm/day) was maintained from November, 1991 to May, 1992, a period of approximately six and one half months. During this study period the left ulnar nerve, which was more intact to begin with, began to show improvement in neurophysiological status.
This slow improvement in nerve conduction status is in accord with what is known of the ability of peripheral nerves to regenerate axons. As Bradley (199O) has noted:

...it may take as long as 18 months before regener-ating axons reach the distal denervated muscles where the site of the lesion lay in proximal nerve roots or plexuses. In neuronopathies, where cell death has occurred, any degree of recovery can only occur by .

WO9~/01096 PCT~S94/07277 2~3~3 ~

peripheral sprouting from axons of surviving neurons.
This also appears to be a relatively slow process.
Hence, therapeutic trials must extend for long enough to ensure that the slow biological reparative processes can be detected.

The available findings on the left ulnar nerve of Subject 1 indicate that conduction velocity has improved, the number of detectable axonal fibers has almost doubled (improved ampli-tude) and a modest increase in re-innervation of the distal muscle group has begun to occur (improved latency).

5. Use of the Invention of US Patent Application 08/026,617 in Combination with Known Medicaments As summarized above, it is evident that presently available pharmaceutical technology for treatment of the diseases ad-dressed herein is almost entirely symptomatic, as well as tem-porary and of partial clinical benefit, at best. The dosages of any of the known medicaments discussed herein, except those which are still the subjects of preliminary laboratory stud-ies, are well known to those skilled in the art. Significant adverse side effects accompany many of these treatments, which limit their use. The present invention-defines the use of previously recognized technology in combination with the invention originally described in US patent application 07/660,561, so as to achieve greater clinical effectiveness in treatment of these diseases. In using the therapeutic technology defined herein, physicians may achieve in some cases the clinical benefits of previously recognized drugs while using lower dosage levels, thus minimizing adverse side effects. Within the context of the present invention, it is important to note the documentation provided by Flood and coworkers (1988). Their findings indicate that when drugs are used in combination they may provide beneficial effect at re-duced dosages which are ineffective when drugs are adminis-WO9~/01096 ~1 ~ PCT~S94tO7277 tered alone. This approach may permit wider and more effec-tive use of previously recognized drug technology. It is acknowledged herein that for many of the previously known medicaments the optimum dosage must be determined on an indi-vidualized basis, and may be below or above the dosage range generally recognized for public use. It is to be understood that in particular cases it may be desirable to go beyond the dosage ranges noted below. Except where stated otherwise, the drugs listed in the following examples are to be administered orally.

Example 1 Clinical treatment of Parkinson's disease may be improved by use of the invention originally disclosed in US patent appli-cation 07/660,561 in combination with known medicaments, includi.ng co-agent use of:
(a) carbidopa and levodopa compositions (Sinemet tablets and Sinemet CR controlled release tablets, Du Pont Pharmaceuti-cals), dosage range from 30 mg carbidopa and 300 mg levodopa daily t:o 600 mg carbidopa and 2,400 mg levodopa daily;
(b) dopamine agonists such as bromocriptine mesylate (Parlodel SnapTabs and capsules, Sandoz Pharmaceuticals), dosage range from 1.25 to 140 mg daily;
pergolide mesylate (Permaxm, Lilly), dosage range from 0.05 mg daily to 5 mg daily;
(+)-4-propyl-9-hydroxynaphthoxazine, dosage range from ~g/kg/day to 0.3 mg/kg/day;
apomorphine, dosage range from 0.1 mg/kg/day to 2 mg/kg/day;
and ciladopa, dosage range from 0.5 mg/kg/day to 20 mg/kg/day;
(c) anticholinergic medications such as benztropine mesylate (Cogentin, Merck & Co.), dosage range from 0.5 mg daily to 6 mg daily; and biperiden, dosage range from 0.5 mg daily to 6 mg daily;
(d) antihistamines such as orphenadrine citrate (Norflex sustained-release tablets, WO9~/01096 PCT~S94107277 Norgesic tablets and Norqesic Forte tablets, 3M Pharmaceu-ticals), dosage range from 100 mg daily to 200 mg daily;
(e) tricyclic antidepressants such as amitriptyline HCl (Elavil, Stuart), dosage range from 50 mg daily to 300 mg daily;
amitriptyline HCl/perphenazine combinations (Etrafon, Scher-ing), dosage range from 4 mg perphenazine and 50 mg amitrip-tyline daily to 16 mg perphenazine and 100 mg amitriptyline daily;
amitriptyline/chlordiazepoxide combinations (Limbitrol, Roche Products), dosage range from 5 mg chlordiazepoxide and 12.5 mg amitriptyline daily to 60 mg chlordiazepoxide and 150 mg amitriptyline daily;
nortriptyline HCl (Pamelor, Sandoz Pharmaceutical), dosage range from 25 mg daily to 150 mg daily;
imipramine, dosage range from 2 mg daily to 150 mg daily; and doxepin, dosage range from 2 mg daily to 150 mg daily;
(f) serotonin reuptake inhibitor antidepressants such as fluoxetine HCl (Prozac, Dista), dosage range from 20 mg daily to 80 mg daily; and sertraline (Zoloft, Pratt Pharmaceuticals), dosage range from 50 mg daily to 200 mg daily;
(g) beta blocker agents such as propranolol HCl (Inderal, Wyeth-Ayerst Laboratories), dosage range from 30 mg daily to 640 mg daily;
pindolol (Visken, Sandoz Pharmaceuticals), dosage range from 10 mg daily to 60 mg daily;
metoprolol tartrate (Lopressor, Geigy), dosage range from 100 mg daily to 450 mg daily;
metoprolol succinate (Toprol XL, Astra), dosage range from 50 mg daily to 400 mg daily; and atenolol (Tenormin, ICI Pharma), dosage range from 50 mg daily to 200 mg daily;
(h) selegiline (Eldepryl, Somerset), dosage range from 5 mg daily to 10 mg daily;
(i) selegiline in combination with tocopherol, dosage range WO95/01096 PCT~S94/07277 ~ 6'63 from 5 mg selegiline and 500 I. U. tocopherol daily to 10 mg selegiline and 3500 I. U. tocopherol daily;
(j) D-cycloserine with or without a cholinesterase inhibitor co-agent, dosage range from 0.1 mg/kg daily to 15 mg/kg daily;
(k) neurotransmission enhancer drugs such as lisuride, dosage range from 0.1 mg daily to 2 mg daily;
(l) peripheral decarboxylase inhibitors other than carbidopa such as benserazide used in combination with levodopa, dosage range from 25 mg benserazide and 500 mg levoclopa daily to 200 mg benserazide and 2,400 mg levodopa daily;
(m) N-methyl-D-aspartate glutamate receptor antagonists admin-istered orally, intramuscularly, subcutaneously or intrave-nously such as trihexyphenidyl (Artane, Lederle), dosage range from 0.1 mg daily to 20 mg daily;
ethopropazine (Paridol), dosage range from 10 mg daily to 400 mg daily;
procyc].idine (Kemadrin, Burroughs Wellcome), dosage range from 1 mg daily to 40 mg daily;
diphenhydramine (BenadrYl, Parke-Davis), dosage range from 5 mg daily to 200 mg daily;
dizocilpine (Neuroqard, Merck Sharp & Dohme), dosage range from 0.1 ~g/kg daily to 10 mg/kg daily;
amantadine (Symmetrel, Du Pont Multi-Source Products), dosage range from 10 mg daily to 400 mg daily;
memantine, dosage range from lO mg daily to 400 mg daily; and milacemide, dosage range from 50 mg daily to 2.5 gm daily;
(n) tacrine (Coqnex, Warner-Lambert), dosage range from 5 mg daily to 200 mg daily, optionally with phosphatidylcholine co-agent, dosage range from zero to 15 gm daily;
(o) (~/ )-9-amino-1,2,3,4-tetrahydroacridin-1-ol, dosage range from 2 mg daily to 200 mg daily;
(p) lazabemide (Hoffmann-La Roche), dosage range from 10 mg daily to 200 mg daily;
(q) tiapride, dosage range from 1 mg da.ily to 400 mg daily;

WO95/01096 PCT~S94/07277 2~663~ --and (r) anti-oxidant agents which may be used in combination such as ascorbic acid, dosage range from 1 mg daily to 60 mg daily;
~-tocopherol, dosage range from 100 I. U. daily to 3,500 I. U.
daily;
N-acetylcysteine, dosage range from 100 mg daily to 1 gm daily;
~-carotene, dosage range from 20 mg daily to 300 mg daily;
penicillamine, dosage range from 25 mg daily to 2 gm daily;
and cysteamine, dosage range from 200 mg daily to 4 gm daily.

Example 2 Clinical treatment of Alzheimer's disease may be improved by use of the invention originally disclosed in US patent appli-cation 07/660,561 in combination with known medicaments, in-cluding co-agent use of:
(a) vasodilator or other nootropic direct brain metabolic enhancer drugs such as idebenone, dosage range from 5 mg/kg daily to 150 mg/kg daily;
propentophylline, intravenous, intramuscular, subcutaneous or oral dosage range from 50 mg daily to 3 gm daily;
pentoxifylline, dosage range from 50 mg daily to 3 gm daily;
citicoline, dosage range from 50 mg daily to 5 gm daily;
ebiratide, subcutaneous dosage range from 3 ~g/kg daily to 1 mg/kg daily;
vinpocetine (Cavinton, Chemical Works of Gedeon Richter, Ltd.), intravenous, intramuscular, subcutaneous or oral dosage range from 5 mg/kg daily to 300 mg/kg daily;
bromvincamine, dosage range from 25 mg daily to 3 gm daily;
cyclandelate, dosage range from 25 mg daily to 3 gm daily;
isoxsuprene, dosage range from 25 mg daily to 3 gm daily;
nafronyl, dosage range from 25 mg daily to 3 gm daily;
papaverine, dosage range from 25 mg daily to 3 gm daily;
suloctidil, dosage range from 25 mg daily to 3 gm daily;

WO95/0109G 7l 6~ o3 PCT~S~4/~7~77 vinburnine, dosage range from 25 mg daily to 3 gm daily;
vincamine, dosage range from 25 mg daily to 3 gm daily;
vindeburnol, dosage range from 25 mg daily to 3 gm daily;
naloxone, intravenous, intramuscular, subcutaneous or oral dosage range from 5 mg daily to 300 mg daily;
ethyl 5-isopropyloxy-4-methyl-~-carboline-3-carboxylate, in-travenous, intramuscular, subcutaneous or oral dosage range from 2 mg/kg daily to lO0 mg/kg daily;
N'-methyl-~-carboline-3-carboxamide, intravenous, intramuscu-lar, subcutaneous or oral dosage range from 2 mg/kg daily to 100 mg/kg daily;
methyl 6,7-dimethoxy-4-ethyl-~-carboline-3-carboxylate, intra-venous, intramuscular, subcutaneous or oral dosage range from 0.1 mg/kg daily to 10 mg/kg daily;
ethyl 5-methoxy-4-ethyl-~-carboline-3-carboxylate, intrave-nous, i.ntramuscular, subcutaneous or oral dosage range from 1 mg/kg daily to 30 mg/kg daily;
ifenprodil tartrate, dosage range from 0.5 mg/kg daily to 120 mg/kg daily;
piracetam, dosage range from l mg daily to lO0 mg daily;
aniracetam, dosage range from 50 mg/kg daily to l gm/kg daily;
pyroglutamic acid, intravenous, intramuscular, subcutaneous or oral dosage range from lO0 mg/kg daily to 5 gm/kg daily;
tenilsetam, dosage range from lO mg daily (or alternate day) to 1 gm daily (or alternate day), or from 25 mg once a week to l gm once a week;
pramiracetam, dosage range from 50 mg/kg daily to 8 gm/kg daily;
oxiracetam, dosage range from 200 mg daily to 2 gm daily;
rolziracetam, intravenous, intramuscular, subcutaneous or oral dosage range from 1 mg daily to 1 gm daily;
razobazam, intravenous, intramuscular, subcutaneous or oral dosage range from O.l mg/kg daily to 25 mg/kg daily;
exifone, intravenous, intramuscular, subcutaneous or oral dos-age range from 1 mg daily to l gm daily;
rolipram, intravenous, intramuscular, subcutaneous or oral wo 95~01096 6 ~ 3 ~ ~ PCT~S94/07277 dosage range from 1 mg daily to 1 gm daily;
sabeluzole, dosage range from 2 mg daily to 40 mg daily;
nimodipine (N.imotoP/ Miles Pharmaceutical), dosage range from 300 mg daily to 3.6 gm daily;
flunarizine, dosage range from 2 mg daily to 100 mg daily;
nicergoli~ne (Sermion), intravenous, intramuscular, subcutan-eous or oral dosage range from 6 mg daily to 10 gm daily;
phosphatidylserine, intravenous or oral dosage range from 1 mg/kg daily to 250 mg/kg daily;
etiracetam, dosage range from 50 mg/kg daily to 8 gm/kg daily;
dupracetam, intravenous, intramuscular, subcutaneous or oral dosage range from 1 mg daily to 1 gm daily; and ergoloid mesylates (HYderqine/ Sandoz Pharmaceuticals), dosage range from 0.5 mg daily to 40 mg daily;
(b) neurotransmission enhancer drugs such as amantadine (SYmmetrel, Du Pont Multi-Source Products), dosage range from 10 mg daily to 400 mg daily;
calcium hopantenate, dosage range from 100 mg daily to 4 gm daily;
lisuride, dosage range from 0.1 mg daily to 2 mg daily;
and indeloxazine, dosage range from S0 mg daily to 1.5 gm daily;
(c) tiapride, dosage range from 1 mg daily to 400 mg daily;
(d) psychotherapeutic drugs such as haloperidol (Haldol, McNeil Pharmaceutical), dosage range from 0.2 mg daily to 15 mg daily; ~
bromperidol, dosage range from 20 ~g/kg daily to 0.25 mg/kg daily;
thioridazine (Mellaril, Sandoz Pharmaceutical), dosage range from 10 mg daily to 800 mg daily;
thiothixene (Navane, Roerig), dosage range from 2 mg daily to 60 mg daily;
fluphenazine (Prolixin, Apothecon), dosage range from 0.2 mg daily to 40 mg daily;
perphenazine in amitriptyline/perphenazine combinations (Etrafon, Schering), dosage range from 4 mg perphenazine and W095101096 63~ PCT~S94/07~77 50 mg amitriptyline daily to 16 mg perphenazine and lO0 mg amitriptyline daily; and molindone (Moban, Du Pont Multi-Source Products), dosage range from 3 mg daily to 225 mg daily;
(e) acetylcholinesterase inhibitors such as physostigmine (Antilirium Iniectable, Forest Pharmaceuticals), oral dosage range from O.l mg daily to 20 mg daily, or intra-venous, intramuscular or subcutaneous dosage range from 5 ~g daily to 3 mg daily, optionally with phosphatidylcholine co-agent, oral dosage range from zero to 15 gm daily;
heptylphysostigmine, dosage range from l mg daily to l gm daily;
tacrine (Cognex, Warner-Lambert), dosage range from 5 mg daily to 200 mg daily, optionally with phosphat.idylcholine co-agent, dosage range from zero to 15 gm daily;
('/ )-9--amino-l,2,3,4-tetrahydroacridin-l-ol, dosage range from 2 mg daily to 200 mg daily;
metrifonate, intramuscular, intravenous, subcutaneous or oral dosage range from O.l mg/kg daily to 125 mg/kg daily;
velnacrine (Mentane, Hoechst-Roussel), dosage range from lO mg daily t:o 350 mg daily:
phenylmethylsulfonyl fluoride, intravenous, subcutaneous, intramuscular or oral dosage range from 5 mg/kg daily to 60 mg/kg daily;
methanesulfonyl fluoride, intravenous, in~ramuscular, subcuta-neous or oral dosage range from 5 mg/kg daily to 350 mg/kg daily;
huperzine A, intramuscular, intravenous, subcutaneous or oral dosage range from lO ~g/kg daily to l mg/kg daily;
huperzi.ne B, intramuscular, intravenous, subcutaneous or oral dosage range from lO ~g/kg daily to l mg/kg daily;
edrophonium chloride (Hoffman LaRoche), intravenous, intra-muscular, subcutaneous or oral dosage range from 2 mg daily to 400 mg daily;
galan~h~;ne, intravenous, intramuscular, subcutaneous or oral dosage range from 5 mg daily to lO0 mg daily; and W095/01096 PCT~S94/07277 2~&~13~

