Methods and compositions for improving cognitive function

Abstract

This invention relates to treating age-related cognitive impairment. This invention in particular relates to the use of inhibitors of synaptic vesicle protein 2A (SV2A), such as levetiracetam, seletracetam, and brivaracetam, in improving cognitive function in subjects that exhibit age-related cognitive impairment or are at risk thereof, including, without limitation, subjects having or at risk for Mild Cognitive Impairment (MCI), Age-related Cognitive Decline (ARCD) or Age-Associated Memory Impairment (AAMI).

1 . A method for treating age-related cognitive impairment in a subject in need or at risk thereof, the method comprising the step of administering to said subject a therapeutically effective amount of a synaptic vesicle protein 2A (SV2A) inhibitor or a pharmaceutically acceptable salt thereof. 
   
   
       2 . The method of  claim 1 , wherein the SV2A inhibitor or a pharmaceutically acceptable salt thereof is selected from the group of SV2A inhibitors referred to in International Patent Application WO 2001/062726, International Patent Application WO 2002/094787, International Patent Application WO 2004/087658, U.S. Pat. No. 7,244,747, International Patent Application WO 2007/065595, US Patent Application 2008/0081832, International Patent Application WO 2006/128692, International Patent Application WO 2006/128693, UK Patent No. 1,039,113, and UK Patent No. 1,309,692. 
   
   
       3 . The method of  claim 2 , wherein the SV2A inhibitor is selected from the group consisting of levetiracetam, seletracetam, and brivaracetam or pharmaceutically acceptable salts thereof. 
   
   
       4 . The method of  claim 3 , wherein the SV2A inhibitor is levetiracetam or a pharmaceutically acceptable salt thereof. 
   
   
       5 . The method of  claim 3 , wherein the SV2A inhibitor is brivaracetam or a pharmaceutically acceptable salt thereof. 
   
   
       6 . The method of any one of  claims 1  to  5 , wherein the SV2A inhibitor or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of 0.1 mg/kg to 5 mg/kg. 
   
   
       7 . The method of  claim 6 , wherein the daily dose is 0.1-0.2 mg/kg. 
   
   
       8 . The method of any one of  claims 1  to  5 , wherein the SV2A inhibitor or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of 0.01 mg/kg to 2.5 mg/kg. 
   
   
       9 . The method of  claim 8 , wherein the daily dose is 0.1-2.5 mg/kg. 
   
   
       10 . The method of  claim 8 , wherein the daily dose is 0.4-2.5 mg/kg. 
   
   
       11 . The method of  claim 8 , wherein the daily dose is 0.6-1.8 mg/kg. 
   
   
       12 . The method of  claim 8 , wherein the daily dose is 0.04-2.5 mg/kg. 
   
   
       13 . The method of  claim 8 , wherein the daily dose is 0.06-1.8 mg/kg. 
   
   
       14 . A method for treating age-related cognitive impairment in a subject in need or at risk thereof, the method comprising the step of administering to said subject an SV2A inhibitor or a pharmaceutically acceptable salt thereof in combination with valproate or an analog or a derivative or a pharmaceutically acceptable salt thereof. 
   
   
       15 . The method of  claim 14 , wherein the valproate is administered at a daily dose such that the subject maintains a blood total valproate level of 0.5 to 5 μg/ml plasma, and wherein the SV2A inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of 0.01 to 1 mg/kg. 
   
   
       16 . The method of  claim 14 , wherein the valproate is administered at a daily dose such that the subject maintains a blood total valproate level of 0.5 to 5 μg/ml plasma, and wherein the SV2A inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of 0.001 to 1 mg/kg. 
   
   
       17 . The method of any one of  claims 14  to  16 , wherein the SV2A inhibitor or a pharmaceutically acceptable salt thereof is selected from the group of SV2A inhibitors referred to in International Patent Application WO 2001/062726, International Patent Application WO 2002/094787, International Patent Application WO 2004/087658, U.S. Pat. No. 7,244,747, International Patent Application WO 2007/065595, US Patent Application 2008/0081832, International Patent Application WO 2006/128692, International Patent Application WO 2006/128693, UK Patent No. 1,039,113, and UK Patent No. 1,309,692. 
   
   
       18 . The method of any one of  claims 14  to  16 , wherein the SV2A inhibitor is selected from the group consisting of levetiracetam, seletracetam, and brivaracetam or pharmaceutically acceptable salts thereof. 
   
   
       19 . The method of  claim 18 , wherein the SV2A inhibitor is levetiracetam or a pharmaceutically acceptable salt thereof. 
   
   
       20 . The method of  claim 18 , wherein the SV2A inhibitor is brivaracetam or a pharmaceutically acceptable salt thereof. 
   
   
       21 . The method of  claim 14 , wherein the SV2A inhibitor or a pharmaceutically acceptable salt thereof and the valproate or a pharmaceutically acceptable salt thereof are administered simultaneously. 
   
