Vascular irrigation solution and method for inhibition of pain, inflammation, spasm and restenosis

Abstract

A method and solution for perioperatively inhibiting a variety of pain, inflammation, spasm and restenosis processes resulting from cardiovascular or general vascular therapeutic and diagnostic procedures. The solution preferably includes multiple pain and inflammation inhibitory agents and spasm inhibitory agents at dilute concentration in a physiologic carrier, such as saline or lactated Ringer's solution. Specific preferred embodiments of the solution of the present invention for use in cardiovascular and general vascular procedures also include anti-restenosis agents. The solution is introduced luminally to continuously irrigate an arterial site during an operative/interventional or diagnostic procedure for preemptive inhibition of pain and inflammation, vascular and non-vascular smooth muscle spasm, and restenosis while avoiding undesirable side effects associated with oral, intramuscular, subcutaneous or intravenous application of larger doses of the agents. One preferred solution to inhibit pain, inflammation, vasospasm and restenosis includes a serotonin 2 antagonist, a cyclooxygenase inhibitor, an endothelin antagonist, an ATP-sensitive K + channel antagonist, a Ca 2+ channel antagonist, a nitric oxide donor, an anti-thrombin agent, a glycoprotein IIb/IIIa receptor blocker, a PKC inhibitor and a protein tyrosine kinase inhibitor.

1 . A solution comprising a plurality of agents selected from the group consisting of pain/inflammation inhibitory agents, spasm inhibitory agents and restenosis inhibitory agents in a liquid carrier adapted for perioperative delivery to an operative vascular site, wherein each of the agents is included at a concentration of no greater than 100,000 nanomolar, wherein the agents are selected to act on a plurality of differing molecular targets, and wherein the solution includes at least one restenosis inhibitory agent selected from the group consisting of: (a) antiplatelet agents selected from the group consisting of (i) direct thrombin inhibitors and receptor antagonists, (ii) purinoceptor receptor antagonists, (iii) thromboxane inhibitors and receptor antagonists and (iv) platelet membrane glycoprotein receptor antagonists; (b) inhibitors of cell adhesion molecules selected from the group consisting of (i) selectin inhibitors and (ii) integrin inhibitors; (c) anti-chemotactic agents; (d) interleukin receptor antagonists; and (e) intracellular signaling inhibitors selected from the group consisting of (i) protein kinase C inhibitors and protein tyrosine kinase inhibitors, (ii) modulators of intracellular protein tyrosine phosphatases, and (iii) inhibitors of src homology 2  domains. 
     
     
         2 . The solution of  claim 1 , wherein each of the plurality of agents in the solution is included at a concentration of no greater than 10,000 nanomolar. 
     
     
         3 . The solution of  claim 1 , wherein the liquid carrier comprises an irrigation fluid. 
     
     
         4 . The solution of  claim 1 , wherein the liquid carrier is selected from the group consisting of a biocompatible solvent, a suspension, a polymerizable or non-polymerizable gel, a paste and a salve. 
     
     
         5 . The solution of  claim 1 , wherein the solution includes at least one spasm inhibitory agent. 
     
     
         6 . The solution of  claim 5 , wherein the at least one spasm inhibitory agent is selected from the group consisting of: serotonin 2  receptor subtype antagonists; tachykinin receptor antagonists; nitric oxide donors; ATP-sensitive potassium channel openers; calcium channel antagonists; and endothelin receptor antagonists. 
     
     
         7 . The solution of  claim 6 , wherein the at least one spasm inhibitory agent is included at a concentration of: 0.1 to 10,000 nanomolar for serotonin 2  receptor antagonists; 0.1 to 10,000 nanomolar for tachykinin receptor antagonists; 1.0 to 10,000 nanomolar for nitric oxide donors; 0.1 to 10,000 nanomolar for ATP-sensitive potassium channel openers; 1.0 to 10,000 nanomolar for calcium channel antagonists; and 0.01 to 100,000 nanomolar for endothelin receptor antagonists. 
     
     
         8 . The solution of  claim 1 , wherein the solution includes at least one pain/inflammation inhibitory agent. 
     