miotine, intravenous, intramuscular, subcutaneous or oral dos-age range from 2 mg daily to 400 mg daily;
(f) calcium channel blocker agents such as diltiazem (Cardizem or Cardizem SR), dosage range from 10 mg daily to 360 mg daily;
verapamil (Calan or Calan SR), dosage range from 10 mg daily to 480 mg daily;
nifedipine (Procardia), dosage range from 3 mg daily to 180 mg daily;
nifedipine (Procardia XL), dosage range from 3 mg daily to 90 mg daily;
nicardipine (Cardene), dosage range from 6 mg daily to 120 mg daily;
isradipine (DynaCirc), dosage range from 0.5 mg daily to 20 mg daily;
amlodipine (Norvasc, Pfizer Labs Division), dosage range from 0.5 mg daily to 10 mg daily; and felodipine (Plendil, Merck & Co.), dosage range from 0.5 mg daily to 20 mg daily;
(g) biogenic amines and agents related thereto such as clonidine (CataPres, Boehringer Ingelheim), dosage range from 0.25 mg daily to 2.4 mg daily;
guanfacine (Tenex, Robins), dosage range from 0.25 mg daily to 3 mg daily;
alaproclate, dosage range from 0.25 mg daily to 3 mg daily;
fipexide, dosage range from 0.25 mg daily to 3 mg daily;
zimeldine, dosage range from 0.25 mg daily to 3 mg daily; and citalopram, dosage range from 0.25 mg daily to 3 mg daily;
(h) anti-rage drugs such as propranolol (Inderal, Wyeth-Ayerst Laborator~es), dosage range from 30 mg daily to 640 mg daily;
carbamazepine (Teqretol, Geigy), dosage range from 40 mg daily to 1.6 gm daily; and 7 fluoxetine (Prozac Pulvules, Dista), dosage range from 20 mg daily to 80 mg daily;
(i) minor tranquilizers such as benzodiazepine agents WO95/010916 PCT~S94/07277 including diazepam (Valium, Roche Products), dosage range from 0.5 mg daily to 40 mg daily;
lorazepam (Ativan, Wyeth-Ayerst Laboratories), dosage range from 0.5 mg daily to 10 mg daily;
prazepam (Centrax, Parke-Davis), dosage range from 5 mg daily to 60 mg daily;
chlordiazepoxide (Libritabs, Roche Products), dosage range from 5 mg daily to 300 mg daily;
chlordiazepoxide/clidinium combination (Librax, Roche Products), dosage range from 5 mg chlordiazepoxide and 2.5 mg clidinium daily to 20 mg chlordiazepoxide and lO mg clidinium daily;
chlordiazepoxide/amitriptyline combination (Limbitrol DS, Roche Products), dosage range from 10 mg chlordiazepoxide and 25 mg daily to 60 mg chlordiazepoxide and 150 mg amitriptyline daily;
chlordiazepoxide/esterified estrogen combination (Menrium, Roche Products), dosage range from 5 mg chlordiazepoxide and 0.2 mg esterified estrogen daily to 30 mg chlordiazepoxide and 1.2 mg esterified estrogen daily;
oxazepam (Serax, Wyeth-Ayerst), dosage ra.nge from 10 mg daily to 120 mg daily; and clorazepate dipotassium (Tranxene, Abbott Laboratories), dos-age range from 3.75 mg daily to 60 mg da:ily;
(j) angiotensin converting enzyme inhibi1_ors such as captopril (Capoten, Squibb), dosage range from 5 mg daily to 300 mg daily;
captopril in combination with hydrochlorothiazide (CaPozide, St~uibb), dosage range from 5 mg captopril and 3 mg hydro-chlorothiazide daily to 150 mg captopri.l and 50 mg hydro-chlorot:hiazide daily;
enalapril maleate (Vasotec, Merck & Co.), dosage range from 0.5 mg daily to 100 mg daily;
enalaprilat, dosage range from 0.5 mg daily to 100 mg daily;
enalapril maleate/hydrochlorothiazide combination (Vaseretic, WO95/01096 PCT~S94/07277 i6~ 76 Merck & Co.), dosage range from 2.5 mg enalapril maleate and 6.25 mg hydrochlorothiazide daily to 20 mg enalapril maleate and 50 mg hydrochlorothiazide daily;
fosinopril (MonoPril, Mead Johnson Pharmaceuticals), dosage range from 2 mg daily to 60 mg daily;
lisinopril (Zestril, Stuart), dosage range from 1 mg daily to 40 mg daily;
ramipril (Altace, Hoechst-Roussel), dosage range from 0.5 mg daily to 10 mg daily;
epi-captopril, dosage range from 1 mg daily to 300 mg daily;
alacepril, dosage range from 5 mg daily to 300 mg daily;
quinapril, dosage range from 0.5 mg daily to 40 mg daily;
perindopril, dosage range from 0.2 mg daily to 40 mg daily;
delapril, dosage range from 4 mg daily to 1.5 gm daily;
cilazapril, dosage range from 0.2 mg daily to 40 mg daily;
pivalopril, dosage range from 2 mg daily to 250 mg daily;
rentiapril, dosage range from 1 mg daily to 150 mg daily;
zofenopril, dosage range from 1 mg daily to 150 mg daily; and zofenoprilat, dosage range from 1 mg daily to 150 mg daily;
(k) agents which may enhance acetylcholine synthesis, storage or release such as phosphatidylcholine, dosage range from 1 gm daily to 15 gm daily;
4-aminopyridine, intravenous, intramuscular, subcutaneous or oral dosage range from 0.25 mg/kg daily to 10 mg/kg daily;
3,4-diaminopyridine, intravenous, intramuscular, subcutaneous or oral dosage range from 50 ~g daily to 100 mg daily;
choline chloride, dosage range from 500 mg daily to 30 gm daily;
choline bitartrate, dosage range from 500 mg daily to 30 gm daily; q bifemelane, dosage range from 1 mg/kg daily to 1.2 gm/kg daily;
vesamicol, dosage range from 50 ~g/kg daily to 500 mg/kg daily;
secoverine, dosage range from 50 ~g/kg daily to 500 mg/kg WO95/01096 PCT~S94/07277 21~63~

daily;
tetraphenylurea, dosage range from 50 ~g/hg daily to 500 mg/kg daily; and nicotinamide, dosage range from l mg/kg daily to 500 mg/kg daily;
(l) postsynaptic receptor agonists such as arecoline, intravenous, intramuscular, subcutaneous or oral dosage range from 2 mg daily to 25 mg daily;
oxotremorine, intravenous, intramuscular, subcutaneous or oral dosage range from 1 ~g/kg daily to 0.2 mg/kg daily;
ethyl nipecotate, intravenous, intramuscular, subcutaneous or oral dosage range from 2 mg daily to 250 mg daily;
bethanechol (Urecholine, Merck & Co.), dosage range from 5 mg daily to 200 mg daily; and levacecarnine (acetyl-L-carnitine or Alcar, Sigma-Tau), dosage range from 500 mg daily to 5 gm daily;
(m) ganglioside GM1, intravenous, intramuscular or subcutane-ous dosage range from 20 mg daily to 200 mg daily;
(n) mixed cow brain gangliosides (Cronassial, Fidia Pharmaceu-tical, marketed in several countries in Western Europe, South America and the Far East), intravenous, intramuscular or sub-cutaneous dosage range from 20 mg daily t.o 200 mg per day;
(o) specific monoamine oxidase-A inhibitors such as moclobemide (Aurorix, Hoffmann-La Roche), dosage range from 50 mg daily to 600 mg daily;
(p) N-methyl-D-aspartate glutamate receptor antagonists admin-istered orally, intravenously, intramuscularly or subcutane-ously such as milacemide, dosage range from 50 mg daily to 2.5 gm daily;
trihexyphenidyl (Artane, Lederle), dosage range from 0.1 mg daily to 20 mg daily;
ethopropazine (Paridol), dosage range from 10 mg daily to 400 mg daily;
procycli.dine (Kemadrin, Burroughs Wellcome), dosage range from l mg dai.ly to 40 mg daily;
diphenhydramine (BenadrYl, Parke-Davis), dosage range from 5 W095/01096 PCT~S94/07277 .

~6 mg daily to 200 mg daily;
dizocilpine (Neurogard, Merck Sharp & Dohme), dosage range from 0.1 ~g/kg daily to 10 mg/kg daily;
amantadine (Symmetrel, Du Pont Multi-Source Products), dosage range from 10 mg daily to 400 mg daily; and memantine, dosage range from 10 mg daily to 400 mg daily;
(q) nonsteroidal anti-inflammatory agents such as those recognized for treatment of rheumatoid arthritis, including flurbiprofen (Ansaid, Upjohn), dosage range from 20 mg daily to 300 mg daily;
aspirin (Arthritis Pain Formula, Whitehall Laboratories), dosage range from 250 mg aspirin daily to 4 gm daily;
mesalamine (Asacol, Procter & Gamble Pharmaceuticals), dosage range from 250 mg daily to 2.4 gm daily;
phenylbutazone (Butazolidin, Geigy), dosage range from 30 mg daily to 400 mg daily;
sulindac (Clinoril, Merck & Co), dosage range from 40 mg daily to 400 mg daily;
penicillamine (Cuprimine, Merck & Co.), dosage range from 25 mg daily to 2 gm daily;
oxaprozin (Davpro, Searle), dosage range from 25 mg daily to 2 gm daily;
salsalate (Disalcid, 3M Pharmaceuticals), dosage range from 300 mg daily to 3 gm daily;
diflunisal (Dolobid, Merck & Co.), dosage range from 100 mg daily to 1.5 gm daily;
piroxicam (Feldene, Pfizer Labs Division), dosage range from 2 mg daily to 20 mg daily;
indomethacin (Indocin, Merck & Co.), dosage range from 10 mg daily to 200 mg daily;
etodolac (Lodine, Wyeth-Ayerst Laboratories), dosage range from 100 mg daily to 1.2 gm daily;
meclofenamate sodium (Meclomen, Parke-Davis), dosage range from 20 mg daily to 400 mg daily;
ibuprofen (Motrin, Upjohn), dosage range from 100 mg daily to 3.2 gm daily;

