Use of opioid antagonists

Abstract

Embodiments of the invention provide methods of attenuating, e.g., inhibiting or reducing, cellular proliferation and migration, particularly endothelial cell proliferation and migration, including that associated with angiogenesis, as well as attenuating cancerous tumor growth and metastasis, using opioid antagonists, including, but not limited to, those that are peripherally restricted antagonists.

1 . A method of treating a disorder characterized by hyperproliferation of cells overexpressing mu-opioid receptors, comprising administering to a subject in need thereof an effective amount of a peripheral opioid antagonist which is not a quaternary derivative of noroxymorphone. 
     
     
         2 . The method of  claim 1 , wherein the cells are endothelial cells. 
     
     
         3 . The method of  claim 2 , wherein the endothelial cells are vascular endothelial cells and the hyperproliferation of the vascular endothelial cells is abnormal/unwanted angiogenesis. 
     
     
         4 . The method of  claim 1 , wherein the peripheral opioid antagonist is a peripheral mu-opioid antagonist. 
     
     
         5 . The method of  claim 4  wherein the peripheral opioid antagonist is a tertiary morphinan, a tertiary benzomorphan, a PEGylated morphinan, or an amino or peptido substituted morphinan. 
     
     
         6 . The method of  claim 5 , wherein the peripheral opioid antagonist is a tertiary noroxymorphone. 
     
     
         7 . The method of  claim 4 , wherein the peripheral mu-opioid antagonist is polymeric conjugate of a mu-opioid antagonist. 
     
     
         8 . The method of  claim 7 , wherein the opioid antagonist is PEGlyated. 
     
     
         9 . The method of  claim 1 , wherein the peripheral opioid antagonist is administered in a mode that maintains a substantially constant plasma or intratumoral level. 
     
     
         10 . The method of  claim 1 , wherein the subject is taking concurrent opioid therapy. 
     
     
         11 . The method of  claim 1 , wherein the subject is not taking concurrent opioid therapy. 
     
     
         12 . A method of inhibiting a cancer which comprises cells that overexpress mu-opioid receptors compared to non-cancerous cells, comprising contacting the cancer cells with an effective amount of a peripheral opioid antagonist which is not a quaternary derivative of noroxymorphone. 
     
     
         13 . The method of  claim 12  wherein the opioid antagonist is administered to a human cancer patient and the amount of antagonist effective to attenuate the growth of the cancer cells. 
     
     
         14 . The method of  claim 12  wherein the cancer is colon, breast, non-small cell lung, pancreatic, prostate or gastric cancer. 
     
     
         15 . The method of  claim 4 , wherein the peripheral mu-opioid antagonist is a N-substituted piperidine. 
     
     
         16 . The method of  claim 15 , wherein the N-piperidine is a piperidine-N-alkylcarbonylate. 
     
     
         17 . The method of  claim 16 , wherein the piperidine-N-alkylcarbonylate is a N-alkylamino-3,4,4 substituted piperidine. 
     
     
         18 . The method of  claim 17 , wherein N-alkylamino-3,4,4 substituted piperidine is alvimopan. 
     
     
         19 . A method of attenuating tumor growth of a cancer, metastasis of a cancer, or both, in which the cancer comprises cells that overexpress mu-opioid receptors, comprising administering to a subject in need thereof an effective amount of a peripheral mu-opioid antagonist which is not a quaternary derivative of noroxymorphone to attenuate the growth and/or metastasis. 
     
     
         20 . A method of achieving an effect in a subject, comprising administering to the subject an effective amount of a peripheral mu-opioid antagonist which is not a quaternary derivative of noroxymorphone, wherein the effect is inhibiting cellular hyperproliferation, treating, cancer, inhibiting tumor growth or treating an autoimmune disease.