Methods and formulations for treatment of and/or protection against acute liver failure and other hepatotoxic conditions

A method of treating and/or protecting against acute liver failure in an individual, comprising

• (a) administering to the individual an effective amount of a first active agent which replenishes, or decreases a loss of, functional glutathione in the individual, wherein the first active agent comprises N-acetylcysteine (NAC), and
• (b) administering an effective amount of a second active agent comprising a manganese complex selected from the group consisting of (i) a calcium manganese mixed metal complex of N,N′-bis-(pyridoxal-5-phosphate)-ethylenediamine-N,N′-diacetic acid (DPDP) having a molar ratio of calcium to manganese in a range of from 1 to 10, or a pharmaceutically acceptable salt thereof, (ii) a mixture of manganese DPDP (MnDPDP), or a pharmaceutically acceptable salt thereof, and a non-manganese-containing DPDP compound, or (iii) a mixture of manganese pyridoxyl ethylenediamine (MnPLED), or a pharmaceutically acceptable salt thereof, and a non-manganese-containing pyridoxyl ethylenediamine (PLED) compound, to the individual.

A method of treating and/or protecting against hepatotoxicity in an individual, comprising

• (a) administering to the individual an effective amount of a first active agent which replenishes, or decreases a loss of, functional glutathione in the individual, wherein the first active agent comprises N-acetylcysteine (NAC), and
• (b) administering an effective amount of a second active agent comprising a manganese complex selected from the group consisting of (i) a calcium manganese mixed metal complex of N,N′-bis-(pyridoxal-5-phosphate)-ethylenediamine-N,N′-diacetic acid (DPDP) having a molar ratio of calcium to manganese in a range of from 1 to 10, or a pharmaceutically acceptable salt thereof, (ii) a mixture of manganese DPDP (MnDPDP), or a pharmaceutically acceptable salt thereof, and a non-manganese-containing DPDP compound, or (iii) a mixture of manganese pyridoxyl ethylenediamine (MnPLED), or a pharmaceutically acceptable salt thereof, and a non-manganese-containing pyridoxyl ethylenediamine (PLED) compound, to the individual.

A method of administering a therapeutic high dosage of acetaminophen to an individual, comprising administering a therapeutic high dosage of acetaminophen to the individual, and administering an effective amount of a second active agent comprising a manganese complex selected from the group consisting of (i) a calcium manganese mixed metal complex of N,N′-bis-(pyridoxal-5-phosphate)-ethylenediamine-N,N′-diacetic acid (DPDP) having a molar ratio of calcium to manganese in a range of from 1 to 10, or a pharmaceutically acceptable salt thereof, (ii) a mixture of manganese DPDP (MnDPDP), or a pharmaceutically acceptable salt thereof, and a non-manganese-containing DPDP compound, or (iii) a mixture of manganese pyridoxyl ethylenediamine (MnPLED), or a pharmaceutically acceptable salt thereof, and a non-manganese-containing pyridoxyl ethylenediamine (PLED) compound, to the individual.

A method of reducing acute kidney injury associated with acute liver failure or other hepatotoxicity in an individual, comprising (a) administering an effective amount of a second active agent comprising a manganese complex selected from the group consisting of (i) a calcium manganese mixed metal complex of DPDP having a molar ratio of calcium to manganese in a range of from 1 to 10, or a pharmaceutically acceptable salt thereof, (ii) a mixture of MnDPDP, or a pharmaceutically acceptable salt thereof, and a non-manganese-containing DPDP compound, or (iii) a mixture of MnPLED, or a pharmaceutically acceptable salt thereof, and a non-manganese-containing PLED compound, to the individual, and optionally (b) administering to the individual an effective amount of a first active agent which replenishes, or decreases a loss of, functional glutathione in the individual, wherein the first active agent comprises N-acetylcysteine (NAC).

-19. (canceled)

A formulation comprising (a) a first active agent which replenishes, or decreases a loss of, functional glutathione, wherein the first active agent comprises N-acetylcysteine (NAC), and (b) a second active agent comprising a manganese complex selected from the group consisting of (i) a calcium manganese mixed metal complex of N,N′-bis-(pyridoxal-5-phosphate)-ethylenediamine-N,N′-diacetic acid (DPDP) having a molar ratio of calcium to manganese in a range of from 1 to 10, or a pharmaceutically acceptable salt thereof, (ii) a mixture of manganese DPDP (MnDPDP), or a pharmaceutically acceptable salt thereof, and a non-manganese-containing DPDP compound, or (iii) a mixture of manganese pyridoxyl ethylenediamine (MnPLED), or a pharmaceutically acceptable salt thereof, and a non-manganese-containing pyridoxyl ethylenediamine (PLED) compound.

-28. (canceled)