WO95/01096 ~ PCT~S94/07277 , it6~ g3 fenoprofen calcium (Nalfon, Dista), dosage range from 100 mg daily to 3.2 gm;
naproxen sodium (Anaprox, Syntex), dosage range from 50 mg daily to 1.65 gm daily;
naproxen (Naprosyn, Syntex), dosage range from 50 mg daily to 1.5 gm daily;
ketoprofen (Orudis, Wyeth-Ayerst), dosage range from 15 mg daily to 300 mg daily;
mefenamic acid (Ponstel, Parke-Davis), dosage range from 150 mg daily to 1.5 gm daily;
nabumetone (Relafen, SmithKline Beecham), dosage range from 100 mg daily to 2 gm daily;
auranofin (Ridaura, SmithKline Beecham), dosage range from 1 mg daily to 9 mg daily;
tolmetin sodium (Tolectin, McNeil Pharmaceutical), dosage range from 100 mg daily to 1.8 gm daily;
ketorolac trome~h~;ne (Toradol, Syntex Laboratories), dosage range from 4 mg daily to 40 mg daily;
diclofenac sodium (Voltaren, Geigy), dosage range from 10 mg daily to 200 mg daily; and deferoxamine mesylate (Desferal, CIBA Pharmaceutical), intra-venous, intramuscular or subcutaneous dosage range from 100 mg daily to 2 gm daily;
(r) selegiline (EldeprYl, Somerset), dosage range from 5 mg daily to 10 mg daily;
(s) thiamine, dosage range from 500 mg daily to 3 gm daily;
(t) anfacine, intravenous, intramuscular, subcutaneous or oral dosage range from 1 mg/kg daily to 350 mg/kg daily;
(u) sulbutiamine (Arcalion, Laboratories Servier), dosage range from 1 mg/kg daily to 350 mg/kg da:ily;
(v) anti-oxidant agents which may be used in combination such as ascorbic acid, dosage range from 1 mg daily to 60 mg daily;
~-tocopherol, dosage range from 100 I. U. daily to 3,500 I. U.
daily;
N-acetylcysteine, dosage range from 10() mg daily to 1 gm WO95/01096 PCT~S94/07277 ?~ 6~i3~3 daily;
~-carotene, dosage range from 20 mg daily to 300 mg daily;
penicillamine, dosage range from 25 mg daily to 2 gm daily;
cyst~A~;ne, dosage range from 200 mg daily to 4 gm daily; and deferoxamine mesylate (Desferal, CIBA Pharmaceutical), intra-venous, intramuscular or subcutaneous dosage range from 100 mg daily to 2 gm daily;
(w) specific monoamine oxidase-B inhibitors such as lazabemide (Hoffmann-La Roche), dosage range from 10 mg daily to 200 mg daily;
(x) linopirdine (Aviva, DuPont Merck), dosage range from 1 mg daily to 500 mg daily;
(y) D-cycloserine, dosage range from 0.1 mg/kg daily to 15 mg/kg daily; and (z) serotonergic receptor antagonists such as ketanserin (Ketan, Janssen Pharmaceutica), intravenous, intra-muscular, subcutaneous or oral dosage range from 0.1 mg/kg daily to 20 mg/kg daily; and mianserin (Mian, Organon International), intravenous, intra-muscular, subcutaneous or oral dosage range from 0.1 mg/kg daily to 20 mg/kg daily.

Example 3 Clinical treatment of various forms of diabetes may be im-proved by use of the invention originally disclosed in US
patent application 07/660,561 in combination with known medicaments, including co-agent use of:
(a) various insulin derivatives and compositions such as human isophane insulin suspension (Mixtard Human 70/30, Novo Nordisk), available in 100 unit/ml vials, dosage as per the Physician's Desk Reference [Dowd, AL, 1993, pg. 1684]); human zinc suspension insulin (Novolin L, Novo Nordisk), available in 100 unit/ml vials, dosage as per the Physician's Desk Reference [Dowd, AL, 1993, pgs. 1683-1684]); and human insulin (HUMULIN compositions, Eli Lilly, available in seven formula-WO95/0109~6 ~3 PCT~S94/07277 tions for intravenous use, dosage as per the Physician's DeskReference [Dowd, AL, 1993, pgs. 1301-1308]);
(b) various oral sulfanilamide derivative hypoglycemic agents such as tolbutamide (Orinase, Upjohn), dosage range from 100 mg daily to 3 gm ~daily;
acetohexamide, dosage range from 25 mg daily to 1.5 gm daily;
tolazamide (Tolinase, Upjohn), dosage range from 10 mg daily to 1 gm daily;
chlorpropamide (Diabinase, Pfizer Labs Division), dosage range from 10 mg daily to 500 mg daily;
glipizide (Glucotrol, Pratt Pharmaceuticals), dosage range from 1 mg daily to 40 mg daily; and glyburide (Micronase, Upjohn), dosage range from 0.5 mg daily to 20 mg daily;
(c) angiotensin converting enzyme inhibitors such as captopril (Capoten, Squibb), dosage range from 10 mg daily to 450 mg daily;
captopril in combination with hydrochlorothiazide (Capozide, Squibb), dosage range from 6.25 mg captopril and 3.75 mg hydrochlorothiazide daily to 150 mg captopril and 50 mg hydro-chlorothiazide daily;
enalapril maleate (Vasotec, Merck & Co.), dosage range from 1 mg daily to 40 mg daily;
enalapril maleate/hydrochlorothiazide combination (Vaseretic, Merck & Co.), dosage range from 2.5 mg enalapril and 6.25 mg hydrochlorothiazide daily to 20 mg enalapril and 50 mg hydro-chlorothiazide daily;
epi-captopril, dosage range from 1 mg daily to 300 mg daily;
and zofenoprilat, dosage range from 1 mg daily to 150 mg daily;
(d) anti-hyperlipidemia agents such as fibric acid derivatives including gemfibrozil (Lopid, Parke-Davis), dosage range from 100 mg daily to 1.2 gm daily;
clofibrate (Atromid-S, Wyeth-Ayerst), dosage range from 20 mg .

2~383 82 daily to 2 gm daily;
bezafibrate, dosage range from lOO mg daily to 1.3 gm daily;
fenofibrate, dosage range from 40 mg daily to 500 mg daily;
metformin, dosage range from lOO mg daily to 4 gm daily:
guar gum, dosage range from 2 gm daily to 20 gm daily;
3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors such as lovastatin (Mevacor, Merck & Co.), dosage range from 2 mg daily to 80 mg daily;
pravastatin sodium (Pravachol, Squibb), dosage range from 1 mg daily to 40 mg daily; and simvastatin (Zocor, Merck & Co.), dosage range from l mg daily to 40 mg daily;
dextrothyroxine sodium (Choloxin, Boots-Flint), dosage range from 0.25 mg daily to 8 mg daily;
probucol (Lorelco, Marion Merrell Dow), dosage range from lOO
mg daily to 1 gm daily;
nicotinic acid (Nicolar, Rhone-Poulenc Rorer), dosage range from 500 mg daily to 6 gm daily;
acipimox, dosage range from l mg/kg daily to 500 mg/kg daily;
or bile acid sequestrants such as cholestyramine resin (Ouestran Liqht, Bristol Laboratories), dosage range from 400 mg anhydrous cholestyramine resin daily to 20 gm anhydrous cholestyramine resin daily; and colestipol (Colestid, Upjohn), dosage range from 500 mg daily to 30 gm daily;
(e) anti-oxidants such as probucol (Lorelco, Marion Merrell Dow), dosage range from lOO
mg daily to l gm daily;
prostaglandin B1 oligomers (also known as polymeric 15-keto prostaglandin B or PGBX), intravenous, intramuscular, subcuta-neous or oral dosage range from 5 mg/kg daily to 400 mg/kg daily;
2-aminomethyl-4-tert-butyl-6-iodophenol, dosage range from 0.5 mg/kg daily to 600 mg/kg daily;
2-aminomethyl-4-tert-butyl-6-propionylphenol, dosage range from 20 mg/kg daily to 500 mg/kg daily;

WO95/~1096 C38~ PCT~S94/07277 2,6-di--tert-butyl-4-[2'-thenoyl]phenol, dosage range from 3 mg/kg daily to 300 mg/kg daily;
and anti-oxidant combinations such as that of ascorbic acid (dosage range from 1 mg daily to 60 mg daily), ~-tocopherol (dosage range from 200 I. U. daily to 3,500 I. U. daily), ~-carotene (1 mg daily to 100 mg daily) and the anti-oxidant co-agent selenium (dosage range from 25 ug daily to 0.5 mg daily) r (f) immunosuppressive drugs such as cyclosporine (Sandimmune, Sandoz Pharmaceutical), dosage range from 1 mg/kg daily to 15 mg/kg daily;
azathioprine (Imuran, Burroughs Wellcome), dosage range from 0.25 mg/kg daily to 5 mg/kg daily; and azathioprine/glucocorticoid combinations such as azathioprine in a dosage range from 0.25 mg/kg daily to 5 mg/kg daily in combination with intravenous, intramuscular, subcutaneous or oral methyl prednisolone, dosage range from 0.1 mg/kg daily (or alternate day) to 5 mg/kg daily (or alternate day);
(g) agents which decrease blood platelet aggregation such as acetylsalicylic acid (Ecotrin, SmithKline Beecham Consumer Brands), dosage range from 25 mg daily to 4 gm daily; and dipyridamole (Persantine, Boehringer Ingelheim), dosage range from 25 mg daily to 400 mg daily;
(h) agents which decrease blood viscosity such as pentoxifylline (Trental, Hoechst-Roussel), dosage range from 100 mg daily to 1.2 gm daily;
(i) mixed cow brain gangliosides (Cronassi.al, Fidia Pharmaceu-tical, marketed in several countries in Western Europe, South America and the Far East), intravenous, intramuscular or sub-cutaneous dosage in the range of 20 mg daily to 100 mg daily;
(j) analgesic agents for treatment of chronic pain such as acetaminophen (Extra Strenqth Tylenol, McNeil Consumer), dos-age range from 300 mg daily to 4 gm dail~;
(k) various agents for treatment of diabetes-related nephrotic syndrome such as furosemide (Lasix, Hoechst-Roussel), dosage range from 5 mg WO95/01096 PCT~S94/07277 33~ 84 daily to 600 mg daily;
metolazone (MYkrox, Fisions Pharmaceuticals), dosage range from 0.1 mg daily to 1 mg daily;
lovastatin (Mevacor, Merck ~ Co.), dosage range from 2 mg daily to 80 mg daily;
heparin sodium (Tubex, Wyeth-Ayerst), intravenous, intramus-cular or subcutaneous dosage range from 1,000 USP units daily to 20,000 USP units daily;
warfarin sodium (Coumadin, Du Pont Pharmaceutical), dosage range from 0.25 mg daily to 10 mg daily; and aminoguanidine (Alteon), intravenous, intramuscular, subcuta-neous or oral dosage range from 5 mg/kg daily to 100 mg/kg daily; and (1) aldose reductase inhibitors such as sorbinil (Pfizer), intravenous, intramuscular, subcutaneous or oral dosage range from 1 mg/kg daily to 25 mg/kg daily;
(E)-3-carboxymethyl-5-[(2E)-methyl-3-phenylpropenylidene]-rhodanine, intravenous, intramuscular, subcutaneous or oral dosage range from 1 mg/kg daily to 40 mg/kg daily;
alrestatin, intravenous, intramuscular, subcutaneous or oral dosage range from 1 mg/kg daily to 100 mg/kg daily;
statil, intravenous, intramuscular, subcutaneous or oral dos-age range from 1 mg/kg daily to 25 mg/kg daily; and tolrestat (Ayerst-Wyeth Laboratories), intravenous, intramus-cular, subcutaneous or oral dosage range from 1 mg/kg daily to 25 mg/kg daily.

Example 4 Clinical treatment of symptomology related to aging may be im-proved by use of the invention originally disclosed in US pa-tent application 07/660,561 in combination with known medica-ments, including co-agent use of:
(a) monoamine oxidase B inhibitors such as selegiline (EldePryl, Somerset), dosage range from 5 mg daily to 10 mg daily;

WO95/01096 ~6~ PCT~S94/07277 (b) acetylcholinesterase inhibitors such as physostigmine (AntiliriumIniectable, Forest Pharmaceuticals), oral dosage range from o.l mg daily to 20 mg daily, or intra-venous, intramuscular or subcutaneous dosage range from 5 ~g daily to 3 mg daily, optionally with phosphatidylcholine co-agent, oral dosage range from zero to 15 gm daily;
heptylphysostigmine, dosage range from l mg daily to l gram daily;
tacrine (Cognex, Warner-Lambert), dosage range from 5 mg daily to 200 mg daily, optionally with phosphatidylcholine co-agent, dosage range from zero to 15 gm daily;
(+/ )-9-amino-l,2,3,4-tetrahydroacridin-l-ol, dosage range from 2 mg daily to 200 mg daily;
metrifonate, intramuscular, intravenous, subcutaneous or oral dosage range from O.l mg/kg daily to 125 mg/kg daily;
velnacrine maleate (Mentane, Hoechst-Roussel), dosage range from lO mg daily to 350 mg daily;
methanesulfonyl fluoride, intravenous, intramuscular, subcuta-neous or oral dosage range from 5 mg/k~ daily to 350 mg/kg daily;
phenylmethylsulfonyl fluoride, intravenous, subcutaneous, in-tramuscular or oral dosage range from 5 mg/kg daily to 60 mg/kg daily;
huperzine A, intramuscular, intravenous, subcutaneous or oral dosage range from lO ~g/kg daily to l mg/kg daily;
huperzine B, intramuscular, intravenous, subcutaneous or oral dosage range from lO ~g/kg daily to l mg/kg daily;
edrophonium chloride (Hoffman LaRoche), i:ntravenous, intramus-cular, subcutaneous or oral dosage range from 2 mg daily to 400 mg daily;
- galant~Am;ne, intravenous, intramuscular~ subcutaneous or oral dosage range from 5 mg daily to lO0 mg daily; and miotine, intravenous, intramuscular, subcutaneous or oral dos-age range from 2 mg daily to 400 mg dai].y;
(c) angiotensin converting enzyme inhibitors such as captopril (CaPoten, Squibb), dosage range from 5 mg daily to WO95/01096 PCT~S94/07277 2 ~

