Pharmaceutical combined preparation containing a therapeutic protein

Abstract

A pharmaceutical combined preparation containing a therapeutic protein having SH-groups which are nitrosated and a compound containing thiol groups and having an average molecular weight of at most 10,000.

1 - 7 . (canceled) 
     
     
         8 . A method for the treatment of at least one of ischemia, cerebral ischemia, reperfusion injury, myocardial infarction, shock, traumatic shock, hypovolemic shock, haemorrhagic shock, neurogenic shock, thrombosis, respiratory tract disease, erectile dysfunction, hypertension, restenosis following angioplasty, or restenosis during a surgical operation, the method comprising:
 administering a pharmaceutical preparation to a subject in need thereof, the pharmaceutical preparation comprising:
 a therapeutic protein having nitrosated SH-groups and which is selected from the group consisting of S-nitroso albumin, S-nitroso orosomucoid, S-nitroso plasminogen activator, S-nitroso fibrinogen, S-nitroso Lys-plasminogen, and S-nitroso haemoglobin; and 
 at least one thiol compound having a molecular weight of up to 10,000 and which is selected from the group consisting of reduced glutathione, L-cysteine, N-acetyl-L-cysteine, L-cysteinyl glycine, y-glutamyl cysteine, penicillamine, amides of penicillamine, N-acetyl penicillamine, amides of N-acetyl penicillamine, homocysteine, captopril (D-2-methyl-3-mercaptopropanoyl-L-proline), and reduced thioctic acid (dihydrolipoic acid), wherein the at least one thiol is included in an amount so as to accelerate nitric oxide release by the therapeutic protein compared to administering the therapeutic protein by itself. 
   
     
     
         9 . The method according to  claim 8 , wherein the at least one thiol compound is selected from the group consisting of reduced glutathione, L-cysteine, L-cysteinyl glycine, y-glutamyl cysteine, and dihydrolipoic acid. 
     
     
         10 . The method according to  claim 8 , wherein at least 90% of the SH-groups of the therapeutic protein are nitrosated. 
     
     
         11 . The method according to  claim 10 , wherein administering the thiol together with the therapeutic protein results in at least one of the following:
 enhanced treatment of ischemia compared to administering the therapeutic protein by itself;   accelerated nitric oxide release by the therapeutic protein of at least 50% compared to administering the therapeutic protein by itself;   reduced arterial pressure compared to administering the therapeutic protein by itself; or   reduced platelet aggregation compared to administering the therapeutic protein by itself.   
     
     
         12 . The method according to  claim 8 , wherein the method comprises administering the therapeutic protein in one or more dosages of 0.035-1.0 μmol/kg/h and the at least one thiol compound in one or more dosages of 12-140 μmol/kg/h. 
     
     
         13 . The method according to  claim 8 , wherein the therapeutic protein comprises S-nitroso albumin 
     
     
         14 . The method according to  claim 8 , wherein the at least one thiol compound comprises reduced glutathione. 
     
     
         15 . A method for the treatment of at least one of ischemia, cerebral ischemia, reperfusion injury, myocardial infarction, shock, traumatic shock, hypovolemic shock, haemorrhagic shock, neurogenic shock, thrombosis, respiratory tract disease, erectile dysfunction, hypertension, restenosis following angioplasty, or restenosis during a surgical operation, the method comprising:
 administering a pharmaceutical preparation to a subject in need thereof, the pharmaceutical preparation comprising:
 S-nitroso albumin; and 
 reduced glutathione in an amount that accelerates nitric oxide release by the S-nitroso albumin compared to administering S-nitroso albumin by itself. 
   
     
     
         16 . The method according to  claim 15 , wherein at least 90% of the SH-groups of the S-nitroso albumin are nitrosated, and wherein in the S-nitroso albumin the degree of nitrosation is made up of S-nitrosation by at least 90% and of N-nitrosation, O-nitrosation, or C-nitrosation by 10%, or less. 
     
     
         17 . The method according to  claim 15 , wherein administering the reduced glutathione together with the S-nitroso albumin results in enhanced treatment of ischemia compared to administering S-nitroso albumin by itself. 
     
     
         18 . The method according to  claim 15 , wherein the method comprises administering the S-nitroso albumin in one or more dosages of up to 10 umol/kg/h and the reduced glutathione in one or more dosages of 12-140 μmol/kg/h. 
     
     
         19 . The method according to  claim 15 , wherein the method includes administering the S-nitroso albumin in one or more dosages of 0.035-1.0 μmol/kg/h and the reduced glutathione in one or more dosages of 12-140 μmol/kg/h. 
     
     
         20 . A method for the treatment of ischemia comprising:
 administering a pharmaceutical preparation to a subject in need thereof, the pharmaceutical preparation comprising:
 S-nitroso albumin; and 
 reduced glutathione in an amount so as to accelerate nitric oxide release by the S-nitroso albumin compared to administering S-nitroso albumin by itself. 
   
     
     
         21 . The method according to  claim 20 , wherein at least 90% of the SH-groups of the S-nitroso albumin are nitrosated. 
     
     
         22 . The method according to  claim 20 , wherein in the S-nitroso albumin the degree of nitrosation is made up of S-nitrosation by at least 90% and of N-nitrosation, O-nitrosation, or C-nitrosation by 10%, or less. 
     
     
         23 . The method according to  claim 20 , wherein administering the reduced glutathione together with the S-nitroso albumin accelerates nitric oxide release by the S-nitroso albumin of at least 50% compared to administering S-nitroso albumin by itself. 
     
     
         24 . The method according to  claim 20 , wherein administering the reduced glutathione together with the S-nitroso albumin results in reduced arterial pressure compared to administering S-nitroso albumin by itself. 
     
     
         25 . The method according to  claim 20 , wherein administering the reduced glutathione together with the S-nitroso albumin results in reduced platelet aggregation compared to administering S-nitroso albumin by itself. 
     
     
         26 . The method according to  claim 20 , wherein the method comprises administering the S-nitroso albumin in one or more dosages of up to 10 umol/kg/h and the reduced glutathione in one or more dosages of 12-140 μmol/kg/h. 
     
     
         27 . The method according to  claim 20 , wherein the method includes administering the S-nitroso albumin in one or more dosages of 0.035-1.0 μmol/kg/h and the reduced glutathione in one or more dosages of 12-140 μmol/kg/h.