Method for comparison of the hemodynamic effects of equi-antinociceptive oral doses of drugs in anesthetized rats.
In a typical flowchart for discovery of novel analgesic (or other) agents, a critical path often involves maximization of the separation of the therapeutic endpoint from known adverse-effect (AE) endpoint(s). Although strategies can easily be designed for in vitro paradigms such as high-throughput screening, extension to in vivo testing can represent a major obstacle to the rapid progression to the next step in development. The problem can be particularly acute when the assessment is required for oral dosing, and when it is not known if the therapeutic and AE mechanism(s) of action are the same. As a case in point, alpha(2)-adrenoceptor (alpha(2)-AR) agonists have potential therapeutic use as analgesics, but they also produce cardiovascular (CV) effects. However, whether the two effects are inexorably linked has not been resolved, particularly for oral administration. The present study used a novel method for comparing the CV effects produced by alpha(2)-AR agonists given by intraduodenal administration to anesthetized rats at fixed ratios of the oral antinociceptive ED(50) dose of each agonist. The technique provided a useful screen of compounds. In addition,there was no correlation between CV endpoints and alpha(2A)-AR affinity, suggesting that oral alpha(2)-AR-mediated analgesia and CV effects might be separable or that other mechanisms might be involved.
Li
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The R.W. Johnson Pharmaceutical Research Institute, Welsh & McKean Roads, Spring House, PA 19477, USA. qli@PRIVS.JNJ.com
Connelly
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Codd
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Raffa
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D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004562:Electrocardiography; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051381:Rats; D020318:Rats, Long-Evans; D013047:Specific Pathogen-Free Organisms
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000700:Analgesics