Methods to prevent and treat diseases

Abstract

This invention discloses methods and compositions that can treat a variety of tissue injuries and infections. Tissue-derived leukocyte chemotactic factors are rapidly released after injury to mammalian tissue and can act as the initial signal leading to the initiation and amplification of acute and chronic inflammation associated with injury and infection. The present invention generally provides methods and compositions to prevent and treat injury of cells, tissue, or organs by blocking or inhibiting the release of leukocyte chemotactic factors, by administering certain effective compositions to the tissue.

1 . A method of treating mammalian tissue subject to injury, pain, ischemia, or infections agents, said method comprising administering to the mammal at least one tissue-protective agent effective for imparting to the tissue an anti-inflammatory response, an anti-apoptotic response, or both anti-inflammatory and anti-apoptotic responses.  
     
     
         2 . The method of  claim 1 , wherein the agent comprises spinorphin, tynorphin, leuhistin, nimbidin, or a combination of more of these.  
     
     
         3 . The method of  claim 1 , wherein the agent comprises the peptide t-Boc-Phe-D-Leu-Phe-D-Leu-Phe (SEQ ID NO: 2) or t-Boc-Methionyl-Leucyl-Phenylalanine (SEQ ID NO: 5).  
     
     
         4 . The method of  claim 1 , wherein the agent comprises Carbobenzoxy-Phe-Met (SEQ ID NO: 10), the Substance P antagonist R(dextro-)PKP (dextro-)FQ(dextro-)WF(dextro-)WLL-NH 2  (SEQ ID NO: 6), or Cyclosporine H.  
     
     
         5 . The method of  claim 1 , wherein the agent comprises a plurality of soluble formyl peptide receptors that can bind to formylated ligands, non-formylated ligands, or both.  
     
     
         6 . The method of  claim 1 , wherein the agent comprises an antibody against formyl peptide receptors that can bind to formylated ligands, an antibody against formyl peptide receptors that can bind to non-formylated ligands, or an antibody against a tissue-derived leukocyte chemotactic factor.  
     
     
         7 . The method of  claim 1 , wherein the agent comprises an antagonist of a tissue-derived leukocyte chemotactic factor.  
     
     
         8 . The method of  claim 1 , further comprising administering to the mammal at least one additional agent selected from the group consisting of anti-oxidants, enzymes, enzyme inhibitors, antibiotics, inhibitors of the bacterial formyl peptides chemoattractants, and endogenous inhibitors of tissue-derived leukocyte chemotactic factors.  
     
     
         9 . The method of  claim 8 , wherein the enzyme inhibitors comprise L-histidine, trasylol, or both L-histidine and trasylol.  
     
     
         10 . The method of  claim 8 , wherein the enzymes comprise at least one deformylase.  
     
     
         11 . The method of  claim 8 , wherein the anti-oxidants comprise ascorbic acid.  
     
     
         12 . The method of  claim 1 , wherein the agent comprises a creatine analogue.  
     
     
         13 . The method of  claim 12 , wherein the creatine analogue is cyclocreatine, a salt thereof, or cyclocreatine phosphate.  
     
     
         14 . The method of  claim 1 , wherein the agent comprises nimbidin or a metabolite of mitochondria.  
     
     
         15 . The method of  claim 14 , wherein the metabolite is acetyl L-carnitine, coenzyme Q10, glutathione, or a-lipoic acid.  
     
     
         16 . The method of  claim 1 , further comprising administering to the mammal an additional agent that is capable of generating nitric oxide in vivo.  
     
     
         17 . The method of  claim 1 , wherein the anti-inflammatory response arises from one or more actions of the agent, said actions selected from the group consisting of delaying the depletion of adenosine triphosphate in the tissue, conserving the total adenylate pool in the tissue, buffering a decrease in the ratio of adenosine triphosphate to free adenosine diphosphate in the tissue, delaying exhaustion of high-energy phosphates in the tissue, maintaining cell-membrane integrity in the tissue, inhibiting caspase enzyme activity in the tissue, reducing intracellular edema in the tissue, and reducing lactic acidosis in the tissue.  
     