300 mg daily;
captopril in combination with hydrochlorothiazide (Capozide, Squibb), dosage range from 5 mg captopril and 3 mg hydro-chlorothiazide daily to 150 mg captopril and 50 mg hydro-chlorothiazide daily;
enalapril maleate (Vasotec, Merck & Co.), dosage range from 0.5 mg daily to 100 mg daily;
enalaprilat, dosage range from 0.5 mg daily to 100 mg daily;
enalapril maleate/hydrochlorothiazide combination (Vaseretic, Merck & Co.), dosage range from 2.5 mg enalapril maleate and 6.25 mg hydrochlorothiazide daily to 20 mg enalapril maleate and 50 mg hydrochlorothiazide daily;
fosinopril (Monopril, Mead Johnson Pharmaceuticals), dosage range from 2 mg daily to 60 mg daily;
lisinopril (Zestril, Stuart), dosage range from 1 mg daily to 40 mg daily;
ramipril (Altace, Hoechst-Roussel), dosage range from 0.5 mg daily to 10 mg daily;
epi-captopril, dosage range from 1 mg daily to 300 mg daily;
alacepril, dosage range from 5 mg daily to 300 mg daily;
quinapril, dosage range from 0.5 mg daily to 40 mg daily;
perindopril, dosage range from 0.2 mg daily to 40 mg daily;
delapril, dosage range from 4 mg daily to 1.5 gm daily;
cilazapril, dosage range from 0.2 mg daily to 40 mg daily;
pivalopril, dosage range from 2 mg daily to 250 mg daily;
rentiapril, dosage range from l mg daily to 150 mg daily;
zofenopril, dosage range from 1 mg daily to 150 mg daily; and zofenoprilat, dosage range from 1 mg daily to 150 mg daily;
(d) N-methyl-D-aspartate glutamate receptor antagonists admin-istered orally, subcutaneously, intramuscularly or intraven-ously such as milacemide, dosage range from 50 mg daily to 2.5 gm daily;
trihexyphenidyl (Artane, Lederle), dosage range from 0.1 mg daily to 20 mg daily;
ethopropazine (Paridol), dosage range from 10 mg daily to 400 mg daily;

WO95101096 ~1 66~ PCT~594/07277 procyclidine (Kemadrin, Burroughs Wellcom.e), dosage range from l mg daily to 40 mg daily;
diphenhydramine (BenadrYl, Parke-Davis), dosage range from 5 mg daily to 200 mg daily;
dizocilpine (Neuroqard, Merck Sharp & I~ohme), dosage range from O.l ~g/kg daily to lO mg/kg daily;
amantadine (Symmetrel, Du Pont Multi-Source Products), dosage range from lO mg daily to 400 mg daily; and memantine, dosage range from lO mg daily to 400 mg daily;
(e) anti-oxidant agents which may be used in combination such as ascorbic acid, dosage range from l mg daily to 60 mg daily;
~-tocopherol, dosage range from 200 I. U. daily to 3,500 I. U.
daily;
~-carotene, l mg daily to lO0 mg daily; and selenium, dosage range from 25 ~g daily to 0.5 mg daily;
(f) vasodilator and other nootropic direct brain metabolic en-hancer drugs such as flunarizine, dosage range from 2 mg daily to lO0 mg daily;
nimodipine (Nimotop, Miles Pharmaceutica].), dosage range from 300 mg daily to 3.6 gm daily;
idebenone, dosage range from 5 mg/kg daily to 150 mg/kg daily;
ebirati.de, subcutaneous dosage range from 3 ~g/kg daily to l mg/kg daily;
vinpocetine (Cavinton, Chemical Works of Gedeon Richter, Ltd.), intravenous or oral dosage range from 5 mg/kg daily to 300 mg/kg daily;
pentoxifylline, dosage range from 50 mg daily to 3 gm daily;
citicoline, dosage range from 50 mg daily to 5 gm daily;
bromvincamine, dosage range from 25 mg daily to 3 gm daily;
cyclandelate, dosage range from 25 mg daily to 3 gm daily;
isoxsuprene, dosage range from 25 mg daily to 3 gm daily;
nafronyl, dosage range from 25 mg daily to 3 gm daily;
papaverine, dosage range from 25 mg daily to 3 gm daily;
suloctidil, dosage range from 25 mg daily to 3 gm daily;
vinburnine, dosage range from 25 mg daily to 3 gm daily;
vincamine, dosage range from 25 mg daily to 3 gm daily;

WO95/01096 PCT~S94/07277 2~66~8~
. 88 vindeburnol, dosage range from 25 mg daily to 3 gm daily;
nicergoline (Sermion), intravenous, intramuscular, subcuta-neous or oral dosage range from 6 mg daily to lo gm;
razobazam, intravenous, intramuscular, subcutaneous or oral dosage range from 0.1 mg/kg daily to 25 mg/kg daily;
exifone, intravenous, intramuscular, subcutaneous or oral dosage range from 1 mg daily to 1 gm daily;
rolipram, intravenous, intramuscular, subcutaneous or oral dosage range from 1 mg daily to 1 gm daily;
naloxone, intravenous, intramuscular, subcutaneous or oral dosage range from 5 mg daily to 200 mg daily;
ethyl 5-isopropyloxy-4-methyl-~-carboline-3-carboxylate, in-travenous, intramuscular, subcutaneous or oral dosage range from 2 mg/kg daily to 100 mg/kg daily;
N'-methyl-~-carboline-3-carboxamide, intravenous, intramus-cular, subcutaneous or oral dosage range from 2 mg/kg daily to loO mg/kg daily;
methyl 6,7-dimethoxy-4-ethyl-~-carboline-3-carboxylate, intra-venous, intramuscular, subcutaneous or oral dosage range from 0.1 mg/kg daily to 10 mg/kg daily;
ethyl 5-methoxy-4-ethyl-~-carboline-3-carboxylate, intraven-ous, intramuscular, subcutaneous or oral dosage range from 1 mg/kg daily to 30 mg/kg daily;
sabeluzole, dosage range from 2 mg daily to 40 mg daily;
phosphatidylserine, intravenous, intramuscular, subcutaneous or oral dosage range from 1 mg/kg daily to 250 mg/kg daily;
piracetam, dosage range from 50 mg/kg daily to 8 gm/kg daily;
aniracetam, dosage range from 50 mg/kg daily to 1 gm/kg daily;
pyroglutamic acid, intravenous, intramuscular, subcutaneous or oral dosage range from 100 mg/kg daily to 5 gm/kg daily;
tenilsetam, dosage range from 10 mg daily (or alternate day) to 1 gm daily (or alternate day), or from 25 mg once a week to 1 gm once a week;
pramiracetam, dosage range from 50 mg/kg daily to 8 gm/kg daily;
oxiracetam, dosage range from 200 mg daily to 2 gm daily;

WO95/01096 383 PCT~S94/07277 rolziracetam, intravenous, intramuscular/ subcutaneous or oral dosage.range from 1 mg daily to 1 gm dai.ly;
etiracetam, dosage range from 50 mg/kg da.ily to 8 gm/kg daily;
propentophylline, intravenous, intramuscular, subcutaneous or oral dosage range from 50 mg daily to 3 gm daily;
dupracetam, intravenous, intramuscular, subcutaneous or oral dosage range from 1 mg daily to 1 gm daily; and ergoloid mesylates (Hyderqine, Sandoz Pha:rmaceuticals), dosage range from 0.5 mg daily to 40 mg daily;
(g) postsynaptic receptor agonists such as arecoline, subcutaneous or oral dosage range from 2 mg daily to 25 mg daily;
oxotremorine, intravenous, intramuscularr subcutaneous or oral dosage range from 1 ~g/kg daily to 0.2 mg/kg daily; and bethanechol (Urecholine, Merck & Co.), dosage range from 5 mg daily to 200 mg daily;
levacecarnine (acetyl-L-carnitine or Alcar, Sigma-Tau), dosage range from 500 mg daily to 5 gm daily; and ethyl nipecotate, intravenous, intramuscular, subcutaneous or oral dosage range from 2 mg daily to 250 mg daily;
(h) biogenic amines and co-agents related thereto such as clonidine (Catapres, Boehringer Ingelheim), dosage range from 20 ~g daily to 2.4 mg daily;
guanfacine (Tenex, Robins), dosage range from 0.25 mg daily to 3 mg daily;
alaproclate, dosage range from 0.25 mg daily to 3 mg daily;
fipexide, dosage range from 0.25 mg dail.y to 3 mg daily;
zimeldine, dosage range from 0.25 mg dai:ly to 3 mg daily; and citalopram, dosage range from 0.25 mg daily to 3 mg daily;
(i) anfacine, intravenous, intramuscular, subcutaneous or oral dosage range from 1 mg/kg daily to 350 mg/kg daily;
(j) agents which may enhance acetylcholine synthesis, storage or release such as phosphatidylcholine, dosage range from l gm daily to 15 gm daily;
4-aminopyridine, intravenous, intramuscular, subcutaneous or WO95/01096 PCT~S94/07277 oral dosage range from 0.25 mg/kg daily to 10 mg/kg daily;
3,4-diaminopyridine, intravenous, intramuscular, subcutaneous or oral dosage range from 50 ~g daily to 100 mg daily;
choline chloride, dosage range from 500 mg daily to 30 gm daily; choline bitartrate, dosage range from 500 mg daily to 30 gm daily;
bifemelane, dosage range from 1 mg/kg daily to 1. 2 gm/kg daily;
vesamicol, dosage range from 50 ~g/kg daily to 500 mg/kg daily;
secoverine, dosage range from 50 ~g/kg daily to 500 mg/kg daily;
tetraphenylurea, dosage range from 50 ~g/kg daily to 500 mg/kg daily; and nicotinamide, dosage range from 1 mg/kg daily to 500 mg/kg daily;
(k) prostaglandin B1 oligomers (also known as polymeric 15-keto prostaglandin B or PGBX), intravenous, intramuscular, subcutaneous or oral dosage range from 5 mg/kg daily to 400 mg/kg daily;
(1) acetylhomocysteine thiolactone, intravenous, intramuscu-lar, subcutaneous or oral dosage range from 0.5 mg/kg daily to 25 mg/kg daily;
(m) ganglioside GM1, intravenous, intramuscular or subcutane-ous dosage range from 20 mg daily to 200 mg daily;
(n) sulbutiamine, dosage range from 1 mg/kg daily to 350 mg/kg daily; and (o) serotonergic receptor antagonists such as ketanserin (Ketan, Janssen Pharmaceutica), intravenous, intra-muscular, subcutaneous or oral dosage range from 0.1 mg/kg daily to 20 mg/kg daily; and mianserin (Mian, Organon International), intravenous, intra-muscular, subcutaneous or oral dosage range from 0.1 mg/kg daily to 20 mg/kg daily.

WO95/0109C PCT~S94/07277 Example 5 Clinical tre.atment of tinnitus (nerve d.eafness) may be im-proved by use of the invention originally disclosed in US pa-tent application 07/660,561 in combination with known medica-ments, including co-agent use of:
(a) antidepressants or antianxiety medications such as amitriptyline (Elavil, Stuart), dosage range from 50 mg daily to 300 mg daily;
amitriptyline/perphenazine combinations (Etrafon, Schering), dosage range from 4 mg perphenazine and 50 mg amitriptyline daily to 16 mg perphenazine and 100 mg amitriptyline daily;
alprazolam (Xanax, Upjohn), dosage range from 125 ~g daily to 4 mg daily; and triptolene, dosage range from 0.1 mg daily to 20 mg daily;
(b) anticonvulsants such as primidone (Mysoline, Wyeth-Ayerst), dosage range from 10 mg daily to 2 gm daily;
phenytoin (Dilantin, Parke-Davis), dosage range from 10 mg daily to 600 mg daily; and carbamaæepine (Tegretol, Basel), dosage range from 40 mg daily to 1.6 gm daily;
(c) lidocaine (Xylocaine, Astra), intravenous, intramuscular or subcutaneous dosage range from 1 mg da.ily to 300 mg daily, or oral forms of lidocaine in a dosage range of 1 mg daily to 300 mg daily;
(d) tocainide, dosage range from 10 mg da.ily to 400 mg daily;
(e) flecinide, dosage range from 10 mg daily to 400 mg daily;
(f) nicotinamide, dosage range from 1 mg/kg daily to 500 mg/kg daily;
(g) aminooxyacetic acid, dosage range from lo mg daily to 500 mg daily;
(h) praxilene, dosage range from 5 mg/kg daily to 100 mg/kg daily;
(i) aniracetam, dosage range from 50 mg/kg daily to 1 gm/kg daily;

W095/01096 PCT~S94107277 ~ 92 (j) piracetam, dosage range from 1 mg daily to 100 mg daily;
(k) 13-cis-retinoic acid, dermal, subcutaneous, intravenous, intramuscular or oral dosage range from 50 ~g/kg daily to 25 mg/kg daily; and (1) 13-trans-retinoic acid, dermal, subcutaneous, intravenous, intramuscular or oral dosage range from 50 ~g/kg daily to 25 mg/kg daily.

Example 6 Clinical treatment of multiple sclerosis may be improved by use of the invention originally disclosed in US patent appli-cation 07/660,561 in combination with known medicaments, including co-agent use of:
(a) azathioprine (Imuran, Burroughs Wellcome), dosage range from 5 mg daily to 300 mg daily;
(b) copolymer-l (random polymer of L-alanine, L-glutamic acid, L-lysine and L-tyrosine, ratio of 6.0:1.9:4.7:1.0, of molecu-lar weight between 14,000 and 23,000 Daltons), intravenous, subcutaneous or intramuscular dosage range 2 mg daily to 40 mg daily;
(c) cyclosporine (Sandimmune, Sandoz Pharmaceutical), dosage range from 1 mg/kg daily to 15 mg/kg daily;
(d) interferons such as alfa-2a interferon (Roferon-A, Roche Laboratories), intraven-ous, intramuscular or subcutaneous dosage range from 300,000 I.U. daily to 36,000,000 IU daily;
alfa-2b interferon (Intron-A, Schering), intravenous, intra-muscular or subcutaneous dosage range from 300,000 I.U. daily to 5,000,000 I.U. daily;
alfa-N3 interferon (Alferon N Iniection, Purdue Frederick), intravenous, intramuscular or subcutaneous dosage range from 250,000 I.U. daily to 2,500,000 I.U. daily;
beta interferon (Betaseron, Berlex), intravenous, intramuscu-lar or subcutaneous dosage range from 5,000 U/kg daily to 50,000 U/kg daily; and ~ WO95/01096 ~ PCT~S94/07277 93 ~3 gamma-lb interferon (Actimmune, Genentech), intravenous, intramuscular or subcutaneous dosage range from 5,000 U/kg daily to 50,000 U/kg daily;
(e) corticosteroids such as prednisone (Deltasone, Upjohn), dosage range from 0.5 mg daily or every other day to 200 mg daily or every other day; and dexamethasone (Decadron, Merck & Co.), dosage range from 0.1 mg daily or every other day to 10 mg daily or every other day;
(f) cyclophosphamide (Cytoxan, Bristol-Myers Oncology), intra-venous, intramuscular, subcutaneous or o:ral dosage range from 0.1 mg/kg daily to 10 mg/kg daily;
(g) 4-aminopyridine, intravenous, intramuscular, subcutaneous or oral dosage range from 0.25 mg/kg dai:ly to 10 mg/kg daily;
(h) baclofen (Atrofen, Athena Neurosciences), dosage range from 1 mg daily to 80 mg daily; and (i) 3,~-diaminopyridine, dosage range from 50 ~g daily to 100 mg daily.

