Drug Identification Method

Abstract

The invention relates to a method to identify compounds exert a transient effect(s) on one or more biological mediators of acute biological responses to acute stimuli or biological insult in subjects exposed to an acute stimulus or biological insult such as systemic exposure to bacterial LPS. The compounds are identified by measuring the effect of the test compound on the mediator of the acute stimulus or biological insult at times when an acute effect(s) to the stimulus or insult is occurring.

What is claimed is: 
     
         1 . A method to identify a biodynamic compound, comprising,
 (a) administering a test compound to a subject;   (b) exposing the subject to an acute stimulus or biological insult;   (c) measuring the effect of the test compound on a mediator of an acute biological response to the acute stimulus or biological insult; and   (d) identifying the test compound of step (c) that exerts a transient effect on the mediator of the acute stimulus or biological insult, wherein a biodynamic compound is identified.   
     
     
         2 . The method of  claim 1  further comprising,
 (e) comparing the biological effect of the test compound or the biodynamic compound with the biological effect of one or more reference compounds. 
 
     
     
         3 . The method of  claim 2  wherein the one or more reference compounds are one or more compounds selected from the group consisting of cortisol, dexamethasone and 17α-ethynylandrost-5-ene-3β, 7β, 17β-triol. 
     
     
         4 . The method of  claim 1 , wherein step (c) is conducted at a time when the acute response to the acute stimulus or biological insult is maximal or about maximal. 
     
     
         5 . The method of  claim 1  wherein the acute stimulus or biological insult is administration of a proinflammatory compound or composition to the subject. 
     
     
         6 . The method of  claim 5  wherein the proinflammatory compound or composition is bacterial lipopolysaccharide or TNFα. 
     
     
         7 . The method of  claim 6  wherein the proinflammatory compound or composition is bacterial lipopolysaccharide. 
     
     
         8 . The method of  claim 7  wherein the subject of step (a) is a mammal. 
     
     
         9 . The method of  claim 8  wherein the mammal is a rodent, optionally a mouse. 
     
     
         10 . The method of  claim 9  wherein the mediator of the acute biological response is NF-κB, IκB, IL-6 or C reactive protein. 
     
     
         11 . The method of  claim 10  wherein the mediator of the acute biological response is NF-κB or IκB. 
     
     
         12 . The method of  claim 11 , wherein step (c) is conducted at a time when the acute response to the bacterial lipopolysaccharide is maximal or about maximal. 
     
     
         13 . The method of  claim 12  wherein the subject's acute response to the bacterial lipopolysaccharide is measured at about 75-105 minutes after administration of the bacterial lipopolysaccharide by intraperitoneal injection and at one or two other time points before and/or after the administration of the bacterial lipopolysaccharide. 
     
     
         14 . The method of  claim 12  wherein the test compound modulates the activity or level of the mediator of the acute biological response by about 20% to about 75% in an assay in vitro. 
     
     
         15 . The method of  claim 12  wherein the test compound does not activate or antagonize a glucocorticoid receptor by more than about 30% when compared to a suitable reference activator or antagonist of the glucocorticoid receptor. 
     
     
         16 . The method of  claim 1  wherein the acute stimulus or biological insult is administration of ionizing radiation, a thermal burn or a chemical burn, a trauma or reperfusion of an ischemic tissue. 
     
     
         17 . The method of  claim 16  wherein the mediator of the acute biological response is NF-κB or IκB. 
     
     
         18 . The method of  claim 17  further comprising comparing the biological effect of the test compound or the biodynamic compound with the biological effect of one or more reference compounds. 
     
     
         19 . The method of  claim 18  wherein the one or more reference compounds are one or more compounds selected from the group consisting cortisol, dexamethasone, 17α-ethynylandrost-5-ene-3β,7β,17β-triol and 17α-ethynylandrost-5-ene-3α,7β,17β-triol. 
     
     
         20 . The method of  claim 1  wherein the subject of step (a) is a rodent, dog or non-human primate and further comprising,
 (f) administering the biodynamic compound of step (d) to a human and assessing a response to the biodynamic compound by the human, wherein a human response to the biodynamic compound is determined. 
 
     
     
         21 . The method of  claim 2  wherein the subject of step (a) is a rodent, dog or non-human primate and further comprising,
 (f) administering the biodynamic compound of step (d) to a human and assessing a response to the biodynamic compound by the human, wherein a human response to the biodynamic compound is determined. 
 
     
     
         22 . The method of  claim 21  wherein the one or more reference compounds are one or more compounds selected from the group consisting of cortisol, dexamethasone and 17α-ethynylandrost-5-ene-3β,7β,17β-triol. 
     
     
         23 . The method of  claim 1  wherein the acute stimulus or biological insult is administration of a proinflammatory compound or composition to the subject of step (a). 
     
     
         24 . The method of  claim 23  wherein the proinflammatory compound or composition is bacterial lipopolysaccharide or TNFα. 
     
     
         25 . The method of  claim 24  wherein the proinflammatory compound or composition is bacterial lipopolysaccharide. 
     
     
         26 . The method of  claim 25  wherein the is a rodent, optionally a mouse. 
     
     
         27 . The method of  claim 26  wherein the mediator of the acute biological response is NF-κB, IκB, IL-6 or C reactive protein. 
     
     
         28 . The method of  claim 27  wherein the mediator of the acute biological response is NF-κB or IκB.