EP1006794B1 - A method for treating or preventing alzheimer's disease - Google Patents

A method for treating or preventing alzheimer's disease Download PDF

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Publication number
EP1006794B1
EP1006794B1 EP98909105A EP98909105A EP1006794B1 EP 1006794 B1 EP1006794 B1 EP 1006794B1 EP 98909105 A EP98909105 A EP 98909105A EP 98909105 A EP98909105 A EP 98909105A EP 1006794 B1 EP1006794 B1 EP 1006794B1
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dione
benzyl
insulin
methyl
disease
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German (de)
French (fr)
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EP1006794A1 (en
EP1006794A4 (en
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Robert W. Esmond
Jack R. Wands
Suzanne De La Monte
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de la Monte Suzanne
Esmond Robert W
WANDS, JACK R.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system

Definitions

  • the present invention is in the field of medicinal chemistry.
  • the present invention is related to a new method to treat or prevent Alzheimer's disease by the use of an agent which causes reduction in serum insulin levels.
  • Alzheimer's disease is characterized by amyloid plaque that deposits around and between nerve cells in the brains.
  • the plaques contain fibrillar aggregates of a small peptide called amyloid ⁇ -peptide. These plaques are centers for the degeneration of nerve endings. Whether the fibers themselves are toxic is somewhat controversial, in view of transgenic animals which have been engineered to express amyloid ⁇ -peptide. These mice make amyloid deposits, and there is damage to nerve cells around the plaque, however, no further neuronal loss is seen in these mice. Thus, there appear to be other mechanisms involved. (Brennan.)
  • amyloid plaques are the cause or the consequence of the disease is a perplexing question according to Brennan.
  • NTP neural tread protein
  • the cathepsins are a family of enzymes that are usually located in lysosomes. It has been found that the inhibition of cathepsin D using an aspartyl protease inhibitor reduces the formation of ⁇ -amyloid protein and the resultant senile plaques. Thus inhibitors of cathepsin D, such as rhodanine derivatives, have been proposed as therapeutic agents for the treatment of Alzheimer's disease. See U.S. Patent Nos. 5,716,975 and 5,523,314 .
  • Athena Neurosciences South San Francisco
  • Athena is sorting through hundreds of molecules in a series to look for the best pharmaceutical to take into development. (Brennan.)
  • Neo-Therapeutics Irvine, CA
  • AIT-082 hypoxanthine analog
  • This drug activates genes that express growth factor proteins known to reverse memory deficits in aged rodents when directly delivered to the brain.
  • CX516 is an agonist of the AMPA receptor, and promotes the uptake of Ca 2+ into nerve cells when the brain levels of glutamate are low, as they are in Alzheimer's disease. This drug reversed age-associated memory impairment in rats. (Brennan.)
  • Estrogen is also being evaluated as an agent that might be helpful in protecting women from Alzheimer's disease. Preliminary results indicate that women who receive estrogen replacement therapy have a lower risk of developing the disease. (Brennan.)
  • prednisone Another agent being evaluated is prednisone. This drug is being tested to see if it can benefit Alzheimer's patients by reducing inflammation in their brains. A further study has just been completed which examined the antioxidant effect of vitamin E and selegiline, a drug used to treat Parkinson's disease. (Brennan.)
  • US4855306 discloses selective dopamine D1 receptor agonists for the treatment of primary degenerative dementia, including senile dementia of the Alzheimer's type.
  • EP677517 and EP587377 disclose 2-thioxo-4-thiazolidinone compounds which are inhibitors of cathepsin D for the treatment of Alzheimer's disease.
  • JP07238035A2 discloses beta amyloid proteolytic agent containing insulin decomposing enzyme for the treatment of Alzheimer's disease.
  • WO95/13823 discloses a complex of IGF and IGFBP-3 for treating neurological disorders.
  • the present invention is related to the discovery that high levels of circulating insulin are a root cause of Alzheimer's disease.
  • insulin stimulates the increased expression of NTP in nerve cell culture. Since insulin crosses the blood-brain barrier, it is now clear that high levels of insulin stimulate brain nerve cells to secrete NTP and develop the hallmarks of Alzheimer's disease.
  • the present invention is directed to the treatment or prevention of Alzheimer's disease, in a human, comprising the use of an agent in the manufacture of a medicament which results in lowered serum insulin levels.
  • the agent useful in the present invention is one that is also useful for treating impaired glucose tolerance.
  • the present invention also relates to the use of a medicament for improving mentation of a patient with Alzheimer's disease, comprising administering to said patient an effective amount of an agent which increases the insulin sensitivity of the patient.
  • the present invention also relates to the use of a medicament which results in lower serum insulin levels and an agent which inhibits the formation of small strokes for treating or preventing or preventing Alzheimer's disease, in a human.
  • the invention relates to use of an agent which results in lowered serum insulin levels, wherein said agent is selected from the list consisting of:
  • Insulin insensitivity can be diagnosed by determining whether the animal has an elevated insulin level. In the case of humans, insulin levels of over 10 mU/ml indicate that the person has at least some insulin insensitivity. Eades and Eades, supra . Insulin values of 25-50 or more are very high and indicative of a high level of insulin resistance. People with insulin levels above 10 mU/ml are considered to be in need of treatment to reduce insulin levels and thereby treat, prevent or reduce the possibility of having Alzheimer's disease in the future.
  • Agents which lower serum insulin levels include drugs which are known to be useful for treating insulin insensitivity.
  • Agents which can be used in the practice of the invention include thiazolidinediones and related antihyperglycemic agents which have been reported to be useful for treating impaired glucose tolerance in order to prevent or delay the onset of non-insulin-dependent diabetes mellitus. See U.S. Patent No. 5,478,852 .
  • An example of a thiazolidinedione that can be used is troglitazone (brand name Rezulin TM ) that has recently been approved by the U.S. Food and Drug Administration for treating insulin resistance. Routes of administration for such thiazolidinediones and related antihyperglycemic agents are described in U.S. 5,478,852 .