Example 7 Clinical treatment of amyotrophic lateral sclerosis may be improved by use of the invention originally disclosed in US
patent application 07/660,561 in combination with known medicaments, including co-agent use of:
(a) mixed cow brain gangliosides (Cronassial, Fidia Pharma-ceutical, marketed in several countries in Western Europe, South A.merica and the Far East), intramuscular, intravenous or subcutaneous dosage range from 20 mg daily to 100 mg daily;
(b) thyrotropin releasing factor (Relefact TRH, Ferring);
intraveneous, subcutaneous or intramuscular dosage range from 0.5 mg daily to 500 mg daily;
(c) serine, dosage range from 500 mg daily to 15 gm daily;
(d) L-threonine, dosage range from 500 mg daily to 15 gm daily;
(e) glycine, dosage range from 500 mg daily to 15 gm daily;
(f) N-methyl-D-aspartate glutamate receptor antagonists admin-WO9~101096 PCT~S94/07277 ~I G6~8~ ~

istered orally, intramuscularly, subcutaneously or intraven-ously such as milacemide, dosage range from 50 mg daily to 2.5 gm daily;
trihexyphenidyl (Artane, Lederle), dosage range from 0.1 mg daily to 20 mg daily;
ethopropazine (Paridol), dosage range from 10 mg daily to 400 mg daily;
procyclidine (Kemadrin, Burroughs Wellcome), dosage range from 1 mg daily to 40 mg daily;
diphenhydramine (Benadryl, Parke-Davis), dosage range from 5 mg daily to 200 mg daily;
dizocilpine (Neuroqard, Merck Sharp & Dohme), dosage range from 0.1 ~g/kg daily to 10 mg/kg daily;
amantadine (SYmmetrel, Du Pont Multi-Source Products), dosage range from 10 mg daily to 400 mg daily; and memantine, dosage range from 10 mg daily to 400 mg daily.

Example 8 Clinical treatment of Huntington's disease may be improved by use of the invention originally disclosed in US patent appli-cation 07/660,561 in combination with known medicaments including (a) N-methyl-D-aspartate glutamate receptor antagonists admin-istered orally, intramuscularly, subcutaneously or intraven-ously such as milacemide, dosage range from 50 mg daily to 2.5 gm daily;
trihexyphenidyl (Artane, Lederle), dosage range from 0.1 mg daily to 20 mg daily;
ethopropazine (Paridol), dosage range from 10 mg daily to 400 mg daily;
procyclidine (Kemadrin, Burroughs Wellcome), dosage range from 1 mg daily to 40 mg daily;
diphenhydramine (BenadrYl, Parke-Davis), dosage range from 5 mg daily to 200 mg daily;
dizocilpine (Neuroqard, Merck Sharp & Dohme), dosage range ~WO95101~96 21 663~3 PCT~59410n77 from 0.1 ~g/kg daily to 10 mg/kg daily;
amantadine (Symmetrel, Du Pont Multi-Source Products), dosage range from 10 mg daily to 400 mg daily; and memantine, dosage range from 10 mg daily to 400 mg daily;
(b) agents which may enhance acetylcholine synthesis, storage or release such as phosphatidylcholine, dosage range from 1 gm daily to 15 gm daily;
3,4-diaminopyridine, dosage range from 50 ~g daily to 100 mg daily;
choline chloride, dosage range from 500 mg daily to 20 gm daily; and choline bitartrate, dosage range from 530 mg daily to 20 gm daily; and (c) postsynaptic receptor agonists such as arecol:ine, intravenous, intramuscular, subcutaneous or oral dosage range from 2 mg daily to 25 mg da.ily.

Example 9 Clinical treatment of olivopontocerebellar atrophy may be improved by use of the invention originally disclosed in US
patent application 07/660,561 in combination with known medicaments including N-methyl-D-aspartate glutamate receptor antagonists adminis-tered orally, subcutaneously, intramusculary or intravenously such as milacemide, dosage range from 50 mg daily to 2.5 gm daily;
trihexyphenidyl (Artane, Lederle), dosage range from 0.1 mg daily to 20 mg daily;
- ethopropazine (Paridol), dosage range from 10 mg daily to 400 mg daily;
procyclidine (Kemadrin, Burroughs Wellcome), dosage range from 1 mg daily to 40 mg daily;
diphenhydramine (Benadryl, Parke-Davis), dosage range from 5 mg daily to 200 mg daily;

W095/01096 PCT~S94/07277 2~6~3~3 dizocilpine (Neurogard, Merck Sharp & Dohme), dosage range from 0.1 ~g/kg daily to 10 mg/kg daily;
amantadine (Symmetrel, Du Pont Multi-Source Products), dosage range from 10 mg daily to 400 mg daily; and memantine, dosage range from 10 mg daily to 400 mg daily.

Example 10 Clinical treatment of alcoholic polyneuropathy may be improved by use of the invention originally disclosed in US patent application 07/660,561 in combination with known medicaments, including (a) mixed cow brain gangliosides (Cronassial, Fidia Pharmaceu-tical, marketed in several countries in Western Europe, South America and the Far East, intravenous, intramuscular or subcu-taneous dosage in the range from 20 mg daily to 100 mg daily;
(b) tiapride, dosage range from 1 mg daily to 400 mg daily;
(c) physostigmine (Antilirium Iniectable, Forest Pharmaceuti-cals), oral dosage range from 0.1 mg daily to 20 mg daily, or intravenous, intramuscular or subcutaneous dosage range from 5 ~g daily to 3 mg daily, optionally with phosphatidylcholine co-agent, oral dosage range from zero to 15 gm daily;
(d) piracetam, dosage range from 1 mg daily to 100 mg daily;
and (e) cyclandelate, dosage range from 25 mg daily to 3 gm daily.

Example 11 Clinical treatment of hereditary motor and sensory neuropath-ies may be improved by use of the invention originally dis-closed in US patent application 07/660,561 in combination with known medicaments, including (a) mixed cow brain gangliosides (Cronassial, Fidia Pharmaceu-tical, marketed in several countries in Western Europe, South America and the Far East, intravenous, intramuscular or subcu-taneous dosage in the range from 20 mg daily to 100 mg daily;

W095/01096 PCT~S94/07277 '~
~8 and (b) 3,4-diaminopyridine, intravenous, intramuscular or sub-cutaneous dosage range from 50 ~g daily to lOo mg daily.

Example 12 Clinical treatment of urinary incontinence resulting from Alzheimer's senile dementia, demyelinat.ing diseases such as multiple sclerosis, peripheral nerve lesions, diabetes melli-tus and alcoholic polyneuropathy may be improved by use of the invention originally disclosed in US patent application 07/660"561 in combination with known medicaments, including co-agent use of:
(a) cholinergics such as bethanechol (Urecholine, Merck & Co.), dosage range from 5 mg daily to 200 mg daily alone, or in combination with prazosin, dosage range from 0.5 mg daily to 4 mg d.aily;
(b) ant:i-cholinergics such as hyoscyamine sulfate, dosage range from 0.1 mg daily to 1 mg daily;
atropine sulfate, dosage range from 25 ~g daily to 0.2 mg daily;
propantheline (Pro-Banthine, Schiapparelli Searle), dosage range from 2.5 mg daily to 75 mg daily;
oxybutynin (Ditro~an, Marion Merrell Dow), dosage range from 2.5 mg daily to 20 mg daily; and dicyclomine (Bentyl, Marion Merrell Dow), dosage range from 10 mg daily to 160 mg daily;
(c) alpha-adrenergics such as ephedri.ne, dosage range from 10 mg daily to 150 mg daily; and phenylpropanolamine, dosage range from 10 mg daily to 150 mg daily;
(d) tricyclic agents such as imipramine (Tofranil, Geigy), dosage range from 10 mg daily to 200 mg daily; and doxepin (Adapin, Lotus Biochemical), dosage range from 10 mg WO95/01096 PCT~S94107277 2~ 383 daily to 300 mg daily;
(e) flavoxate (uriPas~ SmithKline Beecham Pharmaceuticals), dosage range from 30 mg daily to 800 mg daily;
(f) beta-adrenergic blockers such as propranolol (Inderal, Wyeth-Ayerst Laboratories), dosage range from 30 mg daily to 640 mg daily;
pindolol (Visken, Sandoz Pharmaceuticals), dosage range from 10 mg daily to 60 mg daily;
metoprolol tartrate (LoPressor, Geigy), dosage range from 100 mg daily to 450 mg daily;
metoprolol succinate (Toprol XL, Astra), dosage range from 50 mg daily to 400 mg daily; and atenolol (Tenormin, ICI Pharma), dosage range from 50 mg daily to 200 mg daily; and (g) vasopressin analogues such as desmopressin (DDAVP Nasal SPray, Rhone-Poulenc Rorer Pharma-ceuticals), dosage range from 10 ~g daily to 40 ~g daily.

Example 13 Clinical treatment of gastroesophageal reflux disease, hypo-peristalsis and/or delayed gastric emptying may be improved by use of the invention originally disclosed in US patent appli-cation 07/660,561 in combination with known medicaments, including co-agent use of:
(a) metoclopramide (Reglan, A. H. Robins), intravenous, intra-muscular, subcutaneous or oral dosage range from 2 mg daily to 60 mg daily;
(b) cisapride (Prepulsid, Janssen Pharmaceutica), intravenous, intramuscular, subcutaneous or oral dosage range from 1 mg daily to 100 mg daily;
(c) famotidine (Pepcid, Merck & Co.), dosage range from 2 mg daily to 80 mg daily;
(d) cimetidine (Tagamet, SmithKline Beecham), dosage range from 40 mg daily to 1.6 gm daily;
(e) ranitidine (Zantac, Glaxo Pharmaceuticals), dosage range WO95/0109~ PCT~S94/07277 from 30 mg daily to 6 gm daily;
(f) omeprazole (Prilosec, Merck & Co.), dosage range from 5 mg daily to 400 mg daily; and (g) galanthamine, intravenous, intramuscular, subcutaneous or oral dosage range from 5 mg daily to 100 mg daily.
-Example 14 Clinical treatment of symptomology related to onset anddevelopment of atherosclerosis may be improved by use of the invention originally disclosed in US patent application 07/660,561 in combination with known medicaments, including co-agent use of:
(a) angiotensin converting enzyme inhibitor free radical scavenging agents possessing sulfhydryl groups such as captopril (Capoten, Squibb), dosage range from 5 mg daily to 300 mg daily;
captopril in combination with hydrochlorothiazide (Capozide, Squibb), dosage range from 5 mg captop~-il and 3 mg hydro-chlorothiazide daily to 150 mg captopril and 50 mg hydro-chlorothiazide daily;
epi-captopril, dosage range from 1 mg da.ily to 300 mg daily;
alacepril, dosage range from 5 mg daily to 300 mg daily;
pivalopril, dosage range from 2 mg daily to 250 mg daily; and rentiapril, dosage range from 1 mg daily to 150 mg daily;
(b) fibric acid derivative anti-hyperlipidemia agents such as gemfibrozil (Lopid, Parke-Davis), dosage range from 100 mg daily to 1.2 gm daily;
clofibrate (Atromid-S, Wyeth-Ayerst La:boratories), dosage range from 20 mg daily to 2 gm daily;
bezafibrate, dosage range from 100 mg daily to 1.3 gm daily;
and fenofibrate, dosage range from 40 mg daily to 500 mg daily;
(c) metformin, dosage range from 100 mg daily to 4 gm daily;
(d) nicotinic acid (Nicolar, Rhone-Poulenc Rorer), dosage range from 500 mg daily to 6 gm daily;