     
         9 . The solution of  claim 8 , wherein the at least one pain/inflammation inhibitory agent is selected from the group consisting of: serotonin receptor antagonists; serotonin receptor agonists; histamine receptor antagonists; bradykinin receptor antagonists; kallikrein inhibitors; tachykinin receptor antagonists including neurokinin 1  receptor subtype antagonists and neurokinin 2  receptor subtype antagonists; calcitonin gene-related peptide receptor antagonists; interleukin receptor antagonists; phospholipase inhibitors including PLA 2  isoform inhibitors and PLC γ  isoform inhibitors; cyclooxygenase inhibitors; lipooxygenase inhibitors; prostanoid receptor antagonists including eicosanoid EP-1 receptor subtype antagonists and eicosanoid EP-4 receptor subtype antagonists and thromboxane receptor subtype antagonists; leukotriene receptor antagonists including leukotriene B 4  receptor subtype antagonists and leukotriene D 4  receptor subtype antagonists; opioid receptor agonists including μ-opioid receptor subtype agonists, δ-opioid receptor subtype agonists, and κ-opioid receptor subtype agonists; purinceptor agonists and antagonists including P 2Y  receptor agonists and P 2X  receptor antagonists; and ATP-sensitive potassium channel openers. 
     
     
         10 . The solution of  claim 9 , wherein the at least one pain/inflammation inhibitory agent is included at a concentration of: 0.1 to 10,000 nanomolar for serotonin receptor antagonists; 0.1 to 2,000 nanomolar for serotonin receptor agonists; 0.01 to 1,000 nanomolar for histamine receptor antagonists; 0.1 to 10,000 nanomolar for bradykinin receptor antagonists; 0.1 to 1,000 nanomolar for kallikrein inhibitors; 0.1 to 10,000 nanomolar for neurokinin 1  receptor subtype antagonists; 1.0 to 10,000 nanomolar for neurokinin 2  receptor subtype antagonists; 1 to 1,000 nanomolar for calcitonin gene-related peptide receptor antagonists; 1 to 1,000 nanomolar for interleukin receptor antagonists; 100 to 100,000 nanomolar for PLA 2  isoform inhibitors; 100 to 200,000 nanomolar for cyclooxygenase inhibitors; 100 to 10,000 nanomolar for lipooxygenase inhibitors; 100 to 10,000 nanomolar for eicosanoid EP-1 receptor subtype antagonists; 100 to 10,000 nanomolar for leukotriene B 4  receptor subtype antagonists; 0.1 to 500 nanomolar for μ-opioid receptor subtype agonists; 0.1 to 500 nanomolar for δ-opioid receptor subtype agonists; 0.1 to 500 nanomolar for κ-opioid receptor subtype agonists; 100 to 100,000 nanomolar for purinoceptor antagonists; and 0.1 to 10,000 nanomolar for ATP-sensitive potassium channel openers. 
     
     
         11 . A solution comprising a plurality of restenosis inhibitory agents in a liquid carrier adapted for perioperative delivery to an operative vascular site, wherein the agents are selected to act on a plurality of differing molecular targets, wherein each of the agents is included at a concentration of no greater than 100,000 nanomolar, and wherein each of the agents is selected from the group consisting of: (a) antiplatelet agents selected from the group consisting of (i) direct thrombin inhibitors and receptor antagonists, (ii) purinoceptor receptor antagonists, (iii) thromboxane inhibitors and receptor antagonists and (iv) platelet membrane glycoprotein receptor antagonists; (b) inhibitors of cell adhesion molecules selected from the group consisting of (i) selectin inhibitors and (ii) integrin inhibitors; (c) anti-chemotactic agents; (d) interleukin receptor antagonists; (e) intracellular signaling inhibitors selected from the group consisting of (i) protein kinase C inhibitors and protein tyrosine kinase inhibitors, (ii) modulators of intracellular protein tyrosine phosphatases, and (iii) inhibitors of src homology 2  domains; and (f) and calcium channel antagonists. 
     
     
         12 . The solution of  claim 11 , wherein each of the plurality of agents in the solution is included at a concentration of no greater than 10,000 nanomolar. 
     
     
         13 . The solution of  claim 11 , wherein the liquid carrier comprises an irrigation fluid. 
     