  • the thiazolidinediones and related antihyperglycemic agents may be administered to the patient in an amount effective which is, in general, the amount effect to treat impaired glucose tolerance according to U.S. 5,478,852 . See also, U.S. Patent No. 5,457,109 . Unlike sulfonylureas, troglitazone is not an insulin secretagogue, " Physicians' Desk Reference,” Medical Economics Company, Montvale, NJ, 2118-2119 (1998 ).
  • the present invention also relates to a method of improving mentation of a patient with Alzheimer's disease, comprising administering to said patient an effective amount of an agent which increases the insulin sensitivity of the patient.
  • an agent may be administered to a patient with Alzheimer's disease to improve mentation, which agent is effective for treating insulin insensitivity.
  • mentation By decreasing insulin insensitivity, that is by increasing insulin sensitivity, in the patient, glucose utilization is improved in the brain and mentation will improve.
  • Agents which inhibit the formation of small strokes include aspirin.
  • agents described herein may also be administered in conjunction with an antiinflammatory agent such as ibuprofen which has been found useful in some studies in ameliorating Alzheimer's disease.
  • an antiinflammatory agent such as ibuprofen which has been found useful in some studies in ameliorating Alzheimer's disease.
  • the agents that have been described herein may also be administered with compounds which modulate ATP production and have thereby been found useful as an alternative energy source to glucose for conditions in which ischemic or hypoxic conditions have compromised ATP production.
  • Such compounds include, inter alia , fructose-1,6-biphosphate, see U.S. Patent Nos. 4,546,095 , 4,703,040 , 4,757,052 , and 5,039,665 ; pyruvate, see U.S. Patent No. 5,395,822 ; glyceraldehyde-3-phosphate and 3-phosphoglycerate, see U.S. Patent No. 5,707,971 .
  • Administration of these agents may also be useful as an alternative to insulin treatment by providing an energy source alternative to glucose, and may obviate the general decline of aging by enhancing ATP production according to U.S. 5,707,971 .
  • Example 1 Insulin Stimulates the Expression of AD7c-NTP, a Protein which causes neurons to exhibit neuronal sprouting and apoptosis
  • Insulin is an important mediator of growth and differentiation in CNS neurons. Insulin stimulated differentiation of PNET2 cells was associated with rapid (within 10 minutes) but transient increases in the levels of the 39 kD, 18 kD and 15 kD NTP species, followed by sustained increases in synthesis and steady state levels of all five NTP species. In contrast, the failure of insulin to induce differentiation of PNET1 cells was associated with absent insulin modulation of NTP.
  • PNET1 cells lacked insulin responsiveness and failed to phosphorylate IRS-1, but insulin receptor levels and tyrosyl phosphorylation (PY) of the ⁇ -subunit were intact.
  • PNET2 cells responded to insulin stimulation with phosphorylation of IRS-1, up-regulation of NTP, and neuronal differentiation. The results were confirmed by absent association between PI3 kinase and IRS-1-PY in PNET1 cells after insulin stimulation.
  • Neuritic sprouting and neuronal differentiation were induced in PNET2 and SH-Sy5y cells by insulin, PMA, or RA stimulation.
  • Insulin-mediated neuritic growth was associated with increased expression of the fetal brain and PNET-dominant forms of NTP (15 kD and 18 kD).
  • the PMA- and RA-induced neuritic sprouting modulated expression of the 21 kD and 26 kD NTP species, which are primarily expressed in the mature brain, and accumulated in AD brains.
  • expression of the immature or fetal forms of NTP are regulated by mechanisms and growth factors distinct from those involved in modulating expression of the 21 kD and 26 kD NTP molecules. Therefore, expression of fetal NTP molecules/genes can be mediated through the IRS-1 cascade, whereas expression of adult brain/AD-associated NTP genes can be regulated mainly through protein kinase C pathways.

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Abstract

Disclosed is a method for treating or preventing Alzheimer's disease by restricting the level of metabolizable carbohydrate in the diet and/or administering to the patient an effective amount of an agent which reduces serum insulin levels.

Description

    Field of the Invention
  • The present invention is in the field of medicinal chemistry. In particular, the present invention is related to a new method to treat or prevent Alzheimer's disease by the use of an agent which causes reduction in serum insulin levels.
    • Related Art
  • According to a recent review by Mairin B. Brennan published in Chemical and Engineering News 75 (3):29-35 (1997), roughly 4 million people in the United States have Alzheimer's disease. Inherited or not, the disease manifests itself with progressively impaired memory leading to mental confusion as the disease systematically kills off nerve cells in the brain. (Brennan.)
  • The devastating consequences of Alzheimer's disease has led to a prodigious effort to identify drugs that might be useful for treating the condition. Two drugs are currently available for treating Alzheimer's symptoms. Cognex (tacrine), sold by Parke-Davis and CoCensys Inc. was approved by the FDA in 1993. Aricept, sold by Eisai of Japan, was approved late in 1996. Both drugs are designed to improve memory and cognition in the earlier stages of the disease. (Brennan.)
  • Alzheimer's disease is characterized by amyloid plaque that deposits around and between nerve cells in the brains. The plaques contain fibrillar aggregates of a small peptide called amyloid β-peptide. These plaques are centers for the degeneration of nerve endings. Whether the fibers themselves are toxic is somewhat controversial, in view of transgenic animals which have been engineered to express amyloid β-peptide. These mice make amyloid deposits, and there is damage to nerve cells around the plaque, however, no further neuronal loss is seen in these mice. Thus, there appear to be other mechanisms involved. (Brennan.)
  • Whether the amyloid plaques are the cause or the consequence of the disease is a perplexing question according to Brennan. However, "all genetic routes to Alzheimer's known today, 'act by increasing production or deposition of amyloid - or both,'" quoting Dennis J. Selkoe, professor of neurology and neuroscience at Harvard Medical School. Laedtke, et al., Clinical Research 42(1):65A (1994), have also noted an epidemiological correlation between the deposition of amyloid in islet cells, leading to glucose intolerance and non-insulin-dependent diabetes mellitus, and amyloid β-protein deposition in brain cells, as associated with Alzheimer's disease. The authors conclude that there may be an overlap in the molecular defects that predispose to islet and brain amyloid, and therefore NTDDM and AD.