WO95/01096 PCT~S94/07277 21S~3~ --(e) natural hydroscopic non-digestable edible plant carbo-hydrate polymers such as guar gum, dosage range from 2 gm daily to 20 gm daily;
(f) 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors such as lovastatin (Mevacor, Merck & Co.), dosage range from 2 mg daily to 80 mg daily;
pravastatin (Pravachol, Squibb), dosage range from 1 mg daily to 40 mg daily; and simvastatin (Zocor, Merck ~ Co.), dosage range from 1 mg daily to 40 mg daily;
(g) acipimox, dosage range from 1 mg/kg daily to 500 mg/kg daily;
(h) bile acid sequestrants such as cholestyramine resin (Ouestran Light, Bristol Laboratories), dosage range from 400 mg anhydrous cholestyramine resin daily to 16 gm anhydrous cholestyramine resin daily; and colestipol (Colestid, Upjohn), dosage range from 500 mg daily to 30 gm daily;
(i) anti-oxidants such as probucol (Lorelco, Marion Merrell Dow), dosage range from 100 mg daily to 1 gm daily; and prostaglandin 81 oligomers (also known as polymeric 15-keto prostaglandin B or PGBX), intravenous, intramuscular or subcu-taneous dosage range from 5 mg/kg daily to 40 mg/kg daily;
(j) anti-hypertensive agent~ including oral diuretics such as bendroflumethiazide (Naturetin), dosage range from 0.5 mg daily to 5 mg daily;
benzthiazide (Exna), dosage range from 1 mg daily to 50 mg daily;
chlorothiazide (Diuril), dosage range from 10 mg daily to 500 mg daily;
chlorthalidone (Hy~roton), dosage range from 1 mg daily to 50 mg daily;
cyclothiazide (AnhYdron), dosage range from 0.1 mg daily to 2 WO95/OlOg6 PCT~S94/07277 ~83 mg daily;
hydrochlorothiazide (Hydro-Diuril), dosage range from 1 mg daily to 50 mg daily;
hydroflumethiazide (Saluron), dosage range from 1 mg daily to 50 mg daily;
indapamide (Lozol), dosage range from 0.25 mg daily to 5 mg daily;
methylclothiazide (Enduron), dosage range from 0.25 mg daily to 5 mg daily;
metolazone (Zaroxolyn), dosage range from 0.1 mg daily to 10 mg dai.Ly;
polythiazide (Renese), dosage range from 0.2 mg daily to 4 mg daily;
cluinethazone (HYdromox), dosage range from 2.5 mg daily to 100 mg dai:Ly;
trichlormethiazide (Nac~a), dosage range from 0.1 mg daily to 4 mg daily; and idebenone, dosage range from 5 mg/kg daily to 150 mg/kg daily;
loop diuretics such as bumetanide (Bumex), 50 ~g daily to 10 ms daily;
ethacrynic acid (Edecrin), dosage range from 2.5 mg daily to 100 mg daily;
furosemide (Lasix), dosage range from 2 mg daily to 600 mg daily; and torsemide (Presaril, Boehringer-Manheim), dosage range of 0.5 mg daily to 20 mg daily;
and potassium-sparing diuretics such as amiloride (Midamor), dosage range from 0.5 mg daily to 10 mg daily;
spironolactone (Aldactone), dosage range from 2.5 mg daily to 400 mg daily; and triamterene (Dyrenium), dosage range from 5 mg daily to 150 mg daily;
beta-adrenergic antagonists such as acebutolol (Sectral), dosage range from 20 mg daily to 1.2 gm daily;

W09S/01096 2 ~ ~ ~ 3 ~ 3 PCT~S94/072 ~

atenolol (Tenormin), dosage range from 2.5 mg daily to 200 mg daily;
betaxolol (Kerlone), dosage range from 1 mg daily to 20 mg daily;
carteolol (Cartrol), dosage range from 0.25 mg daily to 10 mg daily;
labetalol (Normodyne), dosage range from 20 mg daily to 1.8 gm daily;
metoprolol (Lopressor), 5 mg daily to 200 mg daily;
nadolol (Corgard), dosage range from 4 mg daily to 240 mg daily;
penbutolol (Levatol), dosage range from 2 mg daily to 80 mg daily;
pindolol (Visken), dosage range from 0.5 mg daily to 60 mg daily;
propranolol (Inderal or Inderal LA), dosage range from 4 mg daily to 320 mg daily;
timolol (Blocadren), dosage range from 1 mg daily to 60 mg daily;
and bisoprolol (Zebeta, Lederle), dosage range from 0.5 mg daily to 10 mg daily;
calcium antagonists such as diltiazem (Cardizem or Cardizem SR), dosage range from 10 mg daily to 360 mg daily;
verapamil (Calan or Calan SR), dosage range from 10 mg daily to 480 mg daily;
nifedipine (Procardia), dosage range from 3 mg daily to 180 mg daily;
nifedipine (Procardia XL), dosage range from 3 mg daily to 90 mg daily;
nicardipine (Cardene), dosage range from 6 mg daily to 120 mg daily;
isradipine (DynaCirc), dosage range from 0.5 mg daily to 20 mg daily;
amlodipine (Norvasc, Pfizer Labs Division), dosage range from 0.5 mg daily to 10 mg daily;

WO95/01096 ~ PCT~S94/07277 8~

felodipine (Plendil, Merck & Co.), dosage range from 0.5 mg daily to 20 mg daily;
nimodipine (Nimoto~, Miles Pharmaceutical), dosage range from 300 mg daily to 3.6 gm daily;
flunarizine, dosage range from 2 mg daily to 100 mg daily;
angiotensin converting enzyme inhibitors such as captopril (Capoten), dosage range from 2.5 mg daily to 300 mg daily;
enalapril (Vasotec), dosage range from 0.25 mg daily to 40 mg daily;
fosinopril (Monopril), dosage range from 1 mg daily to 60 mg daily;
lisinopril (Zestril), dosage range from 0.5 mg daily to 40 mg daily;
ramipril (Altace), dosage range from 0.25 mg daily to 10 mg daily;
~uinapril (Accupril, Parke-Davis), dosage range from 1 mg daily to 80 mg daily;
quinapril/hydrochlorothiazide combinations (Accuretic, Parke-Davis), dosage range from 2 mg quinapril and 1.25 mg hydro-chlorothiazide daily to 80 mg quinapril and 125 mg hydro-chlorothiazide daily; and benazepxil (Lotensin, CIBA Pharmaceutical), dosage range from 0.1 mg daily to 80 mg daily;
peptide-based renin inhibitors such as [(2S)-3-(4-methyl-piperazin-l-yl)sulfonyl-2-(phenylmethyl)-propionyl]-N-[(lS,2R,3S)-l-(cyclo-hexylmethyl)-2,3-dihydroxy-5-methyl-hexyl]-L-[3-(thiazol-4-yl)al-aninamide] (A-72517, Abbott Laboratories), oral, intravenous, intramuscular or subcu-taneous dosage range from 0.1 mg/kg daily to 120 mg/kg daily;
centrally acting alpha-adrenergic agonist:s such as clonidine (Catapres), dosage range from 10 ~g daily to 1.2 mg daily;
clonidine TTS (CataPres TTS transdermal skin patch), dosage range from 0.1 mg daily to 0.3 mg daily;
guanabenz (Wytensin), dosage range from 0.4 mg daily to 64 mg WO95/01096 PCT~S94/07277 2 ~6~ 104 daily;
guanfacine (Tenex), 0.1 mg daily to 3 mg daily; and methyldopa (Aldomet), dosage range from 25 mg daily to 2 gm daily;
peripherally acting adrenergic antagonists such as guanadrel (Hylorel), dosage range from 1 mg daily to 100 mg daily;
guanethidine (Ismelin), dosage range from 1 mg daily to 150 mg daily;
whole root Rauwolfia alkaloids (Raudixin), dosage range from 5 mg daily to 100 mg daily; and reserpine (Serpasil), dosage range from 10 ~g daily to 0.25 mg daily;
alpha-adrenergic antagonists such as prazosin (MiniPress, Pfizer Labs Division), dosage range from 0.1 mg daily to 20 mg daily;
prazosin/polythiazide combination (Minizide, Pfizer Labs Divi-sion), dosage range from 0.1 mg prazosin and 50 ~g polythi-azide daily to 20 mg prazosin and 2 mg polythiazide daily;
terazosin (Hytrin), dosage range from 0.1 mg daily to 20 mg daily; and doxazosin (Cardura), dosage range from 0.1 mg daily to 16 mg daily;
direct-acting vasodilators such as hydralazine (Apresoline), dosage range from 3 mg daily to 300 mg daily; and minoxidil (Loniten), 0.25 mg daily to 100 mg daily; and (k) drugs for use in treatment of ischemic heart disease including nitrates such as oral isosorbide dinitrate, dosage range from 2 mg daily to 240 mg daily; and sustained-release trinitroglycerin, dosage range from 1 mg daily to 540 mg daily;
beta-adrenergic antagonists such as acebutolol (Sectral), dosage range from 20 mg daily to 1.2 gm WO95/01096 PCT~S94/07277 æl,6~ 3 daily;
atenolol (Tenormin), dosage range from 2.5 mg daily to 200 mg daily;
betaxolol (Kerlone), dosage range from 1 mg daily to 20 mg daily;
carteolol (Cartrol), dosage range from 0.25 mg daily to 10 mg daily;
labetalol (Normodyne), dosage range from 20 mg daily to 1.8 gm daily;
metoprolol (LoPressor), dosage range from 5 mg daily to 200 mg daily;
nadolol (Corqard), dosage range from 4 mg daily to 240 mg daily;
penbutolol (Levatol), dosage range from 2 mg daily to 80 mg daily;
pindolol (Visken), dosage range from 0.5 mg daily to 60 mg daily;
propranolol (Inderal or Inderal LA), dosage range from 4 mg daily to 320 mg daily;
timolol (Blocadren), dosage range from 1 mg daily to 60 mg daily; and bisoprolol (Zebeta, Lederle), dosage range from 0.5 mg daily to 10 mg daily;
and calcium channel antagonists such as diltiazem (Cardizem or Cardizem SR), dosage range from 10 mg daily to 360 mg daily;
verapamil (Calan or Calan SR), dosage range from 10 mg to 480 mg;
nifedipine (Procardia), dosage range from 3 mg daily to 180 mg daily;
nifedipine (Procardia XL), dosage range f.rom 3 mg daily to 90 mg daily;
nicardipine (Cardene), dosage range from 6 mg daily to 120 mg daily;
isradipine (DYnaCirc), dosage range from 0.5 mg daily to 20 mg daily;

.

WO95/01096 PCT~S94/07277 2~ 3 106 amlodipine (Norvasc, Pfizer Labs Division), dosage range from 0.5 mg daily to 10 mg daily; and felodipine (Plendil, Merck & Co.), dosage range from 0.5 mg daily to 20 mg daily; and (l) ventricular antiarrhythmic drugs such as sotalol (Betapace, Berlex), dosage range from 30 mg daily to 320 mg daily;
mexilitene (Mexitil, Boehringer Ingelheim), dosage range from 60 mg daily to 1.2 gm daily;
propafenone (Rythmol, Knoll), dosage range from 45 mg daily to 900 mg daily;
quinidine (Ouinaqlute Dura-Tabs, Berlex), dosage range from 20 mg daily to 1.2 gm daily;
procainamide (Procan SR, Parke-Davis), dosage range from 200 mg daily to 5 gm daily; and pirmenol (Pimavar, Warner-Lambert), intravenous or oral dosage range from 25 mg daily to 500 mg daily.

6. Clinical Diagnosis of Chromosome 17 Hereditary Motor and Sensory Neuropathy by Electrophoretic Analysis of Cultured Fibroblast Proteins The results of a study conducted by this inventor and dis-closed in US patent application 08/026,617 provide additional evidence that chemical crosslinking of neurofilaments may underlie at least part of the etiology of the chromosome 17 HMSN disorder. Cultured skin fibroblasts from three chromo-some 17 HMSN donors and three control donors matched for age and sex were analyzed by two dimensional gel electrophoresis and subsequent computer image analysis. The HMSN patient skin biopsies came from donors who had previously participated in the organic acid metabolic profiling study noted above. Pro-tein analysis by gel electrophoresis and subsequent computer image analysis were carried out at Protein Databases, Inc.
(Huntington Station, NY), with financial support provided by the National Foundation for Jewish Genetic Diseases (New 095/OlOg6 PCT~S94/07277 107 ` ~ 66~8 York).

Cultured human fibroblast strains used in this study were obtained from the collection established by this inventor in the Microbiology Department of the University of Pennsylvania School of Medicine. For each of the six skin biopsy fibro-blast strains e~m;ned cells were grown in vitro in pH 7.4 RPMI 1~40 media supplemented with 10% fetal calf serum, L-glutamine, and penicillin-streptomycin antibiotics. Fibro-blasts were grown to confluency and then divided 1:3 for each subculture. Sixth subculture fibroblasts were used for pro-tein analysis by gel electrophoresis.

At Protein Databases, Inc. the protein contents of these six cultured fibroblast strains were subjected to two dimensional gel electrophoresis according to the procedure of Garrels (1979). Cultured fibroblast proteins were extracted into a sample buffer containing 0.3% sodium dodecyl sulfate, 5.0% 2-mercaptoethanol and Tris buffer, pH 8Ø For each sample, 30 ~g protein was applied to a 2.7% acrylamide gel containing 2.0% ampholytes (pH range 5-7). After isoelectric focusing electrophoresis, the proteins of each sample were resolved in the second ~;~?n~ion according to molecular weight on a 12.5 acrylamide gel.

Cell proteins were not labeled with one or more radioactive amino acid. Instead, protein gel spots were visualized by use of silver staining according to the methods of Merril and coworkers (1979, 1981) and Morrissey (19~1). Identification of individual protein spots on each gel was accomplished by electronic image processing followed by use of the PDOUESTTM
computer analysis system (Protein Databases, Inc.).
-In this study 145 protein spots were always seen in each ofthe three normal fibroblast strains, and 126 corresponding protein spots were always seen in each of the HMSN strains.

