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.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]The present application is a continuation of copending U.S. application Ser. No. 10 / 180,815 filed Jun. 25, 2002, which is a continuation of U.S. application Ser. No. 09 / 388,837 filed Sep. 1, 1999, now U.S. Pat. No. 6,413,961, which is a continuation-in-part of U.S. application Ser. No. 09 / 072,913 filed May 4, 1998, now U.S. Pat. No. 6,261,279, which is a continuation of U.S. patent application Ser. No. 08 / 670,699 filed Jun. 26, 1996, now U.S. Pat. No. 5,820,583, which is a continuation-in-part of International Patent Application PCT / US95 / 16028 filed Dec. 12, 1995, which designates the United States and which is a continuation-in-part of U.S. patent application Ser. No. 08 / 353,775 filed Dec. 12, 1994 (abandoned), and claims the benefit of U.S. Provisional Application Ser. No. 60 / 098,977 filed Sep. 2, 1998, priority of the filing date of each application which are hereby claimed under 35 U.S.C. §120 or §119(e).I. FIELD OF THE INVENTION[0002...

AI Technical Summary

Benefits of technology

The present invention provides a solution for inhibiting pain, inflammation, spasm, and restenosis at a surgical site by delivering a mixture of multiple agents in low concentrations through a perioperative delivery method. The solution contains anti-pain / anti-inflammation agents, including serotonin receptor antagonists, histamine receptor antagonists, bradykinin receptor antagonists, and others. The solution can be delivered in a lower concentration than other methods, and can be used in various surgical procedures to prevent pain, inflammation, spasm, and restenosis. The invention also provides a method for manufacturing the solution for continuous irrigation of an operative site or wound during a surgical procedure.

Problems solved by technology

Conventional physiologic irrigation fluids do not provide analgesic, anti-inflammatory, anti-spasm and anti-restenotic effects.

The high incidence of nausea and vomiting related to opioids is especially problematic in the postoperative period.

Therapeutic agents aimed at treating postoperative pain while avoiding detrimental side effects are not easily developed because the molecular targets for these agents are distributed widely throughout the body and mediate diverse physiological actions.

Despite the significant clinical need to inhibit pain and inflammation, as well as vasospasm, smooth muscle spasm and restenosis, methods for the delivery of inhibitors of pain, inflammation, spasm and restenosis at effective dosages while minimizing adverse systemic side effects have not been developed.

As an example, conventional (i.e., intravenous, oral, subcutaneous or intramuscular) methods of administration of opiates in therapeutic doses frequently is associated with significant adverse side effects, including severe respiratory depression, changes in mood, mental clouding, profound nausea and vomiting.

In addition, prostaglandins also are known to cause pain and inflammation.

Cyclooxygenase inhibitors are associated with some adverse systemic side effects when applied conventionally.

However, there are differences in pharmacology and receptor sequences between human and animal species.

Furthermore, antagonists of these mediators currently are not used for postoperative pain treatment.

Therefore, the lack of efficacy in reducing postoperative pain in the previously-mentioned studies would appear to conflict with the proposal of a role for endogenous 5-HT in acute pain.

With oral administration, the concentration of amitriptyline in the operative site tissues may not have been sufficiently high for a long enough time period to inhibit the activity of postoperatively released 5-HT in the second study.

(3) Since multiple inflammatory mediators exist, and studies have demonstrated synergism between the inflammatory mediators, blocking only one agent (5-HT) may not sufficiently inhibit the inflammatory response to tissue injury.

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