Neurotherapeutic composition and method

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.

1 - 17 . (Canceled)  
     
     
         18 . A method of enhancing cognitive function in a warm-blooded vertebrate in need of said treatment, said method comprising the step of administering to said warm-blooded vertebrate an effective amount of a compound capable of inhibiting the peptidase activity of one or more neurogenic peptidases in the brain of said patient.  
     
     
         19 . The method of  claim 18  wherein the warm-blooded vertebrate is a human patient suffering from dementia or amnesia.  
     
     
         20 . The method of  claim 18  wherein the warm-blooded vertebrate is a human patient suffering from Alzheimer's Disease.  
     
     
         21 . The method of  claim 18  wherein the compound is a β-lactam compound.  
     
     
         22 . The method of  claim 21  wherein the β-lactam compound is a β-lactamase inhibitor.  
     
     
         23 . The method of  claim 21  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, carbacephems, and analogs thereof.  
     
     
         24 . The method of  claim 23  wherein the β-lactam compound is a 1-oxa-1-dethia-analogue of a cephalosporin.  
     
     
         25 . The method of  claim 18  further comprising the step of administering an effective amount of a P-glycoprotein efflux pump inhibitor.  
     
     
         26 . The method of  claim 23  wherein the β-lactam compound is administered in combination with an effective amount of a P-glycoprotein efflux pump inhibitor.  
     
     
         27 . The method of  claim 18  wherein the compound is a β-lactam antibiotic and the amount administered to the warm-blooded vertebrate is at least 50 μg/kg but less than an amount effective to provide clinically effective antibacterial blood levels of the compound.  
     
     
         28 . The method of  claim 18  wherein the compound is a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R is hydrogen, a salt forming group or an active ester forming group; R 1  is hydrogen or C 1 -C 4  alkoxy; T is C 1 -C 4  alkyl, halo, hydroxy, O(C 1 -C 4 )alkyl, or —CH 2 B, wherein B is the residue of a nucleophile B:H, and Acyl is the residue of an organic acid Acyl-OH.  
     
     
         29 . The method of  claim 28  wherein the compound is moxalactam or flomoxef.  
     
     
         30 . The method of  claim 29  further comprising the step of administering an effective amount of a P-glycoprotein efflux pump inhibitor.  
     
     
         31 . The method of  claim 18  wherein the compound is a 2-optionally substituted oxa-2-deamino analogue of glutamic acid, a 2-optionally substituted carba-2-deamino analogue of glutamic acid, or an N-substituted derivative of glutamic acid.  
     
     
         32 . The method of  claim 31  further comprising the step of administering an effective amount of a P-glycoprotein efflux pump inhibitor.  
     
     
         33 - 61 . (Canceled)  
     
     
         62 . A method of treating cognitive disorders in a warm-blooded vertebrate need of said treatment, said method comprising the step of inhibiting neurogenic peptidase activity in the brain of said vertebrate, said neurogenic peptidase characterized by its inhibition with effective amounts of the peptide Ala-D-γ-Glu-Lys-D-Ala-D-Ala.  
     
     
         63 . The method of  claim 62  wherein the step of inhibiting the neurogenic peptidase is carried out by administering an amount of a β-lactam antibiotic effective to enhance the warm-blooded vertebrate's cognitive performance.  
     
     
         64 . The method of  claim 63  wherein the β-lactam antibiotic is administered in an amount less than that necessary to obtain antibiotically effective blood levels of said antibiotic.  
     
     
         65 - 77 . (Canceled)  
     
     
         78 . A use in the manufacture of a medicament, of an inhibitor of the peptidase activity of a N-acetylated-α-linked-acidic dipeptidase as the active ingredient in a cognition enhancing composition in admixture with a pharmaceutically acceptable carrier.  
     
     
         79 . (Canceled)  
     
     
         80 . The use of  claim 78  in the manufacture of a medicament wherein the inhibitor is a β-lactam antibiotic or a ⊕-lactamase inhibitor.  
     
     
         81 . The use of  claim 80  in the manufacture of a medicament wherein the use further includes a P-glycoprotein efflux pump inhibitor.  
     
     
         82 . The use of  claim 78  in the manufacture of a medicament wherein the inhibitor is a 2-optionally substituted oxa-2-deamino analogue of glutamic acid, a 2-optionally substituted carba-2-deamino analogue of glutamic acid, or an N-substituted derivative of glutamic acid.  
     
     
         83 . The use of  claim 82  in the manufacture of a medicament wherein the use further includes a P-glycoprotein efflux pump inhibitor.  
     
     
         84 - 89 . (Canceled)  
     
     
         90 . The use of  claim 80  in the manufacture of a medicament wherein the inhibitor is a 2-optionally substituted oxa-2-deamino analogue of glutamic acid, a 2-optionally substituted carba-2-deamino analogue of glutamic acid, or an N-substituted derivative of glutamic acid.  
     
     
         91 . The use of  claim 90  in the manufacture of a medicament wherein the use further includes a P-glycoprotein efflux pump inhibitor.