WO95/01096 2 ~ ~ ~ 3 ~ PCT~S94/07277 However, each of the HMSN samples also showed 25 additional protein spots which were never seen in any of the control samples. There were no examples of a protein always seen in each of the control samples but never seen in any of the HMSN
samples. The distribution of molecular weights of the addi-tional HMSN-specific protein spots did not correspond to the molecular weight distribution of control protein spots.
Rather, it was comparatively shifted up scale. Of the protein spots always seen in control samples, the largest had a molecular weight of 118,000. Of the 25 HMSN-specific protein spots, nine had molecular weights in the range of 130,000 to 192,000. The available information on these HMSN-specific proteins may be summarized as follows.

designatedapparent apparent protein numbermolecular weightisoelectric point (PI) 1 89,300 4.53 2 33,100 4.95 3 55,100 5.03 4 94,200 5.10 5130,700 4.92 6130,400 4.97 7149,000 4.97 8149,000 5.01 9150,600 5.11 1053,000 5-35 11145,400 5.37 1237,000 5.71 1347,600 5.46 1463,700 5.42 1571,400 5.57 1673,400 5.48 1767,900 5.92 1867,700 5.84 19109,500 5.77 2029,000 6.42 2146,300 6.48 2280,300 6.30 23138,200 6.31 24159,500 6.25 25192.800 6.26 Such protein mapping data cannot readily be explained by sim-ple genetic principles. The appearance of many supernumerary ~WO95/01096 ~ PCT~S94/07277 protein spots associated with a genetic defect might be ex-plained by a post-translational event, such as excess protein phosphorylation. Such events, however, would be expected to have relatively small effects on observed protein molecular weights. Hence such an explanation appears to lack credence in this case. In fact, the information available from this study can most directly be interpreted as evidence of excess, pathological chemical crosslinking of fibroblast proteins.

Without.further elaboration the foregoing will so fully illus-trate my invention that others may, by applying current or future knowledge, adapt the same for use under various conditions of service.

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3~ ~

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Claims (42)

CLAIMS:

I claim:

1. Use of a composition comprising a therapeutically effec-tive amount of at least one primary agent and a therapeutical-ly effective amount of at least one co-agent, said primary agent comprising a water soluble primary amine or amine-related derivative of benzoic acid in the molecular weight range of from 100 to 1,400 Daltons, for use in the treatment of a mammal suffering from a neurological disease or patho-physiologically related symptomology, wherein said primary agent and co-agent combination serves to impede the progres-sion of said neurological disease or pathophysiologically related symptomology.

2. Use of a composition comprising a primary agent and at least one co-agent for treatment of the symptomology of a neu-rological disease or pathophysiologically related symptomology wherein the neurological disease or pathophysiologically re-lated symptomology is characterized by the deterioration of intracellular and extracellular compartments and pathological chemical crosslinking of the intracellular and extracellular components thereof; said deterioration and said crosslinking resulting in part from reaction of the mammal's nerve cells, other cellular structures and their intracellular and extra-cellular components with disease-induced carbonyl-containing aliphatic or aromatic hydrocarbons present in the mammal; said intracellular and extracellular components comprising pro-teins, lipids and deoxyribonucleic acid; and wherein said chemical crosslinking comprises covalent bond crosslinking of said nerve cells and intracellular and extracellular compo-nents.

3. Use of a composition comprising a primary agent and at least one co-agent for treatment of the symptomology of a neurological disease or pathophysiologically related symptom-ology wherein the disease-related covalent bond crosslinking of said nerve cells, other cellular structures and intracellu-lar structures additionally comprises the formation of at least one neuropathological structure selected from the group consisting of:
a. polymerized aggregates of structural protein filaments such as excess neurofilament accumulation;
b. heterogeneous protein aggregates such as neurofibrillary tangles;
c. amorphous protein and lipid aggregates, such as senile plaques; and d. lipofuscin granules.

4. Use of a composition comprising a primary agent and at least one co-agent for treatment of the symptomology of a neu-rological disease or pathophysiologically related symptomology wherein the disease-related covalent bond crosslinking of said nerve cells, other cellular structures and extracellular structures additionally comprises the formation of at least one neuropathological structure or pathophysiologically re-lated structure selected from the group consisting of:
a. polymerized aggregates of blood serum and structural proteins such as excess amyloid accumulation; and b. amorphous protein and lipid aggregates, such as senile plaques and atherosclerotic plaques.

5. The use of Claim 1 characterized in that the primary agent has at least one primary amine group or amine-related group thereon for reaction with disease-induced carbonyl-con-taining aliphatic or aromatic hydrocarbons to decrease the deterioration of said nerve cells and intracellular and extra-cellular compartments and to decrease the pathological chemi-cal crosslinking of said nerve cells and intracellular and extracellular components by permitting said primary agent to effectively compete with and covalently bind to said disease-induced carbonyl-containing aliphatic or aromatic hydrocar-bons.

6. The use of Claim 1 characterized in that the primary agent additionally does not interact with normal cell metabo-lism of the mammal or does so in a non-cytotoxic manner, is capable of being tolerated by said mammal in dosages in the range of 15 mg/kg daily to 800 mg/kg daily for extended periods of time and wherein said therapeutic agent is readily absorbed by the kidney tissue of said mammal and excreted in the urine of said mammal without nephrotoxic consequences.

7. The use of Claim 1 characterized in that said therapeuti-cally effective amount of the primary agent is administered orally.

8. The use of Claim 1 characterized in that the primary agent is selected from the group consisting of the free acid forms, salts, benzene ring isomers, amide derivatives, carbox-ylic acid ester derivatives and analogous non-aromatic benzene ring derivatives of the group consisting of:

R = -NH2 -aminoalkyl group having 1-10 carbons including hydrocarbon isomers and/or hydroxylated derivatives thereof I -NHC(=NH)NH2 -(CH2)nNHC(=NH)NH2 where n = 1-10 -C(=NH)-NH2 -(CH2)n-CH=NC(=NH)NH2 where n = 1-10 -NHC(=NH)NHNH2 -(CH2)nNHC(=NH)NHNH2 where n = 1-10 -(CH2)n-CH=NC(=NH)NHNH2 where n = 1-10 -NHNHC(=NH)NH2 -(CH2)n-NHNHC(=NH)NH2 where n = 1-10 -(CH2)n-CH=N-NHC(=NH)NH2 where n = 1-10 R1 = -NH2 -aminoalkyl group (1-10 carbons) including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof -(CH2)nNHC(=NH)NH2 where n = 1-10 -C(=NH)-NH2 II -(CH2)n-CH=NC(=NH)NH2 where n = 1-10 -NHC(=NH)NHNH2 -(CH2)nNHC(=NH)NHNH2 where n = 1-10 -(CH2)n-CH=NC(=NH)NHNH2 where n = 1-10 -NHNHC(=NH)NH2 -(CH2)n-NHNHC(=NH)NH2 where n = 1-10 -(CH2)n-CH=N-NHC(=NH)NH2 where n = 1-10 R2 = -NH2 -OH

-O-R' with alkyloxy group R' having 2-10 carbons including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof -aminoalkyl group (1-10 carbons) including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof -(CH2)nCH3 where n = 1-10 including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof R1 = -(CH2)n-NH2 where n = 0-10 including isomers of the aminoalkyl group and hydroxylated derivatives thereof -C(=NH)-NH2 -NHC(=NH)NH2 III -(CH2)nNHC(=NH)NH2 where n = 1-10 -(CH2)n-CH=NC(=NH)NH2 where n = 1-10 -NHC(=NH)NHNH2 -(CH2)nNHC(=NH)NHNH2 where n = 1-10 (CH2)n-CH=NC(=NH)NHNH2 where n = 1-10 -NHNHC(=NH)NH2 -(CH2)n-NHNHC(=NH)NH2 where n = 1-10 -(CH2)n-CH=N-NHC(=NH)NH2 where n = 1-10 R = -NH2 -H
-OH

-O-R3 with alkyloxy group R3 has 2-10 carbons including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof -aminoalkyl group (1-10 carbons) including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof -(CH2)nCH3 where n = 1-10 including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof R' = -H

-OH
R" = -H

-OH

for controlling the symptoms of a human disorder featur-ing neurofilament associated pathology or pathophysiologically related symptomology, wherein said disorder is selected from the group consisting of hereditary motor and sensory neuro-pathies; diabetic polyneuropathy; Alzheimer's presenile demen-tia; 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 including symptoms of hypoperistalisis of the alimentary tract, hiatal hernia, partial food regurgitation, urinary incontinence, breathing insufficiency due to diaphram weakness and 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 including atherosclerosis and symptoms related thereto; alcoholic polyneuropathy; multiple sclerosis; olivopontocerebellar atrophy and Huntington's disease.

9. The use of Claim 1 characterized in that the one or more co-agent is selected from the group consisting of nonabsorb-able polyamine polymers or nonabsorbable polyamine-related polymers, anti-oxidants, suspending reagents, vitamins, co-agents which facilitate glutathione biological activity, a hormone, chemical conjugating co-agents which facilitate kid-ney drug elimination, metabolites at risk of depletion, sulf-hydryl containing co-agents and derivatives thereof, and free radical trapping compounds.

10. The use of Claim 1 characterized in that the nonabsorb-able polyamine polymer co-agent or nonabsorbable polyamine-related derivative thereof is selected from the group consist-ing of:
a. naturally occurring polysaccharides having .beta.-1,2, .beta.-1,3, .beta.-1,4 and/or .beta.-1,6 linkages containing aminosugars including the chitin class of biopolymers having the general structure of poly-.beta.-(1?4)-N-acetyl-D-glucosamine, and bearing at least one free primary amine group;
b. deacetylated naturally occurring polysaccharides, having at least one N-acetylated residue, including chitosan, chon-droitin sulfate, hyaluronic acid and keratan sulfate;
c. chemically aminated polysaccharides selected from the group consisting of:
aminodeoxy polysaccharides such as 2-amino-2-deoxycellu-lose; aminoalkyl-, amino(hydroxyalkyl)-, aminoalkyl-ether-, and amino(hydroxyalkyl)-ether- derivatives of cellulose, chi-tin and other naturally occurring non-digestible carbohydrates selected from the group consisting of H2N-(CH2)n-[carbohydrate] where n = 1-10, including alkyl isomers;
H2N-(CH2)m-CHOH-(CH2)n-[carbohydrate], where m = 0-10 and n = 0-10;
H2N-(CH2)n-O-[carbohydrate] where n = 1-10;
H2 N-(CH2)m-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], H2 CH2-C6H4-(CH2)n-[carbohydrate], and H2N-C6H4-(CH2)n-O[carbohydrate] where n = 0 - 10, and H2N-C6H4-(CH2)m-CHOH-(CH2)n-O-[carbohydrate] where m = O-10 and n = 0-10, including p-, o- and m-benzene ring amino- isomers, aminomethyl- isomers and alkyl group isomers thereof;
guanidine and aminoguanidine derivatives of cellulose, chitin or other naturally occurring nonabsorbable carbohy-drates selected from the group consisting of H2N-C(=NH)- [carbohydrate];
H2N-C(=NH)-(CH2)n-[carbohydrate], where n = 1-10, includ-ing hydrocarbon isomers and hydroxylated derivatives thereof;
H2N-C(=NH)-O-(CH2)n-[carbohydrate], where n = 1-10, in-cluding hydrocarbon isomers, ether linkage isomers and hydroxylated derivatives thereof;
H2N-C(=NH)-NH-[carbohydrate];
H2-C(=NH)-NH-(CH2)n-[carbohydrate], where n = 1-10, in-cluding hydrocarbon isomers and hydroxylated derivatives thereof;
H2N-C(=NH)-NH-(CH2)n-O-[carbohydrate], where n = 1-10, in-cluding hydrocarbon isomers, ether linkage isomers and hydroxylated derivatives thereof;

H2N-C(=NH)-N=CH-(CH2)n-[carbohydrate], where n = 1-10, in-cluding hydrocarbon isomers and hydroxylated derivatives thereof;
H2N-C(=NH)-N=CH-(CH2)n-O-[carbohydrate], where n = 1-10, including hydrocarbon isomers and hydroxylated deriva-tives thereof;
H2N-NHC(=NH)-NH-[carbohydrate];
H2N-NHC(=NH)-NH-(CH2)n-[carbohydrate], where n = 1-10, in-cluding 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 deriva-tives thereof;
H2N-NHC(=NH)-N=CH-(CH2)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 deriva-tives 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 deriva-tives 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 .omega.-, .omega.-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 .beta.-1,2, .beta.-1,3, .beta.-1,4 and/or .beta.-1,6 linkages;
f. mixed polysaccharide polymeric derivatives wherin primary amine, aminoalkyl (one to ten carbons per alkyl group), amino-hydroxyalkyl (one to ten carbons per alkyl group and one to ten hydroxyl groups per alkyl group), aminoguanidine, amino-guanidinyl-alkyl (one to ten carbons per alkyl group), amino-alkylguanidinyl (one to ten carbons per alkyl group), guani-dine, aminobenzene and/or aminoalkylbenzene (one to ten carbons per alkyl group) functional groups are covalently attached to matrices such as epi-chlorohydrin copolymers of cellulose or chitin and wherein hydrocarbon spacer groups may include alkene as well as alkyl groups; and g. non-polysaccharide polymeric derivatives wherein primary amine, aminoalkyl (one to ten carbons per alkyl group), amino-hydroxyalkyl (one to ten carbons per alkyl group and one to ten hydroxyl groups per alkyl group), aminoguanidine, amino-guanidinyl-alkyl (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 may include alkene as well as alkyl groups.

11. The use of Claim 10 characterized in that said co-agent is in a microfibrillated form or microcrystalline form having enhanced surface area, increased porosity, increased water retention capacity and enhanced chemical accessibility.

12. The use of Claim 10 characterized in that the therapeu-tically effective amount of said co-agent is a dosage in the range of one gm/day to forty gm/day.

13. The use of Claim 10 characterized in that said therapeu-tically effective amount is administered orally.

14. The use of Claim 9 characterized in that said anti-oxi-dant is selected from the group consisting of .alpha.-tocopherol, derivatives of .alpha.-tocopherol, .beta.-carotene, selenium, citric acid, ubiquinol, a seleno-containing amino acid, glutathione, sulfhydryl containing proteins, cysteine, homocysteine, N-acetylcysteine, cysteamine and methionine.

15. The use of Claim 9 characterized in that said suspending reagent is selected from the group consisting of carboxymethyl cellulose, microcrystalline cellulose, cellulose, starch, di-calcium phosphate, tricalcium phosphate, stearic acid, magne-sium 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, and wherein suspending reagents may be compounded together with at least one primary agent and at least one co-agent so as to produce a slow release formula.