  • There is evidence of the over-expression of a protein called neural tread protein (NTP) in Alzheimer's disease neurons (see WO94/23756 ). This protein has been cloned (referred to as AD10-7), and expressed in cell-free culture.
  • The cathepsins are a family of enzymes that are usually located in lysosomes. It has been found that the inhibition of cathepsin D using an aspartyl protease inhibitor reduces the formation of β-amyloid protein and the resultant senile plaques. Thus inhibitors of cathepsin D, such as rhodanine derivatives, have been proposed as therapeutic agents for the treatment of Alzheimer's disease. See U.S. Patent Nos. 5,716,975 and 5,523,314 .
  • A number of companies are seeking new therapeutic agents which cross the blood-brain barrier and inhibit amyloid deposition. One such company is Athena Neurosciences, South San Francisco, who has engineered a transgenic mouse model for the disease. Athena is sorting through hundreds of molecules in a series to look for the best pharmaceutical to take into development. (Brennan.)
  • One drug candidate developed by Neo-Therapeutics, Irvine, CA, is nearing clinical trials. The hypoxanthine analog (AIT-082) promotes nerve regeneration in the areas of the brain associated with memory. When the drug is administered directly to the brains of 13 month old mice, about 50% of the animals show a delay of about two months in any memory deficit and the other 50% never develop a memory deficit. This drug activates genes that express growth factor proteins known to reverse memory deficits in aged rodents when directly delivered to the brain. (Brennan.)
  • Another memory enhancing drug ready for clinical trials is CX516, codeveloped by Gary S. Lynch, a professor of psychobiology at the University of California, Irvine, and Gary A. Rogers, vice president of pharmaceutical discovery at Cirtex Pharmaceuticals, Irvine, CA. CX516 is an agonist of the AMPA receptor, and promotes the uptake of Ca2+ into nerve cells when the brain levels of glutamate are low, as they are in Alzheimer's disease. This drug reversed age-associated memory impairment in rats. (Brennan.)
  • An over the counter agent that may lessen the symptoms or delay the progression of the disease is the nicotine patch. According to Ken Kellar, a professor of pharmacology at the Georgetown University Medical School, Washington, D.C., epidemiological data indicate that there is a lower incidence of Alzheimer's disease among people who smoke. The nicotine patch is now being tested in 12 month clinical study. (Brennan.)
  • Estrogen is also being evaluated as an agent that might be helpful in protecting women from Alzheimer's disease. Preliminary results indicate that women who receive estrogen replacement therapy have a lower risk of developing the disease. (Brennan.)
  • Another agent being evaluated is prednisone. This drug is being tested to see if it can benefit Alzheimer's patients by reducing inflammation in their brains. A further study has just been completed which examined the antioxidant effect of vitamin E and selegiline, a drug used to treat Parkinson's disease. (Brennan.)
  • In completely unrelated studies, it has been reported that elevated levels of insulin in the body are responsible for many cases of obesity, diabetes, heart disease, high blood pressure, and high cholesterol levels. Michael R. Eades and Mary Dan Eades, "Protein Power," Bantam Books, New York, NY (1996). Patients with any of these conditions have been successfully treated with a dietetic regimen which is designed to reduce insulin levels, primarily by strict limitation of metabolizable carbohydrate in the diet. A further strategy is to ameliorate insulin insensitivity which progresses in severity in middle age, by adding chromium to the diet. By reducing insulin insensitivity, lower levels of insulin are required by the body to clear glucose from the blood.
  • US4855306 discloses selective dopamine D1 receptor agonists for the treatment of primary degenerative dementia, including senile dementia of the Alzheimer's type.
  • EP677517 and EP587377 disclose 2-thioxo-4-thiazolidinone compounds which are inhibitors of cathepsin D for the treatment of Alzheimer's disease.
  • JP07238035A2 discloses beta amyloid proteolytic agent containing insulin decomposing enzyme for the treatment of Alzheimer's disease.
  • WO95/13823 discloses a complex of IGF and IGFBP-3 for treating neurological disorders.
    • Summary of the Invention
  • The present invention is related to the discovery that high levels of circulating insulin are a root cause of Alzheimer's disease. In particular, it has been discovered that insulin stimulates the increased expression of NTP in nerve cell culture. Since insulin crosses the blood-brain barrier, it is now clear that high levels of insulin stimulate brain nerve cells to secrete NTP and develop the hallmarks of Alzheimer's disease.
  • The present invention is directed to the treatment or prevention of Alzheimer's disease, in a human, comprising the use of an agent in the manufacture of a medicament which results in lowered serum insulin levels. The agent useful in the present invention is one that is also useful for treating impaired glucose tolerance.
  • The present invention also relates to the use of a medicament for improving mentation of a patient with Alzheimer's disease, comprising administering to said patient an effective amount of an agent which increases the insulin sensitivity of the patient.
  • The present invention also relates to the use of a medicament which results in lower serum insulin levels and an agent which inhibits the formation of small strokes for treating or preventing or preventing Alzheimer's disease, in a human.
