Treatment of behavioral disorders with β-lactam compounds

• US 6,627,625 B1
• Filed: 08/16/2000
• Issued: 09/30/2003
• Est. Priority Date: 08/16/1999
• Status: Expired due to Term

• Current Assignee: Revaax Pharmaceuticals, LLC
• Original Assignee: Revaax Pharmaceuticals, LLC
• Inventors: Koppel, Gary A.
• Primary Examiner(s): Jarvis, William R. A.
• Application Number:
  US09/640,363
• Time in Patent Office: 1,140 Days
• Field of Search: 514/192, 514/197, 514/198, 514/199, 514/200, 514/210.08
• US Class Current: 514/198
• 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 β-lactam compounds including β-lactam antibiotics and β-lactamase inhibitors provides significant neurotropic effects in warm-blooded vertebrates evidenced inter alia by anxiolytic and anti-aggressive behavior modification and enhanced cognition. Therapeutic methods for using such compounds and their pharmaceutical formulations are described.

Claims

1. A method of treatment of a behavioral disorder selected from aggressive disorder, obsessive-compulsive disorder, anxiety, depression, or ADHD in a patient in need of such treatment, said method comprising the step of administering to said patient an effective amount of a β

-lactam compound capable of inhibiting the peptidase activity of one or more neurogenic peptidases in the brain of said patient, provided that when the compound is a β

-lactam compound which exhibits antibiotic activity, the effective amount administered to the patient is less than that required to produce clinically effective antibacterial blood levels of the β

-lactam antibiotic.

2. The method of claim 1 wherein the behavioral disorder is depression or obsessive-compulsive disorder.

3. The method of claim 1 wherein the compound is administered as an antiaggressive agent to control impulsivity and violence in a patient afflicted with autism, Tourette'"'"'s syndrome, mental retardation, psychosis, mania, senile dementia or in a patient with a personality disorder and history of inappropriate aggression.

4. The method of claim 1 wherein the compound is administered to a human patient suffering a behavioral disorder comprising anxiety.

5. The method of claim 1 wherein the compound is administered to a human patient suffering a behavioral disorder comprising ADHD.

6. The method of claim 1 wherein the β

-lactam compound is a β

-lactamase inhibitor.

7. The method of claim 1 wherein the β

-lactam compound is selected from the group consisting of penicillins, cephalosporins, penems, 1-oxa-1-dethia cephems, clavams, clavems, azetidinones, carbapenams, carbapenems and carbacephems.

8. The method of claim 7 wherein the compound is a 1-oxa-1-dethia-analogue of a cephalosporin.

9. The method of claim 1 further comprising the step of administering an effective amount of a P-glycoprotein efflux pump inhibitor.

10. The method of claim 6 or claim 7 wherein the peptidase inhibitor is administered in combination with an effective amount of a P-glycoprotein efflux pump inhibitor.

11. The method of claim 1 or claim 3 wherein the compound is a compound of the formula

wherein R is hydrogen, a salt forming group or an active ester forming group;

R¹ is hydrogen or C₁-C₄ alkoxy;

T is C₁-C₄ alkyl, halo, hydroxy, O(C₁-C₄) alkyl, or —

CH₂B wherein B is the residue of a nucleophile B;

H, and Acyl is the residue of an organic acid AcylOH.

12. The method of claim 11 wherein the compound is moxalactam or flomoxef.

19. The method claim 1 wherein the compound is a β

-lactamase inhibitor substantially devoid of antibiotic activity.

20. The method of claim 1 wherein the compound is a penicillin or cephalosporin sulfoxide or sulfone.

22. The method of claim 7 wherein the β

-lactam compound is a cephalosporin sulfoxide or cephalosporin sulfone.

23. The method of claim 7 wherein the β

-lactam compound is a penicillin sulfoxide or penicillin sulfone.

24. The method of claim 7 wherein the β

-lactam compound is a cephalosporin substantially devoid of antibiotic activity.

33. The method of claim 1, claim 14, claim 18 or claim 21 wherein the effective amount of the β

-lactam compound administered is about 1 to about 150 mg per dose.

