Use of adenosine receptor agonists in therapy

Abstract

Use of compounds of formula: (I) wherein R is C 1-4 alkoxy and X is H or OH; for the prevention, treatment, or amelioration of cancer, inflammation, auto-immune disease, ischemia-reperfusion injury, epilepsy, sepsis, septic shock, neurodegeneration (including Alzheimer's Disease), muscle fatigue or muscle cramp is described. The compounds are effective at very low doses, and so can be administered at doses at which serious side effects are not observed.

1 . Use of a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein R is C 1-4  alkoxy and X is OH; 
         for the manufacture of a medicament for the prevention, treatment, or amelioration of cancer, inflammation, auto-immune disease, ischemia-reperfusion injury, epilepsy, sepsis, septic shock, neurodegeneration (including Alzheimer's Disease), muscle fatigue or muscle cramp at a dosage which, after administration to a subject, gives rise to a peak plasma concentration that is less than the EC50 value of the compound at adenosine receptors at pH 7.4 
       
     
     
         2 . Use of a compound of formula (II): 
       
         
           
           
               
               
           
         
         wherein R is C 1-4  alkoxy and X is H; 
         for the manufacture of a medicament for the prevention, treatment, or amelioration of cancer, inflammation, auto-immune disease, ischemia-reperfusion injury, epilepsy, sepsis, septic shock, neurodegeneration (including Alzheimer's Disease), muscle fatigue or muscle cramp at a dosage which, after administration to a subject, gives rise to a peak plasma concentration that is less than the EC50 value of the compound at adenosine receptors at pH 7.4. 
       
     
     
         3 . Use according to  claim 1 , wherein the compound is 2-methoxyadenosine, 2-ethoxyadenosine, or 2-butyloxyadenosine. 
     
     
         4 . Use according to  claim 2 , wherein the compound is 3′-deoxy-2-propoxyadenosine, 3′-deoxy-2-isopropoxyadenosine, or 3′-deoxy-2-butoxyadenosine. 
     
     
         5 . Use according to any preceding claim for preventing, treating, or ameliorating arthritis, bowel inflammation, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, and other arthritic conditions, psoriasis, asthma, chronic obstructive pulmonary disease, fibrosis, multiple sclerosis, endotoxic shock, gram negative shock, toxic shock, hemorrhagic shock, adult respiratory distress syndrome, cerebral malaria TNF-enhanced HIV replication, TNF inhibition of AZT and DDI activity, organ transplant rejection, cachexia secondary to cancer, HIV, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcosis, bone resorption diseases, reperfusion injury (including damage caused to organs as a consequence of reperfusion following ischaemic episodes e.g. myocardial infarcts, strokes), autoimmune damage (including multiple sclerosis, Guillam Barre Syndrome, myasthenia gravis) graft v. host rejection, allograft rejections, fever and myalgia due to infection, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS related complex (ARC), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis and pyresis, irritable bowel syndrome, osteoporosis, cerebral malaria, bacterial meningitis, adverse effects from amphotericin B treatment, neurodegenerative diseases including Alzheimer's Disease, adverse effects from interleukin-2 treatment, adverse effects from OKT3 treatment, and adverse effects from GM-CSF treatment. 
     
     
         6 . Use according to any preceding claim at a dosage that results in plasma concentrations being maintained for more than 1 hour between one thousandth and one fifth of the EC50 value of the compound at adenosine receptors at pH 7.4. 
     
     
         7 . Use according to any of  claims 1  to  5  at a dosage that results in plasma concentrations being maintained for more than 1 hour between one thousandth and one fifth of the minimum plasma concentration of the compound that gives rise to bradycardia, hypotension or tachycardia side effects in animals of the same species as the subject to which the compound is to be administered. 
     
     
         8 . Use according to any preceding claim at a dosage of 0.01 to 15 mg/kg. 
     
     
         9 . Use according to any preceding claim at a dosage of 0.1 to 2 mg/kg. 
     
     
         10 . Use according to any preceding claim at a dosage of 0.6 to 1.2 mg/kg. 
     
     
         11 . Use according to any preceding claim, wherein the medicament is in the form of a unit dose comprising 1 to 500 mg of the compound. 
     
     
         12 . A pharmaceutical composition in unit dose form comprising up to 500 mg of a compound as defined in any of  claims 1  to  4 , and a physiologically acceptable carrier, excipient, or diluent. 
     
     
         13 . A method of prevention, treatment, or amelioration of cancer, inflammation, auto-immune disease, ischemia-reperfusion injury, epilepsy, sepsis, septic shock, neurodegeneration (including Alzheimer's Disease), muscle fatigue or muscle cramp, which comprises administering a compound as defined in any of  claims 1  to  4  to a subject in need of such prevention, treatment, or amelioration at a dosage which gives rise to a peak plasma concentration in the subject that is less than the EC50 value of the compound at adenosine receptors at pH 7.4. 
     
     
         14 . A method according to  claim 13  for preventing, treating, or ameliorating arthritis, bowel inflammation, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, and other arthritic conditions, psoriasis, asthma, chronic obstructive pulmonary disease, fibrosis, multiple sclerosis, endotoxic shock, gram negative shock, toxic shock, hemorrhagic shock, adult respiratory distress syndrome, cerebral malaria TNF-enhanced HIV replication, TNF inhibition of AZT and DDI activity, organ transplant rejection, cachexia secondary to cancer, HIV, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcosis, bone resorption diseases, reperfusion injury (including damage caused to organs as a consequence of reperfusion following ischaemic episodes e.g. myocardial infarcts, strokes), autoimmune damage (including multiple sclerosis, Guillam Barre Syndrome, myasthenia gravis) graft v. host rejection, allograft rejections, fever and myalgia due to infection, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS related complex (ARC), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis and pyresis, irritable bowel syndrome, osteoporosis, cerebral malaria, bacterial meningitis, adverse effects from amphotericin B treatment, adverse effects from interleukin-2 treatment, adverse effects from OKT3 treatment, and adverse effects from GM-CSF treatment. 
     
     
         15 . A method according to  claim 13  or  14 , wherein the compound is administered to the subject at a dosage that results in plasma concentrations of the compound in the subject being maintained for more than 1 hour between one thousandth and one fifth of the EC50 value of the compound at adenosine receptors at pH 7.4. 
     
     
         16 . A method according to any of  claims 13  to  15 , wherein the compound is administered to the subject at a dosage that results in plasma concentrations of the compound in the subject being maintained for more than 1 hour between one thousandth and one fifth of the minimum plasma concentration of the compound that gives rise to bradycardia, hypotension or tachycardia side effects in animals of the same species as the subject to which the compound is to be administered. 
     
     
         17 . A method according to any of  claims 13  to  16 , wherein the compound is administered at a dosage of 0.01 to 15 mg/kg. 
     
     
         18 . A method according to any of  claims 13  to  17 , wherein the compound is administered at a dosage of 0.1 to 2 mg/kg. 
     
     
         19 . A method according to any of  claims 13  to  18 , wherein the compound is administered at a dosage of 0.6 to 1.2 mg/kg. 
     
     
         20 . Use of a compound as defined in any of  claims 1  to  4  for discovery of drugs for the prevention, treatment, or amelioration of cancer, inflammation, ischemia-reperfusion injury, epilepsy, sepsis, septic shock, neurodegeneration (including Alzheimer's Disease), muscle fatigue or muscle cramp.