  • Specifically, the invention relates to use of an agent which results in lowered serum insulin levels, wherein said agent is selected from the list consisting of:
    • (+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy]phenyl]methyl]-2,4-thiazolidinedione (troglitazone);
    • 4-(2-naphthylmethyl)-1,2,3,5-oxathiadiazole-2-oxide;
    • 5-[4-[2-[N-(benzoxazol-2-y1)-N-methylamino]ethoxy]benzyl]-5-methylthiazolidine-2,4-dione;
    • 5-[4-[2-[2,4-dioxo-5-phenylthiazolidin-3-yl)ethoxy]benzyl]thiazolidine-2,4-dione;
    • 5-[4-[2-[N-methyl-N-(phenoxycarbonyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione;
    • 5-[4-(2-phenoxyethoxy)benzyl]thiazolidine-2,4-dione;
    • 5-[4-[2-(4-chlorophenyl)ethylsulfonyl]benzyl]thiazolidine-2,4-dione;
    • 5-[4-[3-(5-methyl-2-phenyloxazol-4-yl)propionyl]benzyl]thiazolidine-2,4-dione;
    • 5-[4-[(1-methylcyclohexyl)methoxy]benzyl]thiadiazolidine-2,4-dione;
    • 5-[[4-(3-hydroxy-1-methylcyclohexyl)methoxy]benzyl]thiadiazolidine-2,4-dione;
    • 5-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxyl]benzyl]thiadizolidione-2,4-dione;
    • 5-[4-[2-(5-ethylpyridin-2-yl)ethoxyl]benzyl]thiadiazolidine-2,4-dione (pioglitazone);
    • 5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl]thiadiazoline-2,4-dione (englitazone);
    • 5-[[2-(2-naphthylmethyl)benzoxazol]-5-ylmethyl]thiadiazoline-2,4-dione;
    • 5-[4-[2-(3-phenylureido)ethoxyl]benzyl]thiadiazoline-2,4-dione;
    • 5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino]ethoxy]benzy]thiadiazoline-2,4-dione;
    • 5-[4-[3-(5-methyl-2-phenyloxazol-4-yl)propionyl]benzyl]thiadiazoline-2,4-dione;
    • 5-[2-(5-methyl-2-phenyloxazol-4-ylmethyl)benzofuran-5-ylmethyl]-oxazolidine-2,4-done;
    • 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione; and
    • 5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino]ethoxy]benzyl]-oxazolidine-2,4-dione;
    and pharmaceutically acceptable salts of any one thereof;
    in the manufacture of a medicament for the prevention and/or treatment of Alzheimer's disease. Detailed Description of the Preferred Embodiments
  • Animals with insulin insensitivity require higher levels of serum insulin to stimulate the metabolism of serum glucose and storage for later use. Although insulin has countless other actions in the body, the main function of insulin is to prevent serum glucose levels from rising too high. Thus, when glucose levels rise, insulin levels rise. However, when cells become resistant to insulin, the insulin receptors begin to malfunction. This malfunction appears to be a result of inherited tendencies and lifestyle abuse (over-consumption of carbohydrates). Thus, the receptors require higher levels of insulin to allow the glucose to be removed from the blood. While low levels of insulin are necessary to clear serum glucose when the insulin receptors are working optimally, insulin insensitive receptors require an excess level of insulin to keep serum glucose within the normal range.
  • Insulin insensitivity can be diagnosed by determining whether the animal has an elevated insulin level. In the case of humans, insulin levels of over 10 mU/ml indicate that the person has at least some insulin insensitivity. Eades and Eades, supra. Insulin values of 25-50 or more are very high and indicative of a high level of insulin resistance. People with insulin levels above 10 mU/ml are considered to be in need of treatment to reduce insulin levels and thereby treat, prevent or reduce the possibility of having Alzheimer's disease in the future.
  • Agents which lower serum insulin levels include drugs which are known to be useful for treating insulin insensitivity.
  • Agents which can be used in the practice of the invention include thiazolidinediones and related antihyperglycemic agents which have been reported to be useful for treating impaired glucose tolerance in order to prevent or delay the onset of non-insulin-dependent diabetes mellitus. See U.S. Patent No. 5,478,852 . An example of a thiazolidinedione that can be used is troglitazone (brand name Rezulin™) that has recently been approved by the U.S. Food and Drug Administration for treating insulin resistance. Routes of administration for such thiazolidinediones and related antihyperglycemic agents are described in U.S. 5,478,852 . The thiazolidinediones and related antihyperglycemic agents may be administered to the patient in an amount effective which is, in general, the amount effect to treat impaired glucose tolerance according to U.S. 5,478,852 . See also, U.S. Patent No. 5,457,109 . Unlike sulfonylureas, troglitazone is not an insulin secretagogue, "Physicians' Desk Reference," Medical Economics Company, Montvale, NJ, 2118-2119 (1998).
  • The present invention also relates to a method of improving mentation of a patient with Alzheimer's disease, comprising administering to said patient an effective amount of an agent which increases the insulin sensitivity of the patient. Several lines of investigation suggest a link between impaired glucose utilization and Alzheimer's disease. This hypothesis has been supported by findings that raising plasma glucose levels through glucose administration in elderly humans and rodents improves memory without affecting motor and nonmemory functions. Craft, S., et al., "Effects of Hyperglycemia on Memory and Hormone Levels in Dementia of the Alzheimer Type: A Longitudinal Study," Behav. Neurosci. 107:926-940 (1993). Thus, according to the present invention, an agent may be administered to a patient with Alzheimer's disease to improve mentation, which agent is effective for treating insulin insensitivity. By decreasing insulin insensitivity, that is by increasing insulin sensitivity, in the patient, glucose utilization is improved in the brain and mentation will improve.
  • Agents which inhibit the formation of small strokes include aspirin.
  • The agents described herein may also be administered in conjunction with an antiinflammatory agent such as ibuprofen which has been found useful in some studies in ameliorating Alzheimer's disease.
  • The agents that have been described herein may also be administered with compounds which modulate ATP production and have thereby been found useful as an alternative energy source to glucose for conditions in which ischemic or hypoxic conditions have compromised ATP production. Such compounds include, inter alia, fructose-1,6-biphosphate, see U.S. Patent Nos. 4,546,095 , 4,703,040 , 4,757,052 , and 5,039,665 ; pyruvate, see U.S. Patent No. 5,395,822 ; glyceraldehyde-3-phosphate and 3-phosphoglycerate, see U.S. Patent No. 5,707,971 . Administration of these agents may also be useful as an alternative to insulin treatment by providing an energy source alternative to glucose, and may obviate the general decline of aging by enhancing ATP production according to U.S. 5,707,971 .
  • Having now generally described the invention, the same will be more readily understood through reference to the following Examples which are provided by way of illustration.
    • Examples Example 1 Insulin Stimulates the Expression of AD7c-NTP, a Protein which causes neurons to exhibit neuronal sprouting and apoptosis
  • Insulin is an important mediator of growth and differentiation in CNS neurons. Insulin stimulated differentiation of PNET2 cells was associated with rapid (within 10 minutes) but transient increases in the levels of the 39 kD, 18 kD and 15 kD NTP species, followed by sustained increases in synthesis and steady state levels of all five NTP species. In contrast, the failure of insulin to induce differentiation of PNET1 cells was associated with absent insulin modulation of NTP.