34. The method of claim 33 wherein the β

-lactam compound is administered per os.

35. The method of claim 33 wherein the β

-lactam compound is formulated in a prolonged release dosage form.

36. The method of claim 34 wherein the β

-lactam compound is in lozenge dosage form.

37. The method of claim 33 wherein the β

-lactam compound is administered transdermally.

38. The method of claim 33 wherein the β

-lactam compound is administered parenterally.

13. A method for treatment of anxiety disorders in a human patient in need of said treatment, said method comprising the step of administering an inhibitor of a neurogenic peptidase to said patient in an amount effective to modulate peptidase or transpeptidase activity in the brain of said patient, wherein said neurogenic peptidase is characterized by its inhibition in vivo by intracerebroventricular administration of a peptide having the sequence Ala-D-γ

-Glu-Lys-D-alanyl-D-alanine with resultant observable anxiolytic effect, with the proviso that the neurogenic peptidase is other than NAALADase and provided further that when the inhibitor is a β

-lactam compound which exhibits antibiotic activity, the effective amount administered to the patient is less than that required to produce clinically effective antibacterial blood levels of the β

-lactam antibiotic.

14. A method of treatment of behavioral disorders in human, canine, feline and equine species, said method comprising the step of inhibiting the activity of a neurogenic peptidase characterized by its inhibition in vivo by intracerebroventricular administration of an effective amount of the peptide Ala-D-γ

-Glu-Lys-D-alanyl-D-alanine with resultant observable behavior modification, provided that the neurogenic peptidase is other than NAALADase, and provided further that when the activity is inhibited using a β

-lactam compound which exhibits antibiotic activity, the amount administered to the species effective to inhibit the peptidase activity is less than that required to produce clinically effective antibacterial blood levels of the β

-lactam antibiotic.

15. The method of claim 14 wherein the step of inhibiting the neurogenic peptidase is effected by administering an amount of a β

-lactam compound effective to inhibit activity of the peptidase in the brain.

16. The method of claim 15 wherein the β

-lactam compound is a 1-oxa-1-dethia analogue of a cephalosporin.

17. The method of claim 15 wherein the β

-lactam compound is selected from the group consisting of moxalactam, ampicillin and carbenicillin and active esters thereof.

18. A method of treatment of a behavioral disorder in human, canine, feline and equine species suffering from said disorder, said method comprising the step of inhibiting the activity of a neurogenic peptidase characterized by its inhibition in vivo by clavulanic acid, moxalactam, or a peptide comprising the sequence Ala-D-γ

-Glu-Lys-D-alanyl-D-alanine with resultant observable behavior modifications by administering to said vertebrate a β

-lactam compound in an amount effective to inhibit said peptidase activity, provided that when the β

-lactam compound is a β

-lactam compound which exhibits antibiotic activity, the effective amount administered to the patient is less than that required to produce clinically effective antibacterial blood levels of the β

-lactam antibiotic.

21. A method of treatment of a behavioral disorder selected from aggressive disorder, obsessive-compulsive disorder, anxiety, depression, or ADHD in a patient in need of such treatment, said method comprising the step of administering to said patient an effective amount of a compound comprising a penicillin or cephalosporin sulfoxide or sulfone, provided that when the compound is a β

-lactam compound which exhibits antibiotic activity, the effective amount administered to the patient is less than that required to produce clinically effective antibacterial blood levels of the β

-lactam antibiotic.

25. A method for treatment of anxiety disorders in a human patient in need of said treatment, said method comprising the step of administering an inhibitor of a neurogenic peptidase to said patient in an amount effective to modulate peptidase or transpeptidase activity in the brain of said patient, said neurogenic peptidase characterized in part by its inhibition in vivo by intraperitoneal administration of clavulanic acid with resultant observable anxiolytic effect provided that the neurogenic peptidase is other than NAALADase and provided further that when the inhibitor is a β

-lactam compound which exhibits antibiotic activity, the effective amount administered to the patient is less than that required to produce clinically effective antibacterial blood levels of the β

-lactam antibiotic.

