5-hydroxytryptamine 1b receptor-stimulating agent for enhancing in vivo engraftment potential

Abstract

The present invention relates to the field of regenerative medicine, and more particularly to the improvement of the in vivo engraftment potential of biological material to be administered to a subject in need thereof.

1 . A method for enhancing the in vivo engraftment potential of a biological material, comprising at least the step of in vitro and/or ex vivo contacting an isolated biological material with at least one 5-hydroxytryptamine 1B receptor (5-HT1 BR)-stimulating agent. 
     
     
         2 . The method according to  claim 1 , wherein said agent is selected from the group consisting of antidepressant agents and antimigraine drugs, pharmaceutically acceptable derivatives, analogs, isomers, metabolites, salts, solvates, clathrates, polymorphs, and co-crystals thereof, and combinations thereof. 
     
     
         3 . The method according to  claim 2 , wherein said antidepressant agent is selected from the group consisting of atypical antidepressants, preferably bisarylsulfanyl amines such as vortioxetine, and tianeptine, agomelatine, nefazodone, trazodone, buspirone, tandospirone, and ketamine; selective serotonin reuptake inhibitors (SSRIs), preferably fluoxetine, citalopram, escitalopram, sertraline, norsertraline, paroxetine, fluvoxamine, femoxetine, indalpine, alaproclate, cericlamine, ifoxetine, zimelidine, dapoxetine, etoperidone, and metabolites thereof desmethylcitalopram, didesmethylcitalopram, and seproxetine; serotonine and norepinephrine reuptake inhibitors (SNRIs), preferably duloxetine, venlafaxine, desvenlafaxine, milnacipran, levominalcipran, and sibutramine; serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRIs), preferably bicifadine, brasofensine, tesofensine, and nomifensine; tricyclic antidepressants (TCAs), preferably clomipramine, amoxapine, nortriptyline, maprotiline, trimipramine, imipramine, desipramine and protriptyline; monoamine oxidase inhibitors (MAOs), preferably iproniazide, phenelzine, tranylcipromine, moclobemide, selegiline and rasagiline; and noradrenergic and specific serotoninergic antidepressants (NaSSAs), preferably mirtazapine, mianserin, aptazapine, esmirtazapine, setiptiline and S32212 (also known as N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1,2-dihydro-3H-benzo[e]indole-3-carbo-xamide). 
     
     
         4 . The method according to  claim 2 , wherein said antimigraine drug is ergotamine or a triptan, said triptan being preferably selected from the group consisting of sumatriptan, rizatriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, naratriptan avitriptan, and donitriptan. 
     
     
         5 . The method according to any one of  claims 1  to  4 , wherein said agent is modified to comprise at least one charged chemical moiety, preferably positively charged. 
     
     
         6 . The method according to  claim 5 , wherein said positively charged chemical moiety is a quaternary ammonium group or a tertiary sulfonium group. 
     
     
         7 . The method according to  claim 6 , wherein
 said quaternary ammonium group has the formula (I)
   —(NR 1 R 2 R 3 ) + Z −   (I)
 
   wherein   Z is an organic or inorganic anion; and   R 1 , R 2  and R 3  are each independently selected from the group consisting of alkyl, aryl and cycloalkyl; or   said tertiary sulfonium group has the formula (II)
   —(SR 4 R 5 ) + Z −   (II)
 
   wherein   Z is an organic or inorganic anion; and   R 4  and R 5  are each independently selected from the group consisting of alkyl, aryl and cycloalkyl.   
     
     
         8 . The method according to any one of  claims 5  to  7 , wherein said agent is a positively charged vortioxetine selected from the group consisting of salts of vortioxetine, vortoxietine coupled to at least one positively charged amino acid such as histidine, arginine or lysine, pyrrolidinium-vortioxetine, pyperazinium-vortioxetine, dimethylammonium-vortioxetine, sulfonium-vortioxetine, N-oxide-vortioxetine, sulfoxide-vortioxetine, and phosphonium-vortioxetine. 
     
     
         9 . The method according to any one of  claims 1  to  8 , wherein said biological material is selected from the group consisting of cells, tissues, organs, derivatives thereof, and combinations thereof. 
     
     
         10 . An isolated biological material with enhanced in vivo engraftment potential, obtainable according to the method as defined in any one of  claims 1  to  9 . 
     
     
         11 . A medical device comprising at least the biological material according to  claim 10  and optionally at least one pharmaceutically acceptable excipient. 
     
     
         12 . The biological material according to  claim 10 , or the medical device according to  claim 11 , further comprising at least one active agent. 
     
     
         13 . An isolated biological material as defined in  claim 10  or  12 , or a medical device as defined in  claim 11  or  12 , for use as a medicament. 
     
     
         14 . An isolated biological material as defined in  claim 10  or  12 , or a medical device as defined  claim 11  or  12 , for use in a subject in need of cell, tissue or organ regeneration. 
     
     
         15 . A 5-hydroxytryptamine 1B receptor (5-HT1 BR)-stimulating agent as defined in any one of  claims 1  to  8 , for a pre-therapeutic use in a subject in need of cell, tissue or organ regeneration. 
     
     
         16 . A 5-hydroxytryptamine 1B receptor (5-HT1 BR)-stimulating agent as defined in any one of  claims 1  to  8 , for a pre-therapeutic use in a subject in need of a treatment intended for cell, tissue or organ regeneration, and co- and/or post-therapeutic use in said subject undergoing said treatment. 
     
     
         17 . A 5-hydroxytryptamine 1B receptor (5-HT1 BR)-stimulating agent as defined in any one of  claims 1  to  8 , for a co-therapeutic and/or post-therapeutic use in a subject undergoing cell, tissue or organ regeneration. 
     
     
         18 . An isolated biological material and a 5-hydroxytryptamine 1B receptor (5-HT1 BR)-stimulating agent as defined in any one of  claims 1  to  8 , as a combined preparation for simultaneous, separate or sequential administration in a treatment intended to regenerate cells, tissues or organs in a subject in need thereof.