  • Analysis of the signal transduction pathways demonstrated that the insulin-induced up-regulation of NTP molecules in PNET2 cells was mediated through phosphorylation of the insulin receptor substrate-1 (IRS -1) and the insulin receptor β subunit (IRβs) itself. In PNET1 cells, the lack of insulin responsiveness was associated with impaired insulin-mediated tyrosyl phosphorylation of IRS-1, but normal insulin receptor phosphorylation. Correspondingly, the insulin-stimulated association between PI3 kinase and phosphorylated IRS-1 was also impaired in PNET1 cells. In essence, impaired insulin-mediated tyrosyl phosphorylation of IRS-1 in PNET1 cells halted activation of the insulin signal transduction cascade, and subsequent events leading to modulated gene (NTP) expression. PNET1 cells lacked insulin responsiveness and failed to phosphorylate IRS-1, but insulin receptor levels and tyrosyl phosphorylation (PY) of the β-subunit were intact. PNET2 cells responded to insulin stimulation with phosphorylation of IRS-1, up-regulation of NTP, and neuronal differentiation. The results were confirmed by absent association between PI3 kinase and IRS-1-PY in PNET1 cells after insulin stimulation.
  • Neuritic sprouting and neuronal differentiation were induced in PNET2 and SH-Sy5y cells by insulin, PMA, or RA stimulation. Insulin-mediated neuritic growth was associated with increased expression of the fetal brain and PNET-dominant forms of NTP (15 kD and 18 kD). In contrast, the PMA- and RA-induced neuritic sprouting modulated expression of the 21 kD and 26 kD NTP species, which are primarily expressed in the mature brain, and accumulated in AD brains. Thus, expression of the immature or fetal forms of NTP are regulated by mechanisms and growth factors distinct from those involved in modulating expression of the 21 kD and 26 kD NTP molecules. Therefore, expression of fetal NTP molecules/genes can be mediated through the IRS-1 cascade, whereas expression of adult brain/AD-associated NTP genes can be regulated mainly through protein kinase C pathways.

Claims (3)

  1. Use of an agent which results in lowered serum insulin levels, wherein said agent is selected from the list consisting of:
    (+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy]phenyl]methyl]-2,4-thiazolidinedione (troglitazone);
    4-(2-naphthylmethyl)-1,2,3,5-oxathiadiazole-2-oxide;
    5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino]ethoxy]benzyl]-5-methylthiazolidine-2,4-dione;
    5-[4-[2-[2,4-dioxo-5-phenylthiazolidin-3-yl)ethoxy]benzyl]thiazolidine-2,4-dione;
    5-[4-[2-[N-methyl-N-(phenoxycarbonyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione;
    5-[4-(2-phenoxyethoxy)benzyl]thiazolidine-2,4-dione;
    5-[4-[2-(4-chlorophenyl)ethylsulfonyl]benzyl]thiazolidine-2,4-dione;
    5-[4-[3-(5-methyl-2-phenyloxazol-4-yl)propionyl]benzyl]thiazolidine-2,4-dione;
    5-[4-[(1-methylcyclohexyl)methoxy]benzyl]thiadiazolidine-2,4-dione;
    5-[[4-(3-hydroxy-1-methylcyclohexyl)methoxy]benzyl]thiadiazolidine-2,4-dione;
    5-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxyl]benzyl]thiadizolidione-2,4-dione;
    5-[4-[2-(5-ethylpyridin-2-yl)ethoxyl]benzyl]thiadiazolidine-2,4-dione (pioglitazone);
    5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl]thiadiazoline-2,4-dione (englitazone);
    5-[[2-(2-naphthylmethyl)benzoxazol]-5-ylmethyl]thiadiazoline-2,4-dione;
    5-[4-[2-(3-phenylureido)ethoxyl]benzyl]thiadiazoline-2,4-dione;
    5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino]ethoxy]benzy]thiadiazoline-2,4-dione;
    5-[4-[3-(5-methyl-2-phenyloxazol-4-yl)propionyl]benzyl]thiadiazoline-2,4-dione;
    5-[2-(5-methyl-2-phenyloxazol-4-ylmethyl)benzofuran-5-ylmethyl]-oxazolidine-2,4-dione;
    5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione; and
    5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino]ethoxy]benzyl]-oxazolidine-2,4-dione;
    and pharmaceutically acceptable salts of any one thereof;
    in the manufacture of a medicament for the prevention and/or treatment of Alzheimer's disease.
  2. Use of an agent according to claim 1, wherein said agent is (+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy]phenyl]methyl]-2,4-thiazolidinedione (troglitazone) or a pharmaceutically acceptable salt thereof.
