Irrigation solution and methods for inhibition of tumor cell adhesion, pain and inflammation

Abstract

A method and solution for perioperatively inhibiting tumor cell adhesion and a variety of pain and inflammation processes at wounds from general surgical procedures including oral/dental procedures. The solution preferably includes at least one anti-tumor cell adhesion agent and multiple pain and inflammation inhibitory agents at dilute concentration in a physiologic carrier, such as saline or lactated Ringer's solution. The solution is applied by continuous irrigation of a wound during a surgical procedure for preemptive inhibition of pain and while avoiding undesirable side effects associated with oral, intramuscular, subcutaneous or intravenous application of larger doses of the agents. One preferred solution to inhibit tumor cell adhesion, pain and inflammation includes at least one anti-tumor cell adhesion agent, a serotonin 2 antagonist, a serotonin 3 antagonist, a histamine antagonist, a serotonin agonist, a cyclooxygenase inhibitor, a neurokinin 1 antagonist, a neurokinin 2 antagonist, a purinoceptor antagonist, an ATP-sensitive potassium channel opener, a calcium channel antagonist, a bradykinin 1 antagonist, a bradykinin 2 antagonist and a μ-opioid agonist.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:  
     
         1 . A solution for use in inhibiting tumor cell adhesion, pain and inflammation at a wound during a surgical procedure, comprising: 
 therapeutically effective amounts of at least one tumor-cell anti-adhesion agent and at least one pain/inflammation inhibitory agent in a dilute solution within a liquid irrigation carrier, the agents being selected to act on differing molecular targets, the at least one tumor-cell anti-adhesion agent being selected to be deliverable by irrigation of the wound to provide without metabolic transformation a therapeutic anti-adhesion effect.    
     
     
         2 . The solution of  claim 1 , wherein said anti-adhesion agent is selected from the group consisting of CD44 receptor antagonists, integrin receptor antagonists and selectin receptor antagonists.  
     
     
         3 . The solution of  claim 1 , wherein said anti-adhesion agent comprises an inhibitor of matrix metalloproteinases.  
     
     
         4 . The solution of  claim 1 , wherein the pain/inflammation inhibitory 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 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; purinoceptor agonists and antagonists including P 2Y  receptor agonists and P 2X  receptor antagonists; and ATP-sensitive potassium channel openers.  
     
     
         5 . The solution of  claim 1 , wherein the pain/inflammation inhibitory 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 including neurokinin 1  receptor subtype antagonists and neurokinin 2  receptor subtype antagonists; calcitonin gene-related peptide receptor antagonists; phospholipase inhibitors including PLA 2  isoform inhibitors and PLC γ  isoform 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; purinoceptor agonists and antagonists including P 2Y  receptor agonists and P 2X  receptor antagonists; and ATP-sensitive potassium channel openers.  
     
     
         6 . The solution of  claim 1 , further comprising a plurality of pain/inflammation inhibitory agents.  
     
     
         7 . The solution of  claim 1 , wherein each of the agents in the solution applied is included at a concentration or dosage that is sufficient to provide a level of inhibitory effect at the wound when locally applied, and that results in a plasma concentration that is less than a plasma concentration which would be required to provide the same level of inhibitory effect at the wound if applied systemically.  
     
     
         8 . The solution of  claim 1 , wherein each of the plurality of agents in the solution is delivered locally at a concentration of no greater than 100,000 nanomolar.  
     
     
         9 . The solution of  claim 8 , wherein each of the plurality of agents in the solution is delivered locally at a concentration of no greater than 10,000 nanomolar.  
     
     
         10 . A solution for use in the inhibition of tumor cell attachment and implantation during a surgical procedure within a body cavity of a patient in need of such treatment, comprising: 
 therapeutically effective amounts of at least one tumor-cell anti-adhesion agent and at least one pain/inflammation inhibitory agent in a dilute solution within a liquid irrigation carrier, the agents being selected to act on differing molecular targets, the at least one tumor-cell anti-adhesion agent being selected to be deliverable by irrigation in the body cavity to provide without metabolic transformation a therapeutic anti-tumor cell attachment and anti-tumor cell implantation effect.    
     
     
         11 . A solution for use in inhibiting tumor cell adhesion, pain and inflammation at a wound during a surgical procedure, comprising: 
 therapeutically effective amounts of at least one tumor-cell anti-adhesion agent and at least one pain/inflammation inhibitory agent in a dilute solution within a liquid irrigation carrier, the agents being selected to act on differing molecular targets, the at least one tumor-cell anti-adhesion agent being selected from the group consisting of CD44 receptor antagonists, integrin receptor antagonists, selectin receptor antagonists and inhibitors of matrix metalloproteinases and being selected to be deliverable by irrigation of the wound to provide without metabolic transformation a therapeutic anti-adhesion effect.    
     