     
         18 . The method of  claim 1 , wherein the agent crosses the blood-brain barrier of the mammal, accumulates in nerve tissue of the mammal, enhances energy production in the tissue, reduces lactic acidosis in the tissue, and/or reduces the level of malondialdehyde in the tissue.  
     
     
         19 . The method of  claim 1 , wherein the agent is administered prophylactically or therapeutically during injury or post-injury.  
     
     
         20 . The method of  claim 1 , wherein the agent is administered by injection, orally, topically, or by inhalation.  
     
     
         21 . The method of  claim 1 , wherein the mammalian tissue is human tissue.  
     
     
         22 . The method of  claim 1 , wherein the injury is related to ischemia or infection.  
     
     
         23 . A composition for treating animal tissue subject to injury, the composition comprising: (i) an anti-inflammatory agent; and (ii) an anti-apoptotic agent, wherein the anti-inflammatory agent is capable of inhibiting a tissue-derived leukocyte chemotactic factor.  
     
     
         24 . The composition of  claim 23 , wherein the anti-inflammatory agent comprises an antagonist of a tissue-derived leukocyte chemotactic factor.  
     
     
         25 . The composition of  claim 24 , further comprising at least one agent selected from the group consisting of anti-oxidants, enzymes, enzyme inhibitors, antibiotics, inhibitors of the bacterial formyl peptides chemoattractants, and endogenous inhibitors of tissue-derived leukocyte chemotactic factors.  
     
     
         26 . The composition of  claim 25 , wherein the enzyme inhibitors comprise L-histidine, trasylol, or both L-histidine and trasylol.  
     
     
         27 . The composition of  claim 25  wherein the enzymes comprise at least one deformylase.  
     
     
         28 . The composition of  claim 25 , wherein the anti-oxidants comprise ascorbic acid.  
     
     
         29 . The composition of  claim 23 , wherein the anti-inflammatory agent comprises the antagonist spinorphin, leuhistin, tynorphin, nimbidin, or a combination of two or all three of these; the synthetic compound t-Boc-Phe-Leu-Phe-Leu-Phe (SEQ ID NO: 2); the immunosuppressive cyclosporine H; Carbobenzoxy-Phe-Met (SEQ ID NO: 10); a plurality of soluble formyl peptide receptors that can bind to formylated ligands; a plurality of soluble formyl peptide receptors that can bind to non-formylated ligands; an antibody against formyl peptide receptors that can bind to formylated ligands; an antibody against formyl peptide receptors that can bind to non-formylated ligands; an antibody against a tissue-derived leukocyte chemotactic factor; Substance P antagonist R(dextro-)PKP(dextro-)FQ(dextro-)WF(dextro-)WLL-NH 2  (SEQ ID NO: 6); or combinations of two or more of these.  
     
     
         30 . The composition of  claim 23 , wherein the anti-apoptotic agent comprises a creatine analogue.  
     
     
         31 . The composition of  claim 30 , wherein the creatine analogue is cyclocreatine or a salt thereof, or cyclocreatine phosphate.  
     
     
         32 . The composition of  claim 23 , wherein the anti-apoptotic agent comprises a metabolite of mitochondria.  
     
     
         33 . The composition of  claim 32 , wherein the metabolite is acetyl L-carnitine, coenzyme Q10, glutathione, or α-lipoic acid.  
     
     
         34 . A method of using a composition to protect or treat a first tissue of a mammal, said first tissue suspected of being injured or of being susceptible to injury, comprising providing an effective amount of the composition to said first tissue, wherein the composition comprises (i) an anti-inflammatory agent and (ii) an anti-apoptotic agent, and wherein the anti-inflammatory agent is capable of inhibiting a leukocyte chemotactic factor derived from a second tissue of the mammal.  
     
