Neurotherapeutic clavulanate composition and method

• US 20040014739A1
• Filed: 07/15/2003
• Published: 01/22/2004
• Est. Priority Date: 08/16/1999
• Status: Abandoned Application

• Current Assignee: Gary A. Koppel
• Original Assignee: Gary A. Koppel
• Inventors: Koppel, Gary A.
• Application Number:
  US10/620,221
• Publication Number:
  US 20040014739A1
• Time in Patent Office: Days
• US Class Current: 514/210.09
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• CPC Class Codes: A61K 31/424 condensed with heterocyclic ring systems, e.g. clavulanic acid
• CPC Class Codes: A61K 31/43 Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula , e.g. penicillins, penems
• CPC Class Codes: A61K 31/431 containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
• CPC Class Codes: A61K 31/4353 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/5365 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/5383 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/545 Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula: , e.g. cephalosporins, cefaclor, or cephalexine
• CPC Class Codes: A61K 31/546 containing further heterocyclic rings, e.g. cephalothin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 : Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 : for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 : Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 : Anxiolytics
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/28 : 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
• CPC Class Codes: A61P 25/32 : Alcohol-abuse
• CPC Class Codes: A61P 25/34 : Tobacco-abuse
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: Y02A 90/10 : Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Abstract

Administration of clavulanic acid and related compounds at low dosages provides significant neurotropic effects in warm-blooded vertebrates evidenced inter alia by anxiolytic and anti-aggressive behavior and enhanced cognition believed to be mediated by inhibition of neurogenic enzyme activity. Therapeutic methods for using such compounds and their pharmaceutical formulations are described.

Claims

1. A method of treatment of behavioral disorders in a patient in need of such treatment, said method comprising the step of administering a compound selected from the group consisting of clavulanic acid, pharmaceutically acceptable salts thereof, and active ester forms thereof that are hydrolyzed in vivo to clavulanic acid to said patient in an amount effective to provide a concentration of clavulanic acid in the brain of said patient sufficient to modify patient behavior.

2. A method of enhancing cognitive function in a patient suffering from a condition characterized by impaired cognitive function, said method comprising the step of administering to said patient an effective amount of an active compound selected from the group consisting of clavulanic acid, pharmaceutically acceptable salts thereof, and active ester forms thereof that are hydrolyzed in vivo to clavulanic acid, to provide a cognition enhancing concentration of clavulanic acid in the brain of said patient.

3. The method of claim 2 wherein the patient is a human patient suffering from dementia or amnesia.

4. The method of claim 2 wherein the patient is a human patient suffering from Alzheimer'"'"'s Disease.

5. The method of claim 2 further comprising the step of administering an effective amount of a P-glycoprotein efflux pump inhibitor.

6. The method of claim 2 wherein the compound is administered in combination with an effective amount of a P-glycoprotein efflux pump inhibitor.

7. A method of treating a human patient afflicted with a condition, or having a medical history predictive of the development of a condition characterized at least in part by abnormal extracellular glutamate concentration in the brain or other nervous tissue, said method comprising the step of administering to said patient a composition comprising a neurologically effective amount of compound selected from the group consisting of clavulanic acid, pharmaceutically acceptable salts thereof, and active ester forms thereof that are hydrolyzed in vivo to clavulanic acid in neurologically effective quantities.

8. The method of claims 7 wherein the condition is selected from the group consisting of ischemia, epilepsy, hypoglycemia, Huntington'"'"'s disease, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, Amyotrophic Lateral Sclerosis (ALS), chronic pain, and nervous tissue trauma.

9. The method of claim 7 wherein the patient condition is nervous tissue ischemia resulting from a temporary interruption of blood flow to said tissue.

10. A method of treating prostate disease selected from prostate cancer or benign prostatic hyperplasia in a human patient, said method comprising the step of administering to said patient a composition comprising a compound selected from the group consisting of clavulanic acid, pharmaceutically acceptable salts, and ester forms thereof that are hydrolyzed in vivo to clavulanic acid, wherein said compound is administered in an amount effective to retard the progress of the disease or to reduce the symptoms of the disease.

11. A method for treatment of cognitive and behavioral disorders in a human patient in need of said treatment, said method comprising the step of administering to said patient a compound selected from the group consisting of clavulanic acid, a salt, and an active ester form thereof that are hydrolyzed in vivo to clavulanic acid, in an amount effective to modulate neurogenic carboxy peptidase or transpeptidase activity in the brain.

12. A pharmaceutical formulation in unit dosage form effective for treatment of behavioral and cognitive disorders in a human patient in need thereof, said formulation comprising a compound selected from the group consisting of clavulanic acid, pharmaceutically acceptable salts, and active ester forms thereof that are hydrolyzed in vivo to clavulanic acid, and a pharmaceutically acceptable carrier therefor, the amount of said compound in said unit dosage being effective to provide a concentration of clavulanic acid in the brain sufficient to modulate cognitive or behavioral performance of said patient, said unit dosage form being without concomitant effective antibacterial activity in said patient.

13. The pharmaceutical formulation of claim 12 further comprising an effective amount of a P-glycoprotein efflux pump inhibitor.

14. The pharmaceutical formulation of claim 12 wherein the formulation is an oral dosage form.

15. The pharmaceutical formulation of claim 12 wherein the formulation is a parenteral dosage form.

16. The pharmaceutical formulation of claim 12 wherein the formulation is a prolonged release dosage form.

17. A method for treating a patient afflicted with or disposed to develop a disease characterized by abnormally elevated glutamate concentrations in neuronal tissue or elevated NAALADase levels in prostate tissue, said method comprising the step of administering to said patient clavulanic acid or a pharmaceutically acceptable salt or ester form thereof that is hydrolyzed in vivo to clavulanic acid.