26. A method for treatment of anxiety disorders in a human patient in need of said treatment, said method comprising the step of administering an inhibitor of a neurogenic peptidase to said patient in an amount effective to modulate peptidase or transpeptidase activity in the brain of said patient, said neurogenic peptidase characterized in part by its inhibition in vivo by intraperitoneal administration of moxalactam with resultant observable anxiolytic effect provided that the neurogenic peptidase is other than NAALADase and provided further that when the inhibitor is a β

-lactam compound which exhibits antibiotic activity, the effective amount administered to the patient is less than that required to produce clinically effective antibacterial blood levels of the β

-lactam antibiotic.

27. A method of treatment of behavioral disorders in human, canine, feline and equine species, said method comprising the step of inhibiting the activity of a neurogenic peptidase characterized in part by its inhibition in vivo by administration of an effective amount of clavulanic acid with resultant observable behavior modification provided that the neurogenic peptidase is other than NAALADase and provided further that when the inhibitor is a β

-lactam compound which exhibits antibiotic activity, the effective amount administered to the patient is less than that required to produce clinically effective antibacterial blood levels of the β

-lactam antibiotic.

28. A method of treatment of behavioral disorders in human, canine, feline and equine species, said method comprising the step of inhibiting the activity of a neurogenic peptidase in the brain said peptidase characterized in part by its inhibition in vivo by intraperitoneal administration of 50 μ

g/kg of moxalactam with resultant observable behavior modification provided that the neurogenic peptidase is other than NAALADase and provided further that when the inhibitor is a β

-lactam compound which exhibits antibiotic activity, the effective amount administered to the patient is less than that required to produce clinically effective antibacterial blood levels of the β

-lactam antibiotic.

29. A method of treatment of a behavioral disorder in human, canine, feline and equine species suffering from said disorder, said method comprising the step of inhibiting the activity of a neurogenic peptidase characterized in part by its inhibition in vivo by clavulanic acid, moxalactam, or a peptide comprising the sequence Ala-D-γ

-Glu-Lys-D-alanyl-D-alanine with resultant observable behavior modification by administering to said vertebrate a β

-lactam compound selected from penicillin sulfoxides, penicillin sulfones, cephalosporin sulfoxides, cephalosporin sulfones or other cephalosporins substantially devoid of antibiotic activity in an amount effective to inhibit said peptidase activity, provided that when the compound is a β

-lactam compound which exhibits antibiotic activity, the effective amount administered to the patient is less than that required to produce clinically effective antibacterial blood levels of the β

-lactam antibiotic.

30. A method of treatment of a behavior disorder in a patient in need of such treatment, said treatment comprising the step of inhibiting the activity of an enzyme in the brain of said patient, said enzyme characterized in part by its inhibition in vivo by the intracerebroventricular administration of 1 mg/kg of the peptide Ala-D-γ

-Glu-Lys-D-Ala-D-Ala, by the intraperitoneal administration of 50 μ

g/kg of moxalactam, or by the intraperitoneal administration of 10 ng/kg of clavulanic acid, with resultant observable behavior modification provided that the neurogenic peptidase is other than NAALADase and provided further that when the inhibitor is a β

-lactam compound which exhibits antibiotic activity, the effective amount administered to the patient is less than that required to produce clinically effective antibacterial blood levels of the β

-lactam antibiotic.

31. The method of claim 30 wherein the step of inhibiting the neurogenic enzyme activity is carried out by administering a compound selected from the group consisting of penicillin sulfoxides, penicillin sulfones, cephalosporin sulfoxides, cephalosporin sulfones, and other cephalosporins substantially devoid of antibiotic activity.

32. A method of treatment of a behavior disorder of a patient in need of such treatment, said method comprising the step of administering to said patient an effective amount of a compound selected from the group consisting of a penicillin sulfoxide, a cephalosporin sulfoxide, a penicillin sulfone, a cephalosporin sulfone, or another cephalosporin substantially devoid of antibiotic activity, provided that when the compound is a β

-lactam compound which exhibits antibiotic activity, the effective amount administered to the patient is less than that required to produce clinically effective antibacterial blood levels of the β

-lactam antibiotic.