Inhibition of synovial plasma extravasation by preemptive administration of an antiinflammatory irrigation solution in the rat knee.
Inflammation and hyperalgesia during surgical procedures are caused by the local release of multiple inflammatory mediators. We used a rat knee joint model of acute inflammation (synovial plasma extravasation) to determine whether preemptive intraarticular irrigation of the antiinflammatory drugs ketoprofen, amitriptyline, or oxymetazoline, alone or in combination, can reduce inflammatory soup-induced plasma extravasation. These three drugs were selected because of their abilities to collectively inhibit the inflammatory effects of biogenic amines, eicosanoid production, and the release of neuropeptides from C-fiber terminals. Synovial perfusion of each one of the three drugs 10 min before, and then in combination with, the inflammatory soup (bradykinin, 5-hydroxytryptamine, and mustard oil) did not reduce plasma extravasation. Similarly, two-drug combinations did not significantly reduce inflammatory soup-induced plasma extravasation. The combination of all three drugs (amitriptyline, ketoprofen, and oxymetazoline) produced a dramatic inhibition of plasma extravasation and was more effective than any of the two-drug combinations. A comparison between the preemptive (10 min before inflammatory soup perfusion) and postinflammatory administration (10 min after inflammatory soup perfusion) showed that the postinflammatory administration of the three-drug solution lost all ability to inhibit inflammatory soup-induced plasma extravasation. We conclude that acute synovial inflammation, which is induced and maintained by multiple mediators, can be substantially inhibited only by the preemptive administration of a drug combination that targets multiple inflammatory mediators.


CONCLUSIONS
Preemptive, intraarticular irrigation of a combination of multiple antiinflammatory drugs is a novel and potentially effective method for reducing the synovial inflammatory response, such as that during arthroscopy. In this study, a three-drug combination infusion was statistically superior to one- or two-drug infusions in a rat model.
Grond
S
S
Department of Anesthesia, University of California-San Francisco, 513 Parnassus Ave., San Francisco, CA 94143-0464, USA.
Demopulos
G
G
Herz
J
J
Pierce Palmer
P
P
D000639:Amitriptyline / Q000008:administration & dosage; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D002199:Capillary Permeability / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage*; D005070:Evans Blue; D018836:Inflammation Mediators / Q000378:metabolism; D007660:Ketoprofen / Q000008:administration & dosage; D007719:Knee Joint / Q000098:blood supply; D008297:Male; D010109:Oxymetazoline / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D011969:Receptors, Histamine H1 / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000008:administration & dosage*; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage*; D013585:Synovitis / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control; D007507:Therapeutic Irrigation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D018836:Inflammation Mediators; D011969:Receptors, Histamine H1; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D000639:Amitriptyline; D005070:Evans Blue; D010109:Oxymetazoline; D007660:Ketoprofen