  3. Use of an agent according to claim 1, wherein said agent is 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof.
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Families Citing this family (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1006794B1 (en) * 1997-03-12 2007-11-28 Robert W. Esmond A method for treating or preventing alzheimer's disease
JP2002501887A (en) * 1998-01-28 2002-01-22 ワーナー−ランバート・カンパニー How to treat Alzheimer's disease
US6191154B1 (en) * 1998-11-27 2001-02-20 Case Western Reserve University Compositions and methods for the treatment of Alzheimer's disease, central nervous system injury, and inflammatory diseases
WO2000043007A1 (en) * 1999-01-19 2000-07-27 Sankyo Company, Limited Troglitazone-containing medicinal compositions for inhibiting apoptosis
US6835750B1 (en) 2000-05-01 2004-12-28 Accera, Inc. Use of medium chain triglycerides for the treatment and prevention of alzheimer's disease and other diseases resulting from reduced neuronal metabolism II
PT1292294E (en) * 2000-05-01 2009-06-01 Accera Inc Use of medium chain triglycerides for the treatment and prevention of alzheimer`s disease
US20070179197A1 (en) * 2000-05-01 2007-08-02 Accera, Inc. Compositions and methods for improving or preserving brain function
US6770797B2 (en) 2001-06-01 2004-08-03 Rhode Island Hospital Non-Transgenic nonhuman model for Alzheimer's Disease using a AD7c-NTP nucleic acid
CN100457122C (en) 2002-05-14 2009-02-04 尼普洛株式会社 Application of compounds containing trivalent chromium ions in the preparation of medicines for preventing and/or treating amyloidosis
JP2004043443A (en) * 2002-05-14 2004-02-12 Kumamoto Technology & Industry Foundation Pharmaceutical for prevention and treatment of amyloidosis
EP1562562B1 (en) * 2002-11-12 2006-09-06 L'oreal Use of cellulose microbeads to make the skin matt
WO2004077938A2 (en) * 2003-03-06 2004-09-16 Accera Inc. Novel chemical entities and methods for their use in treatment of metabolic disorders
US20090088367A1 (en) * 2004-05-10 2009-04-02 Burnham Institute For Medical Research Treatment of Insulin Resistance/Metabolic Syndrome to Alleviate the Risks of Dementia
US7833513B2 (en) * 2004-12-03 2010-11-16 Rhode Island Hospital Treatment of Alzheimer's Disease
US8114847B2 (en) 2005-03-16 2012-02-14 Case Western Reserve University Selective inhibitors of translesion DNA replication
WO2008147454A1 (en) 2006-11-16 2008-12-04 Case Western Reserve University Selective inhibitors of translesion dna replication
US20060252775A1 (en) * 2005-05-03 2006-11-09 Henderson Samuel T Methods for reducing levels of disease associated proteins
WO2007001883A2 (en) * 2005-06-20 2007-01-04 Accera, Inc. Method to reduce oxidative damage and improve mitochondrial efficiency
PT2500017T (en) 2006-04-03 2017-11-14 Accera Inc Use of ketogenic compounds for treatment of age-associated memory impairment
CA3078084C (en) 2007-07-31 2023-08-15 Cerecin Inc. Use of genomic testing and ketogenic compounds for treatment of reduced cognitive function
US20090216178A1 (en) * 2008-02-26 2009-08-27 Lee Susan J Method And Apparatus For Preventing Localized Stasis Of Cerebrospinal Fluid
US8105809B2 (en) * 2008-07-03 2012-01-31 Accera, Inc. Enzymatic synthesis of acetoacetate esters and derivatives
WO2010003114A1 (en) * 2008-07-03 2010-01-07 Neuera Pharmaceuticals, Inc. Monoglyceride of acetoacetate and derivatives for the treatment of neurological disorders
US8846315B2 (en) 2008-08-12 2014-09-30 Zinfandel Pharmaceuticals, Inc. Disease risk factors and methods of use
PE20110565A1 (en) * 2008-08-12 2011-09-02 Zinfandel Pharmaceuticals Inc METHOD OF IDENTIFICATION OF RISK FACTORS OF THE DISEASE
PL2448412T3 (en) * 2009-07-01 2019-11-29 Jds Therapeutics Llc Chromium complexes as enhancers of brain glucose transporters
EA201391017A1 (en) 2011-01-10 2014-04-30 Зинфандел Фармасьютикалз, Инк. METHODS AND READY MEDICATION FORMS FOR THE TREATMENT OF ALZHEYMER
WO2013033705A2 (en) 2011-09-01 2013-03-07 Case Western Reserve University Non-natural nucleosides as theranostic agents
US9821173B2 (en) 2013-02-08 2017-11-21 Case Western Reserve University Anti-cancer agents and methods of use
KR101642042B1 (en) * 2013-10-24 2016-07-22 건국대학교 글로컬산학협력단 The Use of Thiazolidinediones for inhibiting p35 and p25 activity
GB2564295A (en) 2016-02-11 2019-01-09 Nutrition 21 Llc Chromium containing compositions for improving health and fitness
WO2019004321A1 (en) * 2017-06-28 2019-01-03 国立大学法人京都大学 Agent for preventing and/or treating alzheimer's disease

Family Cites Families (94)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5522636A (en) 1978-08-04 1980-02-18 Takeda Chem Ind Ltd Thiazoliding derivative
JPS5697277A (en) 1980-01-07 1981-08-05 Takeda Chem Ind Ltd Thiazolidine derivative
US4546095A (en) 1980-07-21 1985-10-08 Markov Angel K Use of fructose-1,6-diphosphate for treating myocardial infarction
US5039665A (en) 1980-07-21 1991-08-13 Markov Angel K Use of fructose-1,6-diphosphate for treating myocardial infarction
US4873191A (en) 1981-06-12 1989-10-10 Ohio University Genetic transformation of zygotes
JPS58118577A (en) 1982-01-07 1983-07-14 Takeda Chem Ind Ltd Thiazolidine derivative
US4540564A (en) 1982-05-18 1985-09-10 University Of Florida Brain-specific drug delivery
US4757052A (en) 1982-09-03 1988-07-12 Markov Angel K Method of preserving blood
US4775665A (en) 1983-05-16 1988-10-04 Massachusetts Institute Of Technology Method and composition for treating neurological disorders and aging
JPS6051189A (en) 1983-08-30 1985-03-22 Sankyo Co Ltd Thiazolidine derivative and its preparation