16. The use of Claim 9 characterized in that said vitamin is selected from the group consisting of vitamin A, D, K, B1 and B6.

17. The use of Claim 9 characterized in that said co-agent which facilitates glutathione biological activity is selected from the group consisting of N-acetylcysteine; oxo-thiazoli-dinecarboxylate; timonacic acid; cysteamine; lipoamide deriva-tives such as malotilate, sulfarlem and oltipraz.

18. The use of Claim 9 characterized in that said hormone is human growth hormone.

19. The use of Claim 9 characterized in that said chemical conjugating agent which facilitates kidney drug elimination is selected from the group consisting of glycine and derivatives thereof.

20. The use of Claim 9 characterized in that said metabolite at risk of depletion i5 selected from the group consisting of pantothenic acid and derivatives thereof.

21. The use of Claim 9 characterized in that said co-agent is a sulfhydryl containing agent or derivative thereof selected from the group consisting of cysteine, homocysteine, methi-onine and thioctic acid (.alpha.-lipoic acid).

22. The use of Claim 9 characterized in that said co-agent is administered orally.

23. The use of Claim 9 characterized in that said co-agent is administered intravenously, intramuscularly or subcutaneously.

24. Use of a composition for treating a mammal suffering from a veterinary disorder featuring neurofilament associated path-ology or pathophysiologically related symptomology comprising administration of a therapeutically effective amount of a pri-mary agent sufficient to treat said mammal; wherein said mam-malian veterinary disorder is selected from the group consist-ing of diabetic polyneuropathy; metabolic symptomology related to diabetic polyneuropathy; amyotrophic lateral sclerosis;
age-related atrophy of peripheral sensory and motor nerves and symptomology related thereto including tinnitus; age-related atrophy of autonomic nerves and symptomology thereof includ-ing hypoperistalisis of the alimentary tract, hiatal hernia, partial food regurgitation, urinary incontinence, breathing insufficiency due to diaphram weakness and 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 including atherosclerosis and symptoms related thereto; wherein the primary agent is selected so that it does not interact with the normal cell metabolism of the mammal or does so in a non-cytotoxic manner, is capable of being tolerated by said mammal in dosages in the range of 15 mg/kg daily to 800 mg/kg daily for extended periods of time, is readily absorbed by the kidney tissue of said mammal and excreted in the urine of said mammal without nephrotoxic consequences to said mammal and is selected from the group consisting of water soluble, small molecular weight, primary amine containing chemical agents or amine-related derivatives thereof as defined in Claim 8.

25. The use of Claim 24 characterized in that the mammal is also treated with a therapeutically effective amount of at least one co-agent.

26. The use of Claim 24 characterized in that the mammal is treated with a therapeutically effective amount of at least one co-agent as defined in Claim 9.

27. A composition for use in the treatment of the symptoms of a disorder featuring neurofilament associated pathology or pathophysiologically related symptomology, wherein said dis-order 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 including symptoms of hypoperistalisis of the alimentary tract, hiatal hernia, partial food regurgitation, urinary incontinence, breathing insufficiency due to diaphram weakness and 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 including atherosclerosis and symptoms related thereto;
alcoholic polyneuropathy; multiple sclerosis; olivopontocere-bellar atrophy and Huntington's disease, wherein the at least one primary agent of said composi-tion is a water soluble substance having a molecular weight of from 100 to 1,400 Daltons selected from the group consisting of the free acid forms, salts, benzene ring isomers, amide derivatives, carboxylic acid ester derivatives and analogous non-aromatic benzene ring derivatives of the group consisting of:

R = -NH2 -aminoalkyl group having 1-10 carbons including hydrocarbon isomers and/or hydroxylated derivatives thereof I -NHC(=NH)NH2 -(CH2)nNHC(=NH)NH2 where n = 1-10 -C(=NH)-NH2 -(CH2)n-CH=NC(=NH)NH2 where n = 1-10 -NHC(=NH)NHNH2 -(CH2)nNHC(=NH)NHNH2 where n = 1-10 -(CH2)n-CH=NC(=NH)NHNH2 where n = 1-10 -NHNHC(=NH)NH2 -(CH2)n-NHNHC(=NH)NH2 where n = 1-10 -(CH2)n-CH=N-NHC(=NH)NH2 where n = 1-10 R1 = -NH2 -aminoalkyl group (1-10 carbons) including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof -(CH2)nNHC(=NH)NH2 where n = 1-10 -C(=NH)-NH2 II -(CH2)n-CH=NC(=NH)NH2 where n = 1-10 -NHC(=NH)NHNH2 -(CH2)nNHC(=NH)NHNH2 where n = 1-10 -(CH2)n-CH=NC(=NH)NHNH2 where n = 1-10 -NHNHC(=NH)NH2 -(CH2)n-NHNHC(=NH)NH2 where n = 1-10 -(CH2)n-CH=N-NHC(=NH)NH2 where n = 1-10 R2 = -NH2 -OH

-O-R' with alkyloxy group R' having 2-10 carbons including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof -aminoalkyl group (1-10 carbons) including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof -(CH2)nCH3 where n = 1-10 including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof R1 = -(CH2)n-NH2 where n = 0-10 including isomers of the aminoalkyl group and hydroxylated derivatives thereof -C(=NH)-NH2 -NHC(-=NH)NH2 III -(CH2)nNHC(=NH)NH2 where n = 1-10 -(CH2)n-CH=NC(=NH)NH2 where n = 1-10 -NHC(==NH)NHNH2 -(CH2)nNHC(=NH)NHNH2 where n = 1-10 -(CH2)n-CH=NC(=NH)NHNH2 where n = 1-10 -NHNH('(=NH)NH2 -(CH2)n-NHNHC(=NH)NH2 where n = 1-10 -(CH2)n-CH=N-NHC(=NH)NH2 where n = 1-10 R2 = -NH2 -H
-OH

-O-R3 with alkyloxy group R3 has 2-10 carbons including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof -aminoalkyl group (1-10 carbons) including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof -(CH2)nCH3 where n = 1-10 including hydrocarbon isomers and/or hydroxyl-ated derivatives thereof R' = -H

-OH
R" = -H

-OH

in a dosage range of from 15 mg/kg daily to 800 mg/kg daily, in association with a pharmaceutically acceptable carrier thereof.

28. The composition of Claim 27 additionally comprising at least one co-agent present in an effective amount.

29. The composition of Claim 28 characterized in that the one or more co-agent is selected from the group consisting of non-absorbable polyamine polymers or nonabsorbable polyamine-re-lated polymers, anti-oxidants, suspending reagents, vitamins, co-agents which facilitate glutathione biological activity, a hormone, chemical conjugating co-agents which facilitate kid-ney drug elimination, metabolites at risk of depletion, sulf-hydryl containing co-agents and derivatives thereof, and free radical trapping compounds.

30. The composition of Claim 28 characterized in that the one or more co-agent is selected from the group consisting of a neuroactive drug; an antihistaminic drug; a vasoactive drug;
an immunoregulatory drug; an anti-oxidant drug recognized as having neuroprotective properties; an anti-diabetic drug; an antiulcerative drug; or a chemical selected from the group consisting of acetylhomocysteine thiolactone, alaproclate, aminooxyacetic acid, anfacine, arecoline, cimetidine, cisa-pride, cyclandelate, D-cycloserine optionally with a cholin-esterase inhibitor, famotidine, flavoxate, galanthamine, ganglioside GM1, ifenprodil, isosorbide dinitrate, lazabemide, levodopa optionally with a peripheral decarboxylase inhibitor, linopirdine, metoclopramide, mixed cow brain gangliosides, nafronyl, omeprazole, ranitidine, 13-cis-retinoic acid, 13-trans-retinoic acid, serine, thiamine disulfide O,O-diiso-butyrate, L-threonine, thyrotropin releasing factor, tiapride, trinitroglycerin, and vasopressin analogues including desmo-pressin.

31. The composition according to Claim 30 characterized in that the neuroactive drug is a dopamine agonist; an anti-cholinergic drug; an antidepressant drug; a serotonin reuptake inhibitor; a neurotransmission enhancer drug; an N-methyl-D-aspartate glutamate receptor antagonist; a vasodilator or oth-er nootropic direct brain metabolic enhancer drug; an acetyl-cholinesterase inhibitor; an antirage drug; a drug which en-hances acetylcholine synthesis, storage or release; an acetyl-choline postreceptor agonist; a monoamine oxidase inhibitor;
an anxiolytic drug; an anticonvulsant drug; a skeletal muscle relaxant drug; an antipsychotic drug; or a cholinergic mus-carinic agonist.

32. The composition according to Claim 30 characterized in that the vasoactive drug is a calcium channel antagonist; an angiotensin converting enzyme inhibitor; a .beta.-adrenergic antag-onist; an antihypertensive drug; an .alpha.-adrenergic agonist; an anti-hyperlipidemia fibric acid derivative; a nitrate drug; or an antiarrhythmic drug.

33. The composition according to Claim 30 characterized in that the immunoregulatory drug is a nonsteroidal anti-inflam-matory drug; an immunosuppressive drug; a glucocorticosteroid drug; or an immunomodulator drug.

34. The composition according to Claim 30 characterized in that the anti-oxidant drug recognized as having neuroprotec-tive properties is a chemical selected from the group consist-ing of ascorbic acid, penicillamine, deferoxamine, probucol, prostaglandin B1 oligomers, 2-aminomethyl-4-tert-butyl-6-iodophenol, 2-aminomethyl-4-tert-butyl-6-propionyl-phenol, and 2,6-di-tert-butyl-4-[2'-thenoyl]phenol.

35. The composition according to Claim 30 characterized in that the anti-diabetic drug is an insulin derivative; a sul-fanilamide derivative hypoglycemic drug; an anti-hyperlipid-emia drug; a drug which decreases blood platelet aggregation;
a drug which decreases blood viscosity; an analgesic drug; a drug for treatment of diabetes-related nephrotic syndrome; or an aldose reductase inhibitor.

36. A process for determining if the genomic contents of a human includes the presence of the gene which encodes for chromosome 17 hereditary motor and sensory neuropathy, also known as chromosome 17 Charcot-Marie-Tooth disease, the pro-cess comprising the steps of:
(a) establishment of a cultured fibroblast strain derived from a skin biopsy or amneotic fluid sample obtained from said human;
(b) homogenation of a sample of said fibroblast strain so as to obtain a solubilized suspension of proteins;
(c) resolution of said proteins according to molecular charge by use of isoelectric focusing gel electrophoresis of said solubilized protein suspension;
(d) and/or resolution of proteins according to molecular weight by use of sodium dodecyl sulfate gel electrophor-esis;
(e) visualization of resolved protein spots on said electro-phoresis gel;
(f) analysis of the electrophoretic pattern of the resolved cultured fibroblast proteins by visual examination or use of computer-assisted image processing technology, includ-ing reference to protein standards of known molecular weight and known isoelectric point, so as to determine the presence or absence of at least one chromosome 17 hereditary motor and sensory neuropathy-specific super-numerary protein.

37. The process of Claim 36 part (a) wherein the establish-ment of a cultured fibroblast strain of cells in the labora-tory includes conditions such as the use of pH 7.4 RPMI 1640 media supplemented with 10% fetal calf serum, L-glutamine, and penicillin-streptomycin antibiotics, including from one to twenty sub-culturing steps, each consisting of dilution of the cell strain by a factor of from 1:1 to 1:20 into new tissue culture media, which may optionally include the radiolabeling of fibroblast proteins by the addition of one or more radio-active amino acids such as [35S]methionine, [3H]lysine or [14C]arginine to the culture media prior to resolution of pro-teins by gel electrophoresis.

38. The process of Claim 36 part (b) wherein homogenation of a sample of said fibroblast strain so as to obtain a solubil-ized protein suspension includes treatment: with agents such as a suspending buffer consisting of 0.3% sodium dodecyl sulfate, 5.0% 2-mercaptoethanol and Tris buffer, pH 8.0, followed by treatment with enzymes such as DNase I and RNase A.

39. The process of Claim 36 part (c) wherein isoelectric focusing gel electrophoresis includes use of from 1 to 200 µg of said solubilized protein suspension under conditions such as the application of an electric field of 19,000 volt/hours overnight to a 2.7% or 2.9% acrylamide gel containing the fibroblast protein sample at a starting boundary or point, and wherein said acrylamide gel contains 9.5 M urea, 2.0% or 4.0%
NP-40 non-ionic detergent and 2.0% ampholytes (pH range 5-7 or pH range 6-8).

40. The process of Claim 36 part (d) wherein the use of sodi-um dodecyl sulfate gel electrophoresis to separate proteins according to molecular weight either as a substitute for the procedure of Claim 37 part c or in addition to the procedure of Claim 37 part (c) includes conditions such as the applica-tion of an electric field of 60 watts (constant wattage) for a time period sufficient to achieve protein resolution to a 12.5% acrylamide gel which contains the fibroblast protein sample at a starting boundary or point.

41. The process of Claim 36 part (e) wherein visualization of non-radioactive resolved protein spots on said electrophoresis gel includes use of a staining agent such as Coomassie bril-liant blue R250 or silver staining by a procedure such as treatment with glutaraldehyde followed by ammoniacal silver/
formaldehyde, or visulaization of radiolabeled resolved pro-tein spots by autoradiography, so as to reveal the presence of individually separated proteins and/or individual protein complexes which have remained intact under the laboratory analytical conditions employed.

42. The process of Claim 36 wherein the presence of at least one chromosome 17 hereditary motor and sensory neuropathy-specific supernumerary protein not seen in an analogous cul-tured fibroblast protein sample derived from a human lacking this genetic disease shall be interpreted as evidence of the presence of the chromosome 17 hereditary motor and sensory neuropathy gene in said human.