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 surgical, therapeutic and diagnostic procedures. The solution preferably includes multiple pain and inflammation inhibitory agents, including at least one local anesthetic agent, 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.

1 . A solution for use in the inhibition of pain and inflammation at a wound during a surgical procedure, the solution including a plurality of agents comprising at least one pain and inflammation inhibitory agent and one or more local anesthetic agent in a liquid procedural irrigation carrier, wherein the total concentration of the one or more local anesthetic in the solution is in the range of 125 to 1,600,000 nanomolar, the plurality of agents being selected to act on a plurality of differing molecular targets, wherein each agent in the solution is included at a concentration or dosage that is sufficient such that the agents collectively provide a constant level of inhibitory effect at the wound during at least a portion of the procedure and that results in a plasma concentration that is less than a plasma concentration that would be required to achieve the same level of inhibitory effect at the wound when delivered systemically. 
   
   
       2 . The solution of  claim 1 , wherein the at least one local anesthetic agent in the solution is selected from the group consisting of benzocaine, bupivacaine, chloroprocaine, cocaine, etiodocaine, lidocaine, mepivacaine, pramoxine, prilocaine, procaine, proparacaine, ropivacaine, tetracaine, dibucaine, QX-222, QX-314, RAC-109, HS-37 and the pharmacologically active enantiomers thereof. 
   
   
       3 . The solution of  claim 1 , wherein the at least one local anesthetic agent in the solution is delivered locally at a concentration in the range of about 225,000 to about 1,100,000 nanomolar. 
   
   
       4 . The solution of  claim 1  which comprises at least one local anesthetic agent at a concentration of no greater than 750,000 nanomolar. 
   
   
       5 . The solution of  claim 4  which comprises at least one local anesthetic agent at a concentration of no greater than 500,000 nanomolar. 
   
   
       6 . The solution of  claim 2  which comprises lidocaine at a concentration of about 500 to 1,600,000 nanomolar. 
   
   
       7 . The solution of  claim 2  which comprises bupivacaine at a concentration of about 125 to 400,000 nanomolar. 
   
   
       8 . The solution of  claim 1 , wherein each of the plurality of agents in the solution other than local anesthetic agents is included at a concentration of no greater than 100,000 nanomolar, adjusted for dilution in the absence of metabolic transformation, at an intended local delivery site. 
   
   
       9 . The solution of  claim 8 , wherein each of the plurality of agents in the solution other than local anesthetic agents is included at a concentration of no greater than 10,000 nanomolar, adjusted for dilution, in the absence of metabolic transformation, at an intended local delivery site. 
   
   
       10 . The solution of  claim 1 , wherein the at least one local anesthetic agent is included at a sub-anesthetic concentration. 
   
   
       11 . The solution of  claim 1 , wherein the pain/inflammation inhibitory agents other than local anesthetic agents are selected from the group consisting of: serotonin receptor antagonists; serotonin receptor agonists; histamine receptor antagonists; bradykinin receptor antagonists; kallikrein inhibitors; tachykinin receptor antagonists; calcitonin gene-related peptide receptor antagonists; interleukin receptor antagonists; phospholipase inhibitors; cyclooxygenase inhibitors; lipooxygenase inhibitors; prostanoid receptor antagonists; leukotriene receptor antagonists; opioid receptor agonists; purinoceptor agonists and antagonists; and ATP-sensitive potassium channel openers. 
   
   
       12 . The solution of  claim 11 , wherein the selected pain/inflammation inhibitory agents other than the local anesthetic agents are 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. 
   
   
       13 . The solution of  claim 12 , wherein the solution comprises: a serotonin 2  receptor subtype antagonist included at a concentration of 50 to 500 nanomolar; a serotonin 3  receptor subtype antagonist included at a concentration of 200 to 2,000 nanomolar; a histamine 1  receptor subtype antagonist included at a concentration of 5 to 200 nanomolar; a serotonin receptor agonist included at a concentration of 10 to 200 nanomolar; a cyclooxygenase inhibitor included at a concentration of 500 to 5,000 nanomolar; a neurokinin 1  receptor subtype antagonist included at a concentration of 10 to 500 nanomolar; a neurokinin 2  receptor subtype antagonist included at a concentration of 10 to 500 nanomolar; a purinoceptor antagonist included at a concentration of 10,000 to 100,000 nanomolar; an ATP-sensitive potassium channel opener included at a concentration of 100 to 1,000 nanomolar; a calcium channel antagonist included at a concentration of 100 to 5,000 nanomolar; a bradykinin 1  receptor subtype antagonist included at a concentration of 10 to 200 nanomolar; a bradykinin 2  receptor subtype antagonist included at a concentration of 50 to 500 nanomolar; and a μ-opioid receptor subtype agonist included at concentration of 10 to 200 nanomolar. 
   
   
       14 . A solution for use in the inhibition of pain and inflammation at a wound during a surgical procedure, the solution including a plurality of agents comprising at least one pain and inflammation inhibitory agent and one or more local anesthetic agent in a liquid procedural irrigation carrier, wherein the total concentration of the one or more local anesthetic in the solution is in the range of 125 to 1,600,000 nanomolar, the plurality of agents being selected to act on a plurality of differing molecular targets, the concentration of each agent within the solution being the concentration of that agent which is desired to be delivered locally by continuous irrigation of the wound during at least a portion of the procedure in order to maintain a constant level of inhibitory effect at the wound. 
   
   
       15 . The solution of  claim 14 , wherein the at least one local anesthetic agent is included at a sub-anesthetic concentration.