     
         12 . A solution for use in inhibiting tumor cell adhesion, pain and inflammation at a wound during a surgical procedure, comprising: 
 therapeutically effective amounts of at least one tumor-cell anti-adhesion agent and at least one pain/inflammation inhibitory agent in a dilute solution within a liquid carrier, the agents being selected to act on a plurality of differing molecular targets, the at least one tumor-cell anti-adhesion agent being selected from the group consisting of CD44 receptor antagonists, integrin receptor antagonists and selectin receptor antagonists, and being selected to be deliverable to the wound to provide without metabolic transformation a therapeutic anti-adhesion effect.    
     
     
         13 . A solution for use in inhibiting tumor cell adhesion at a wound during a surgical procedure, comprising: 
 therapeutically effective amounts of a first tumor-cell anti-adhesion agent and a second tumor-cell anti-adhesion agent in a dilute solution within a liquid irrigation carrier, the agents being selected to act on differing molecular targets, at least one of the agents being selected to be deliverable by irrigation of the wound to provide without metabolic transformation a therapeutic anti-adhesion effect.    
     
     
         14 . The solution of  claim 13 , wherein each of the agents in the solution applied is included at a concentration or dosage that is sufficient to provide a level of inhibitory effect at the wound when locally applied, and that results in a plasma concentration that is less than a plasma concentration which would be required to provide the same level of inhibitory effect at the wound if applied systemically.  
     
     
         15 . The solution of  claim 13 , wherein each of the plurality of agents in the solution is delivered locally at a concentration of no greater than 100,000 nanomolar.  
     
     
         16 . The solution of  claim 13 , wherein each of the plurality of agents in the solution is delivered locally at a concentration of no greater than 10,000 nanomolar.  
     
     
         17 . The solution of  claim 13 , further comprising at least one pain/inflammation inhibitory agent.  
     
     
         18 . The solution of  claim 17 , wherein each of the agents in the solution applied is included at a concentration or dosage that is sufficient to provide a level of inhibitory effect at the wound when locally applied, and that results in a plasma concentration that is less than a plasma concentration which would be required to provide the same level of inhibitory effect at the wound if applied systemically.  
     
     
         19 . The solution of  claim 17 , wherein each of the plurality of agents in the solution is delivered locally at a concentration of no greater than 100,000 nanomolar.  
     
     
         20 . The solution of  claim 17 , wherein each of the plurality of agents in the solution is delivered locally at a concentration of no greater than 10,000 nanomolar.  
     
     
         21 . The solution of  claim 13 , wherein at least one of the agents is selected from the group consisting of CD44 receptor antagonists, integrin receptor antagonists, selectin receptor antagonists and inhibitors of matrix metalloproteinases.  
     
     
         22 . A solution for use in inhibiting tumor cell adhesion, pain and inflammation at a wound during a surgical procedure, comprising: 
 therapeutically effective amounts of at least one tumor-cell anti-adhesion agent and at least one pain/inflammation inhibitory agent in a dilute solution within a sustained release carrier, the agents being selected to act on differing molecular targets, the at least one tumor-cell anti-adhesion agent being selected to provide without metabolic transformation a therapeutic anti-adhesion effect at the wound.    
     
     
         23 . The solution of  claim 22 , wherein the sustained release carrier comprises a gel.  
     
     
         24 . The solution of  claim 22 , wherein said anti-adhesion agent is selected from the group consisting of CD44 receptor antagonists, integrin receptor antagonists and selectin receptor antagonists.  
     
     
         25 . A solution for use in inhibiting tumor cell adhesion at a wound during a surgical procedure, comprising: 
 therapeutically effective amounts of a first tumor-cell anti-adhesion agent and a second tumor-cell anti-adhesion agent in a dilute solution within a sustained release carrier, the agents being selected to act on differing molecular targets, at least one of the agents being selected to provide without metabolic transformation a therapeutic anti-adhesion effect.    
     
     
         26 . The solution of  claim 25 , wherein the sustained release carrier comprises a gel.  
     
     
         27 . The solution of  claim 25 , wherein said anti-adhesion agent is selected from the group consisting of CD44 receptor antagonists, integrin receptor antagonists and selectin receptor antagonists.  
     
     
         28 . A solution for use in inhibition of tumor cell attachment and implantation during a surgical procedure within a body cavity of a patient in need of such treatment, comprising: 
 therapeutically effective amounts of at least one tumor-cell anti-adhesion agent and at least one pain/inflammation inhibitory agent in a dilute solution within a sustained release carrier, the agents being selected to act on differing molecular targets, the at least one tumor-cell anti-adhesion agent being selected to provide in the body cavity without metabolic transformation a therapeutic anti-tumor cell attachment and anti-tumor cell implantation effect.    
     
     
         29 . A solution for use in inhibition of tumor cell attachment and implantation during a surgical procedure within a body cavity of a patient in need of such treatment, comprising: 
 therapeutically effective amounts of a first tumor-cell anti-adhesion agent and a second tumor-cell anti-adhesion agent in a dilute solution within a sustained release carrier, the agents being selected to act on differing molecular targets, at least one of the agents being selected to provide in the body cavity without metabolic transformation a therapeutic anti-tumor cell attachment and anti-tumor cell implantation effect.