CN1003445B (en) 1984-10-03 1989-03-01 武田药品工业株式会社 Thiazolidinedione derivatives, their preparation methods and uses
AR240698A1 (en) 1985-01-19 1990-09-28 Takeda Chemical Industries Ltd Process for the preparation of 5-(4-(2-(5-ethyl-2-pyridil)-ethoxy)benzyl)-2,4-thiazolodinedione and their salts
US4683195A (en) 1986-01-30 1987-07-28 Cetus Corporation Process for amplifying, detecting, and/or-cloning nucleic acid sequences
US4965188A (en) 1986-08-22 1990-10-23 Cetus Corporation Process for amplifying, detecting, and/or cloning nucleic acid sequences using a thermostable enzyme
US4683202A (en) 1985-03-28 1987-07-28 Cetus Corporation Process for amplifying nucleic acid sequences
US4703040A (en) 1985-04-03 1987-10-27 Markov Angel K Treatment of adult respiratory distress syndrome (ARDS) using fructose diphosphate (FDP)
WO1986007056A1 (en) 1985-05-21 1986-12-04 Pfizer Inc. Hypoglycemic thiazolidinediones
US5039794A (en) 1986-09-19 1991-08-13 Otsuka Pharmaceutical Co., Ltd. Tumor egress factor and processes for producing the same
US4873255A (en) 1987-02-04 1989-10-10 Sankyo Company Limited Thiazolidinone derivatives, their preparation and their use
FI91869C (en) 1987-03-18 1994-08-25 Tanabe Seiyaku Co Process for the preparation of benzoxazole derivatives as antidiabetic agents
NL8800823A (en) * 1987-04-10 1988-11-01 Sandoz Ag METHOD FOR USING DOPAMINE RECEPTOR AGONISTS AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE AGONISTS
EP0295828A1 (en) 1987-06-13 1988-12-21 Beecham Group Plc Novel compounds
US5260445A (en) 1987-09-04 1993-11-09 Beecham Group P.L.C. 2,4-thiazolidinediones
ATE186724T1 (en) 1987-09-04 1999-12-15 Beecham Group Plc SUBSTITUTED THIAZOLIDINEDIONE DERIVATIVES
US5232925A (en) 1987-09-04 1993-08-03 Beecham Group P.L.C. Compounds
US5194443A (en) 1987-09-04 1993-03-16 Beecham Group P.L.C. Compounds
US4980350A (en) 1988-02-25 1990-12-25 Merck & Co., Inc. Piperazinylalkylpyrimidines as hypoglycemic agents
MX15171A (en) 1988-03-08 1993-05-01 Pfizer DERIVATIVES OF TIAZOLIDINODIONA HIPOGLICEMICOS
US5223522A (en) 1988-03-08 1993-06-29 Pfizer Inc. Thiazolidinedione hypoglycemic agents
US5120754A (en) 1988-03-08 1992-06-09 Pfizer Inc. Thiazolidinedione hypoglycemic agents
WO1989008650A1 (en) 1988-03-08 1989-09-21 Pfizer Inc. Thiazolidinedione hypoglycemic agents
US5468755A (en) 1988-05-10 1995-11-21 The Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Therapeutic process for the treatment of the pathologies of Type II diabetes
US5208250A (en) 1988-05-25 1993-05-04 Warner-Lambert Company Known and selected novel arylmethylenyl derivatives of thiazolidinones, imidazolidinones and oxazolidinones useful as antiallergy agents and anti-inflammatory agents
US5948634A (en) 1988-12-21 1999-09-07 The General Hospital Coporation Neural thread protein gene expression and detection of alzheimer's disease
GB8901778D0 (en) 1989-01-27 1989-03-15 Univ Court Of The University O Manipulatory technique
US4897405A (en) 1989-04-21 1990-01-30 American Home Products Corporation Novel naphthalenylalkyl-3H-1,2,3,5-oxathiadiazole 2-oxides useful as antihyperglycemic agents
GB8919434D0 (en) 1989-08-25 1989-10-11 Beecham Group Plc Novel compounds
WO1991007107A1 (en) 1989-11-13 1991-05-30 Pfizer Inc. Oxazolidinedione hypoglycemic agents
US5143928A (en) 1990-03-27 1992-09-01 Warner-Lambert Company 3,5-di-tertiarybutyl-4-hydroxyphenylmethylene derivatives of 2-substituted thiazolidinones, oxazolidinones, and imidazolidinones as antiinflammatory agents
EP0526598B1 (en) 1990-04-27 1996-12-18 Orion-Yhtymà„ Oy New pharmacologically active catechol derivatives
GB9017218D0 (en) 1990-08-06 1990-09-19 Beecham Group Plc Novel compounds
US5334604A (en) 1990-08-23 1994-08-02 Pfizer Inc. Hypoglycemic hydroxyurea derivatives
US5364769A (en) 1990-09-25 1994-11-15 Genentech, Inc. Nucleic acid encoding neurotrophic factor four (NT-4), vectors, host cells and methods of production
US5668117A (en) * 1991-02-22 1997-09-16 Shapiro; Howard K. Methods of treating neurological diseases and etiologically related symptomology using carbonyl trapping agents in combination with previously known medicaments
US6746678B1 (en) * 1991-02-22 2004-06-08 Howard K. Shapiro Method of treating neurological diseases and etiologically related symptomology using carbonyl trapping agents in combination with medicaments
US5192753A (en) 1991-04-23 1993-03-09 Mcgeer Patrick L Anti-rheumatoid arthritic drugs in the treatment of dementia
US5143929A (en) 1991-05-09 1992-09-01 Warner-Lambert Company 2-substituted thiazolidinone, oxazolidinone, and imidazolidinone derivatives of fenamates as antiinflammatory agents
US5164384A (en) 1991-06-19 1992-11-17 Metagenics, Inc. Anabolic mineral formula
US5714470A (en) 1991-08-22 1998-02-03 Merrell Pharmaceuticals, Inc. Orally-active elastase inhibitors
US5270319A (en) 1991-09-09 1993-12-14 Warner-Lambert Company 5-hydroxy-2-pyrimidinylmethylene derivatives useful as antiinflammatory agents
US5256697A (en) 1992-04-16 1993-10-26 Abbott Laboratories Method of administering pyruvate and methods of synthesizing pyruvate precursors
US5326770A (en) 1992-07-17 1994-07-05 The Du Pont Merck Pharmaceutical Company Monoamine oxidase-B (MAO-B) inhibitory 5-substituted 2,4-thiazolidinediones useful in treating memory disorders of mammals
IT1260155B (en) 1992-08-03 1996-03-28 Fidia Spa THERAPEUTIC USE OF PHOSPHORYL-L-SERINE-N-ACYL-SPHINGOSINE
GB2269992A (en) 1992-08-14 1994-03-02 Rh Ne Poulenc Rorer Limited Powder inhalation formulations
