Increasing cerebral bioavailability of drugs

Abstract

A method and compositions are provided for increased cerebral bioavailability of blood-born compositions by administering the composition of interest while increasing production of NO by eNOS, especially by administering L-arginine, by administering agents that increase NO levels independent of ecNOS, or by any combination of these methods. As NO is increased, cerebral blood flow is consequently increased, and drugs in the blood stream are carried along with the increased flow into brain tissue. By increased flow, the site of action will be exposed to more drug molecules. By stimulating increased NO production, administration of drugs that are not easily introduced to the brain may be facilitated and/or the serum concentration necessary to achieve desired physiologic effects may be reduced.

1 - 19 . (canceled)  
     
     
         20 . A method of increasing cerebral bioavailability of a neuroprotectant composition in a subject comprising administering an NO-increasing agent to the subject, wherein the agent is administered substantially contemporaneously with the neuroprotectant composition.  
     
     
         21 . A method of increasing cerebral bioavailability of a neuroprotectant composition in a subject comprising introducing the neuroprotectant composition into the blood stream of the subject substantially contemporaneously with an NO enhancing amount of L-arginine.  
     
     
         22 . A method of increasing cerebral bioavailability of a neuroprotectant composition in a subject comprising introducing the neuroprotectant composition into the blood stream of the subject substantially contemporaneously with a blood flow enhancing amount of an agent which increases the production of NO by preexisting ecNOS.  
     
     
         23 . A method of increasing cerebral bioavailability of a neuroprotectant composition in a subject comprising introducing the neuroprotectant composition into the blood stream of the subject substantially contemporaneously with a blood flow enhancing amount of an agent which increases the production of NO by preexisting ecNOS and at least one other NO-increasing agent.  
     
     
         24 . The method of any one of claims  20 - 23 , wherein the neuroprotectant composition comprises a neuroprotectant selected from the group consisting of MK-801, a gamma-aminobutyric acid (GABA) agonist, clomethiazole, an N-methyl-D-aspartate (NMDA) antagonist, Dizocilpine, a platelet aggregation inhibitor, and Lotrafiban.  
     
     
         25 . The method according to  claim 22  or  claim 23 , wherein the agent which increases the production of NO by preexisting ecNOS is selected from the group consisting of L-arginine, NADPH, and tetrahydrobiopterin.  
     
     
         26 . The method according to  claim 22  or  claim 23 , wherein the agent which increases the production of NO by preexisting ecNOS is L-arginine.  
     
     
         27 . The method according to  claim 23 , wherein the agent which increases the production of NO by preexisting ecNOS is L-arginine and the at least one other NO-increasing agent is a different agent which increases the production of NO by preexisting ecNOS.  
     
     
         28 . The method according to  claim 23 , wherein the agent which increases the production of NO by preexisting ecNOS is L-arginine and the at least one other NO-increasing agent is a non-ecNOS NO-generating system.  
     
     
         29 . The method according to any one of  claims 20  to  23 , wherein the subject has experienced, is experiencing, or is at abnormally elevated risk of experiencing, an ischemic stroke.  
     
     
         30 . The method according to any one of  claims 20  to  23 , wherein the neuroprotectant composition has a site of action in the brain.  
     
     
         31 . A composition for increasing cerebral bioavailability of a neuroprotectant in a subject comprising a blood-flow enhancing amount of an NO-increasing agent and the neuroprotectant.  
     
     
         32 . The composition according to  claim 31 , wherein the NO-increasing agent increases the production of NO by preexisting ecNOS.  
     
     
         33 . The composition according to  claim 32 , comprising at least one other NO-increasing agent.  
     
     
         34 . The composition of any one of claims  31 - 33 , wherein the neuroprotectant is selected from the group consisting of MK-801, a gamma-aminobutyric acid (GABA) agonist, clomethiazole, an N-methyl-D-aspartate (NMDA) antagonist, Dizocilpine, a platelet aggregation inhibitor, and Lotrafiban.  
     
     
         35 . The composition according to  claim 32 , wherein the agent which increases the production of NO by preexisting ecNOS is selected from the group consisting of L-arginine, NADPH, and tetrahydrobiopterin.  
     
     
         36 . The composition according to  claim 32 , wherein the agent which increases the production of NO by preexisting ecNOS is L-arginine.  
     
     
         37 . The composition according to  claim 32 , comprising L-arginine and at least one other NO-increasing agent which is a different agent which increases the production of NO by preexisting ecNOS.  
     
     
         38 . The composition according to  claim 32  or  37 , comprising L-arginine and at least one NO-increasing agent which is a non-ecNOS NO-generating system.  
     
     
         39 . The composition according to any one of claims  31 - 33 , wherein the neuroprotectant has a site of action in the brain.  
     
     
         40 . The composition according to any one of claims  31 - 33 , wherein the composition is packaged according to Blow/Fill/Seal technology.