Pharmaceutical compositions and therapeutic methods employing a combination of a manganese complex compound and a non-manganese complex form of the compound
AssigneePledpharma AB
InventorsJan-Olof Karlsson, Rolf Andersson
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Abstract
A pharmaceutical composition for treatment of a pathological condition in a patient comprises, as a first component, a manganese complex of Formula I( ), and, as a second component, a non-manganese complex compound of Formula (I), optionally together with one or more physiologically acceptable carriers and/or excipients, wherein X, R, R, R, and R are as defined herein. Methods for treatment of a pathological condition in a patient, for example, a pathological condition caused by the presence of oxygen-derived free radicals, comprises administering to said patient the first component and the second component.
Claims41
A method of reducing uptake of manganese to the brain of a patient when a pathological condition in a patient caused by superoxide radicals is treated by administration of manganese N,N′-bis-(pyridoxal-5-phosphate)-ethylenediamine-N,N′-diacetic acid (MnDPDP) or a salt thereof in an amount effective to treat the pathological condition, the method comprising administering, as a second component, N,N′-bis-(pyridoxal-5-phosphate)-ethylenediamine-N,N′-diacetic acid (DPDP) or a salt or non-manganese complex thereof in an amount effective to reduce uptake of manganese to the brain of the patient as compared with administration of MnDPDP in the absence of the second component, wherein the second component is administered in an amount of about 1 to 20 μmol/kg body weight, wherein MnDPDP and the second component are included in a MnDPDP:second component molar ratio in the range of about 1:1 to 1:10, and wherein the administration of MnDPDP and/or the administration of the second component are optionally together with one or more physiologically acceptable carriers and/or excipients.
A method of reducing uptake of manganese to the brain of a patient when a pathological condition in a patient caused by superoxide radicals is treated by administration of a manganese complex of a compound of Formula I in an amount effective to treat the pathological condition, the method comprising administering, as a second component, a compound of Formula I or a non-manganese metal complex of a compound of Formula I in an amount effective to reduce uptake of manganese to the brain of the patient as compared with administration of the manganese complex in the absence of the second component, wherein the second component is administered in an amount of about 1 to 20 μmol/kg body weight, wherein the manganese complex and the second component are included in a manganese complex:second component molar ratio in the range of about 1:1 to 1:10, and wherein the administration of the manganese complex and/or the administration of the second component are optionally together with one or more physiologically acceptable carriers and/or excipients,
- wherein
- X represents CH,
- each R1 represents CH2COR5;
- R5 represents hydroxy;
- each R2 independently represents ZYR6 wherein Z represents a bond, CH2 or —CH2O—;
- Y represents a bond or an oxygen atom;
- R6 is a hydrogen atom, COOR8, alkyl, alkenyl, cycloalkyl, aryl or aralkyl group optionally substituted by one or more groups selected from COOR8, CONR82, NR82, OR8, ═NR8, ═O, OP(O) (OR8)R7 and OSO3M;
- R7 is hydroxy, optionally hydroxylated, optionally alkoxylated alkyl or aminoalkyl group;
- R8 is a hydrogen atom or an optionally hydroxylated, optionally alkoxylated alkyl group;
- provided that each ZYR6 includes a —CH2O— linkage to the respective pyridine ring;
- M is a hydrogen atom or one equivalent of a physiologically tolerable cation;
- R3 represents ethylene;
- and
- each R4 independently represents hydrogen or C1-3 alkyl.
A method of reducing uptake of manganese to the brain of a patient when a pathological condition in a patient caused by superoxide radicals is treated by administration of a manganese complex of a compound of Formula I in an amount effective to treat the pathological condition, wherein the pathological condition is:
- a cytotoxic or cytostatic drug injury;
- an ischemia-reperfusion-induced injury;
- a result of myocardial ischemia-reperfusion-induced injury;
- associated with a thrombolytic treatment, a cardiopulmonary bypass, or percutaneous transluminal angioplasty;
- a result of cardiac or organ transplantation surgery;
- acetaminophen-induced acute liver failure;
- a pathological condition of iron;
- thalassemia;
- sickle cell anemia;
- transfusional hemosiderosis;
- hepatitis-induced liver cirrhosis;
- or radiation-induced injury,
- the method comprising administering, as a second component, a compound of Formula I or a non-manganese metal complex of a compound of Formula I in an amount effective to reduce uptake of manganese to the brain of the patient as compared with administration of the manganese complex in the absence of the second component, wherein the second component is administered in an amount of about 1 to 20 μmol/kg body weight, wherein the manganese complex and the second component are included in a manganese complex:second component molar ratio in the range of about 1:1 to 1:10, and wherein the administration of the manganese complex and/or the administration of the second component are optionally together with one or more physiologically acceptable carriers and/or excipients,
- wherein
- X represents CH,
- each R1 represents CH2COR5;
- R5 represents hydroxy;
- each R2 independently represents ZYR6 wherein Z represents a bond, CH2 or —CH2O—;
- Y represents a bond or an oxygen atom;
- R6 is a hydrogen atom, COOR8, alkyl, alkenyl, cycloalkyl, aryl or aralkyl group optionally substituted by one or more groups selected from COOR8, CONR82, NR82, OR8, ═NR8, ═O, OP(O) (OR8)R7 and OSO3M;
- R7 is hydroxy, optionally hydroxylated, optionally alkoxylated alkyl or aminoalkyl group;
- R8 is a hydrogen atom or an optionally hydroxylated, optionally alkoxylated alkyl group;
- provided that each ZYR6 includes a —CH2O— linkage to the respective pyridine ring;
- M is a hydrogen atom or one equivalent of a physiologically tolerable cation;
- R3 represents ethylene;
- and
- each R4 independently represents hydrogen or C1-3 alkyl.
Dependencies are inferred from the claim text.