CZ181493A3 (en) * 1992-09-10 1994-03-16 Lilly Co Eli The use of rhodanine derivative for the preparation of a pharmaceutical composition reducing level of sugar in blood and for treating alzheimer's disease
US5543297A (en) 1992-12-22 1996-08-06 Merck Frosst Canada, Inc. Human cyclooxygenase-2 cDNA and assays for evaluating cyclooxygenase-2 activity
WO1994016722A1 (en) 1993-01-25 1994-08-04 The Beth Israel Hospital Association Method for modifying, diagnosing, and screening for igf-i sensitive cell barrier properties
DK0690863T3 (en) 1993-04-06 2003-06-30 Abbott Lab Tetracyclic compounds as dopamine agonists
DK1564293T3 (en) 1993-04-20 2009-01-12 Gen Hospital Corp Nerve Thread Protein Gene Expression and Detection of Alzheimer's Disease
US5360614A (en) 1993-04-26 1994-11-01 The Estee Corporation Method of controlling the release of carbohydrates by encapsulation and composition therefor
US5478852C1 (en) 1993-09-15 2001-03-13 Sankyo Co Use of thiazolidinedione derivatives and related antihyperglycemic agents in the treatment of impaired glucose tolerance in order to prevent or delay the onset of noninsulin-dependent diabetes mellitus
US5395822A (en) 1993-09-20 1995-03-07 Izumi; Yukitoshi Use of pyruvate to prevent neuronal degeneration associated with ischemia
JPH09509140A (en) * 1993-11-15 1997-09-16 セルトリックス ファーマシューティカルズ，インコーポレイテッド How to treat neurological disorders
CA2182731A1 (en) 1994-02-03 1995-08-10 Michael P. Vitek Compositions and methods for advanced glycosylation endproduct-mediated modulation of amyloidosis
JPH07238035A (en) * 1994-02-28 1995-09-12 Kyowa Hakko Kogyo Co Ltd β-amyloid proteolytic agent
US6251928B1 (en) * 1994-03-16 2001-06-26 Eli Lilly And Company Treatment of alzheimer's disease employing inhibitors of cathepsin D
US5534615A (en) 1994-04-25 1996-07-09 Genentech, Inc. Cardiac hypertrophy factor and uses therefor
US5594015A (en) 1994-06-22 1997-01-14 Regents Of The University Of California Thiazolidine derivatives for the treatment of psoriasis
WO1996003087A1 (en) 1994-07-22 1996-02-08 University Of Washington Methods for stereotactic implantation
US5483070A (en) * 1994-08-02 1996-01-09 Packard Instrument Company Scintillation counter
US5607967A (en) 1994-10-27 1997-03-04 Merck & Co., Inc. Treatment of alzheimer's disease with 5-(tetradecyloxy)-2-furan carboxylic acid
US5641796A (en) 1994-11-01 1997-06-24 Eli Lilly And Company Oral hypoglycemic agents
US5602120A (en) 1994-12-12 1997-02-11 Allelix Biopharmaceuticals, Inc. Benzyl-substituted compounds having dopamine receptor affinity
US5602121A (en) 1994-12-12 1997-02-11 Allelix Biopharmaceuticals, Inc. Alkyl-substituted compounds having dopamine receptor affinity
US5824692A (en) 1995-01-06 1998-10-20 Lippiello; Patrick Michael Pharmaceutical compositions for prevention and treatment of central nervous system disorders
US6022897A (en) 1995-04-25 2000-02-08 The Salk Institute For Biological Studies Selective modulators of peroxisome proliferator activated receptor-gamma, and methods for the use thereof
US5708012A (en) * 1995-04-28 1998-01-13 Sankyo Company, Limited Use of thiazolidinedione derivatives and related antihyperglycemic agents in the treatment of insulin resistant subjects with normal glucose tolerance in order to prevent or delay the onset of noninsulin-dependent mellitus
US5707971A (en) 1995-06-07 1998-01-13 Life Resuscitation Technologies, Inc. Modulation of glycolytic ATP production
US5618835A (en) 1996-02-01 1997-04-08 The Procter & Gamble Company Dihydrobenzofuran and related compounds useful as anti-inflammatory agents
IN182496B (en) 1996-02-20 1999-04-17 Reddy Research Foundation
GB9604242D0 (en) 1996-02-28 1996-05-01 Glaxo Wellcome Inc Chemical compounds
US5783556A (en) 1996-08-13 1998-07-21 Genentech, Inc. Formulated insulin-containing composition
GB9627005D0 (en) 1996-12-27 1997-02-12 Knoll Ag Therapeutic agents
GB9627006D0 (en) 1996-12-27 1997-02-12 Knoll Ag Therapeutic agents
US6025157A (en) 1997-02-18 2000-02-15 Genentech, Inc. Neurturin receptor
US5814647A (en) 1997-03-04 1998-09-29 Board Of Regents, The University Of Texas System Use of troglitazone and related compounds for the treatment of the climacteric symptoms
EP1006794B1 (en) * 1997-03-12 2007-11-28 Robert W. Esmond A method for treating or preventing alzheimer's disease
WO1998046588A2 (en) 1997-04-11 1998-10-22 Neorx Corporation Compounds and therapies for the prevention of vascular and non-vascular pathologies
US5925657A (en) 1997-06-18 1999-07-20 The General Hospital Corporation Use of PPARγ agonists for inhibition of inflammatory cytokine production
US5789401A (en) * 1997-08-08 1998-08-04 Nutrition 21 High-dose chromium/biotin treatment of type II diabetes
CA2311125C (en) 1997-11-19 2011-01-18 Takeda Chemical Industries, Ltd. Apoptosis inhibitor
US20040058873A1 (en) * 1998-03-12 2004-03-25 Esmond Robert W. Method for treating or preventing Alzheimer's disease
US6028088A (en) 1998-10-30 2000-02-22 The University Of Mississippi Flavonoid derivatives
US6191154B1 (en) 1998-11-27 2001-02-20 Case Western Reserve University Compositions and methods for the treatment of Alzheimer's disease, central nervous system injury, and inflammatory diseases

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WO1998039967A1 (en) 1998-09-17
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US20050043242A1 (en) 2005-02-24
US20040060077A1 (en) 2004-03-25
US7300927B2 (en) 2007-11-27
DE69838789T2 (en) 2008-10-30
CA2323889A1 (en) 1998-09-17
JP2009280586A (en) 2009-12-03
JP2001514663A (en) 2001-09-11
EP1006794A4 (en) 2004-07-07

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