     
         14 . The solution of  claim 11 , wherein the liquid carrier is selected from the group consisting of a biocompatible solvent, a suspension, a polymerizable or non-polymerizable gel, a paste and a salve. 
     
     
         15 . The solution of  claim 11 , wherein the solution includes at least one spasm inhibitory agent. 
     
     
         16 . The solution of  claim 15 , wherein the at least one spasm inhibitory agent is selected from the group consisting of: serotonin 2  receptor subtype antagonists; tachykinin receptor antagonists; nitric oxide donors; ATP-sensitive potassium channel openers; calcium channel antagonists; and endothelin receptor antagonists. 
     
     
         17 . The solution of  claim 16 , wherein the at least one spasm inhibitory agent is included at a concentration of: 0.1 to 10,000 nanomolar for serotonin 2  receptor antagonists; 0.1 to 10,000 nanomolar for tachykinin receptor antagonists; 1.0 to 10,000 nanomolar for nitric oxide donors; 0.1 to 10,000 nanomolar for ATP-sensitive potassium channel openers; 1.0 to 10,000 nanomolar for calcium channel antagonists; and 0.01 to 100,000 nanomolar for endothelin receptor antagonists. 
     
     
         18 . The solution of  claim 11 , wherein the solution includes at least one pain/inflammation inhibitory agent. 
     
     
         19 . The solution of  claim 18 , wherein the at least one pain/inflammation inhibitory agent is selected from the group consisting of: serotonin receptor antagonists; serotonin receptor agonists; histamine receptor antagonists; bradykinin receptor antagonists; kallikrein inhibitors; tachykinin receptor antagonists including neurokinin 1  receptor subtype antagonists and neurokinin 2  receptor subtype antagonists; calcitonin gene-related peptide receptor antagonists; interleukin receptor antagonists; phospholipase inhibitors including PLA 2  isoform inhibitors and PLC γ  isoform inhibitors; cyclooxygenase inhibitors; lipooxygenase inhibitors; prostanoid receptor antagonists including eicosanoid EP-1 receptor subtype antagonists and eicosanoid EP-4 receptor subtype antagonists and thromboxane receptor subtype antagonists; leukotriene receptor antagonists including leukotriene B 4  receptor subtype antagonists and leukotriene D 4  receptor subtype antagonists; opioid receptor agonists including μ-opioid receptor subtype agonists, δ-opioid receptor subtype agonists, and κ-opioid receptor subtype agonists; purinceptor agonists and antagonists including P 2Y  receptor agonists and P 2x  receptor antagonists; and ATP-sensitive potassium channel openers. 
     
     
         20 . The solution of  claim 19 , wherein the at least one pain/inflammation inhibitory agent is included at a concentration of: 0.1 to 10,000 nanomolar for serotonin receptor antagonists; 0.1 to 2,000 nanomolar for serotonin receptor agonists; 0.01 to 1,000 nanomolar for histamine receptor antagonists; 0.1 to 10,000 nanomolar for bradykinin receptor antagonists; 0.1 to 1,000 nanomolar for kallikrein inhibitors; 0.1 to 10,000 nanomolar for neurokinin 1  receptor subtype antagonists; 1.0 to 10,000 nanomolar for neurokinin 2  receptor subtype antagonists; 1 to 1,000 nanomolar for calcitonin gene-related peptide receptor antagonists; 1 to 1,000 nanomolar for interleukin receptor antagonists; 100 to 100,000 nanomolar for PLA 2  isoform inhibitors; 100 to 200,000 nanomolar for cyclooxygenase inhibitors; 100 to 10,000 nanomolar for lipooxygenase inhibitors; 100 to 10,000 nanomolar for eicosanoid EP-1 receptor subtype antagonists; 100 to 10,000 nanomolar for leukotriene B 4  receptor subtype antagonists; 0.1 to 500 nanomolar for μ-opioid receptor subtype agonists; 0.1 to 500 nanomolar for δ-opioid receptor subtype agonists; 0.1 to 500 nanomolar for κ-Opioid receptor subtype agonists; 100 to 100,000 nanomolar for purinoceptor antagonists; and 0.1 to 10,000 nanomolar for ATP-sensitive potassium channel openers.