   
       22 . The method of  claim 14 , wherein the SV2A inhibitor or a pharmaceutically acceptable salt thereof and the valproate or a pharmaceutically acceptable salt thereof are administered in a single formulation. 
   
   
       23 . The method of  claim 14 , wherein the SV2A inhibitor or a pharmaceutically acceptable salt thereof and the valproate or a pharmaceutically acceptable salt thereof are administered sequentially. 
   
   
       24 . A pharmaceutical composition for improving cognitive function in a subject with age-related cognitive impairment or at risk thereof, the composition comprising a SV2A inhibitor or a pharmaceutically acceptable salt thereof, the SV2A inhibitor or a pharmaceutically acceptable salt thereof being present in an amount of 5-140 mg. 
   
   
       25 . A pharmaceutical composition for improving cognitive function in a subject with age-related cognitive impairment or at risk thereof, the composition comprising a SV2A inhibitor or a pharmaceutically acceptable salt thereof, the SV2A inhibitor or a pharmaceutically acceptable salt thereof being present in an amount of 0.7-180 mg. 
   
   
       26 . A pharmaceutical composition for improving cognitive function in a subject with age-related cognitive impairment or at risk thereof, the composition comprising a SV2A inhibitor or a pharmaceutically acceptable salt thereof, the SV2A inhibitor or a pharmaceutically acceptable salt thereof being present in an amount of 3-50 mg, and valproate or an analog or a derivative or a pharmaceutically acceptable salt thereof. 
   
   
       27 . A pharmaceutical composition for improving cognitive function in a subject with age-related cognitive impairment or at risk thereof, the composition comprising a SV2A inhibitor or a pharmaceutically acceptable salt thereof, the SV2A inhibitor or a pharmaceutically acceptable salt thereof being present in an amount of 0.07-50 mg, and valproate or an analog or a derivative or a pharmaceutically acceptable salt thereof. 
   
   
       28 . A method for treating age-related cognitive impairment in a subject in need or at risk thereof, the method comprising the step of administering to said subject a therapeutically effective amount of levetiracetam or a pharmaceutically acceptable salt thereof. 
   
   
       29 . The method of  claim 28 , wherein the levetiracetam is administered every 12 or 24 hours at a daily dose of 1-2 mg/kg. 
   
   
       30 . The method of  claim 28 , wherein the levetiracetam is administered every 12 or 24 hours at a daily dose of 70-150 mg. 
   
   
       31 . The method of  claim 28 , wherein the levetiracetam is administered every 12 or 24 hours at a daily dose of 0.1-2.5 mg/kg. 
   
   
       32 . The method of  claim 28 , wherein the levetiracetam is administered every 12 or 24 hours at a daily dose of 7-180 mg. 
   
   
       33 . The method of  claim 28 , wherein the levetiracetam is administered every 12 or 24 hours at a daily dose of 0.4-2.5 mg/kg. 
   
   
       34 . The method of  claim 28 , wherein the levetiracetam is administered every 12 or 24 hours at a daily dose of 25-180 mg. 
   
   
       35 . The method of  claim 28 , wherein the levetiracetam is administered every 12 or 24 hours at a daily dose of 0.6-1.8 mg/kg. 
   
   
       36 . The method of  claim 28 , wherein the levetiracetam is administered every 12 or 24 hours at a daily dose of 40-130 mg. 
   
   
       37 . A method for treating age-related cognitive impairment in a subject in need or at risk thereof, the method comprising the step of administering to said subject a therapeutically effective amount of brivaracetam or a pharmaceutically acceptable salt thereof. 
   
   
       38 . The method of  claim 37 , wherein the brivaracetam is administered every 12 or 24 hours at a daily dose of 0.1-0.2 mg/kg. 
   
   
       39 . The method of  claim 37 , wherein the brivaracetam is administered every 12 or 24 hours at a daily dose of 7-15 mg. 
   
   
       40 . The method of  claim 37 , wherein the brivaracetam is administered every 12 or 24 hours at a daily dose of 0.01-2.5 mg/kg. 
   
   
       41 . The method of  claim 37 , wherein the brivaracetam is administered every 12 or 24 hours at a daily dose of 0.7-180 mg. 
   
   
       42 . The method of  claim 37 , wherein the brivaracetam is administered every 12 or 24 hours at a daily dose of 0.04-2.5 mg/kg. 
   
   
       43 . The method of  claim 37 , wherein the brivaracetam is administered every 12 or 24 hours at a daily dose of 2.5-180 mg. 
   
   
       44 . The method of  claim 37 , wherein the brivaracetam is administered every 12 or 24 hours at a daily dose of 0.06-1.8 mg/kg. 
   
   
       45 . The method of  claim 37 , wherein the brivaracetam is administered every 12 or 24 hours at a daily dose of 4.0-130 mg. 
   
   
       46 . A method for treating age-related cognitive impairment in a subject in need or at risk thereof, the method comprising the step of administering to said subject a therapeutically effective amount of seletracetam or a pharmaceutically acceptable salt thereof.