     
         35 . The method of  claim 34 , wherein said first tissue and said second tissue are the same.  
     
     
         36 . The method of  claim 34 , wherein the anti-inflammatory agent comprises an antagonist of a tissue-derived leukocyte chemotactic factor.  
     
     
         37 . The method of  claim 36 , wherein the composition further comprises at least one of the following agents: anti-oxidants, enzymes, enzyme inhibitors, antibiotics, inhibitors of the bacterial formyl peptides chemoattractants, and endogenous inhibitors of tissue-derived leukocyte chemotactic factors.  
     
     
         38 . The method of  claim 37 , wherein the enzyme inhibitors comprise L-histidine, trasylol, or both L-histidine and trasylol.  
     
     
         39 . The method of  claim 37 , wherein the enzymes comprise at least one deformylase.  
     
     
         40 . The method of  claim 37 , wherein the anti-oxidants comprise ascorbic acid.  
     
     
         41 . The method of  claim 36 , wherein the antagonist comprises spinorphin, tynorphin, or both.  
     
     
         42 . The method of  claim 41 , wherein the antagonist further comprises leuhistin.  
     
     
         43 . The method of  claim 34 , wherein the anti-inflammatory agent comprises nimbidin, the synthetic compound t-Boc-Phe-Leu-Phe-Leu-Phe (SEQ ID NO: 2), the immunosuppressive cyclosporine H, Carbobenzoxy-Phe-Met (SEQ ID NO: 10), a plurality of soluble formyl peptide receptors that can bind to formylated ligands, a plurality of soluble formyl peptide receptors that can bind to non-formylated ligands, an antibody against formyl peptide receptors that can bind to formylated ligands, an antibody against formyl peptide receptors that can bind to non-formylated ligands, an antibody against a tissue-derived leukocyte chemotactic factor, Substance P antagonist R(dextro-)PKP(dextro-)FQ(dextro-)WF(dextro-)WLL-NH 2  (SEQ ID NO: 6), or a combination of two or more of these.  
     
     
         44 . The method of  claim 34 , wherein the anti-apoptotic agent comprises a creatine analogue or a metabolite of mitochondria.  
     
     
         45 . The method of  claim 44 , wherein the creatine analogue is cyclocreatine or a salt thereof or cyclocreatine phosphate.  
     
     
         46 . The method of  claim 44 , wherein the metabolite is selected from the group consisting of acetyl L-carnitine, coenzyme Q10, glutathione, and α-lipoic acid.  
     
     
         47 . The method of  claim 34 , further comprising administering to the mammal an additional agent that is capable of generating nitric oxide in vivo.  
     
     
         48 . A method of treating injured mammalian tissue in a patient, said method comprising: 
 (a) taking a sample of patient mammalian tissue suspected of being damaged;    (b) detecting the release of at least one protein from the mammalian tissue, to indicate that the mammalian tissue is in an injured state in the patient; and    (c) if the tissue is injured, administering to the mammal an effective amount of a composition comprising (i) an anti-inflammatory agent and (ii) an anti-apoptotic agent, wherein the anti-inflammatory agent is capable of inhibiting a tissue-derived leukocyte chemotactic factor.    
     
     
         49 . A method of treating mammalian tissue subject to injury, said method comprising the step of administering to the mammal a creatine analogue in an amount between 0.03 g and 0.08 g creatine analogue per kg of mammal body weight.  
     
     
         50 . The method of  claim 49 , wherein the creatine analogue reduces intracellular cAMP production in the tissue.  
     
     
         51 . The method of  claim 49 , wherein the treatment reduces or eliminates apoptosis in the injured tissue.  
     
     
         52 . The method of  claim 49 , wherein the creatine analogue is cyclocreatine or a salt thereof or cyclocreatine phosphate.  
     
     
         53 . The method of  claim 49 , further comprising administering to the mammal an additional agent that is capable of generating nitric oxide in vivo.