HK1008983B - Irrigation solution and method for inhibition of pain, inflammation and spasm - Google Patents

Description

Irrigation solution and method for inhibiting pain, inflammation and spasm

I. Field of the invention

The present invention relates to surgical irrigation fluids and methods, particularly for use in anti-inflammatory, anti-pain, and anti-spasm surgical irrigation fluids.

II. background of the invention

Arthroscopy is a surgical examination that operates by placing a camera, connected to a remote light source and video monitor, into an anatomically significant joint (e.g., knee, shoulder, etc.) through a small incision in the overlying skin and joint capsule. Through a similar incision, surgical instruments may also be placed into the joint for application under arthroscopic guidance. With the increasing sophistication of arthroscopists, many surgical procedures that were previously required to be performed by "open" surgical techniques are now performed by arthroscopy. Such procedures include, for example, meniscectomy and ligament reconstruction in the knee segment, shoulder-shoulder angioplasty and rotator cuff debridement, and elbow synovectomy. Wrist and ankle endoscopy has also become routine as a result of the expansion of surgical indications and the development of small diameter arthroscopes.

During each arthroscopy, a physiological irrigant (e.g., saline or lactated ringer's solution) continually irrigates the joint, distends the joint capsule, and removes surgical debris, thereby providing a clearer intra-articular view. U.S. patent 4,504,493 to masshore discloses an aqueous equimolar solution of glycerol as a non-conductive and visually transparent irrigation solution for arthroscopic examinations.

Irrigation techniques may also be used for other types of procedures, such as intravascular diagnostic and therapeutic procedures, urological procedures, and treatment of burns and surgical wounds. In each case, physiological fluids are used to irrigate a wound, or a body cavity, or a passage. Conventional physiological irrigation solutions do not provide analgesic and anti-inflammatory effects.

Relief of pain and suffering in post-operative patients is an interesting aspect in clinical medicine, especially in the case of an increasing number of patients in the outpatient setting of surgery each year. Currently the most widely used analgesics, cyclooxygenase inhibitors (e.g. ibuprofen) and opioids (e.g. morphine, fentanyl) have significant side effects, including gastrointestinal irritation or bleeding and respiratory depression. The high incidence of nausea and vomiting associated with opioids during the post-operative period is even more problematic. Therapeutic agents aimed at treating post-operative pain while avoiding damaging side effects are not readily developed because the molecular targets of these analgesics are located throughout the body and mediate a wide range of physiological effects. Although the clinical need for inhibition of pain and inflammation, as well as vasospasm and smooth muscle spasm is apparent, methods of inhibiting pain transmission and inhibitors of inflammation and spasm that are effective for therapeutic purposes with minimal systemic side effects have not been developed. By way of example, opioid agonists are administered in therapeutic doses by conventional methods (e.g., intravenous, oral, or intramuscular) and are often associated with several significant adverse side effects, including severe respiratory depression, mood changes, mental confusion, and profound nausea and vomiting.

Previous studies have demonstrated the ability of certain endogenous substances such as 5-hydroxytryptamine (sometimes referred to herein simply as "5-HT"), bradykinin and histamine to produce pain and inflammation. Sicuteri, f., et al, 5-hydroxytryptamine-bradykinin potentiation of human pain receptors, Life sciences (Life Sci)4, pp 309-; rosenthal, s.r., histamine as a chemical mediator of skin pain, journal of skin research (j. invest.dermat.)69, pp.98-105 (1977); richardson, b.p., et al, identification of the 5-hydroxytryptamine M-receptor subgroup and the specific blocking effect thereof by a novel class of drugs, Nature 316, pp.126-131 (1985); whalley, E.T.et.al., action of agonist and antagonist peptides, Nauyn-Schmiedeb pharmacological literature (Nauyn-Schmiedeb Arch. Pharmacol.)36, pp.652-57 (1987); lang, e.et.al, chemosensitivity of fine afferents from rat skin in vitro. Journal of neurophysiology (J.neurophysiol)63, pp.887-901 (1990).

For example, it has been demonstrated that 5-HT can be induced by 5-HT when applied to human blisters (exfoliative skin)₃Pain inhibited by receptor antagonists, Richardson et al 1985. Similarly, peripheral application of bradykinin produces pain which can be blocked by bradykinin receptor antagonists, Sicuteri et al, 1965; whalley et al, 1987; dray, a., et al, bradykinin and inflammatory pain, neuroscience movement (Trends neurosci.16, pp.99-104 (1993)). Peripheral application of histamine produces vasodilation, itching and pain that can be inhibited by histamine receptor antagonists. Rosenthal, 1977; douglas, w.w., "histamine and 5-hydroxytryptamine and antagonists thereof" are described in: goodman, l.s., et al, ed., pharmacological Basis for therapy (The pharmacological Basis of Thorapeutics), macmillan publishing Company, New York, pp.605-638 (1985); rumore, m.m., et.al., analgesic action of antihistamines, life scienceScience (Life Sci)36, pp.403-416 (1985). The combined use of these three agonists (5-HT bradykinin and histamine) has been shown to produce a synergistic pain-inducing effect, producing a persistent intense pain signal, Sicuteri et al, 1965; richardson et al, 1985; kessler, w., et al, inflammatory mediation of agonism of cutaneous afferent nerve endings and substance P modulation by in vitro co-application. Experimental brain studies, (exp. brainres.)91, pp.467-476 (1992).

In vivo, 5-HT is localized in platelets and central neurons, histamine is found in mast cells, and bradykinin is produced from large precursor molecules during tissue trauma, pH changes, and temperature changes. Since 5-HT is released from platelets at the site of tissue injury in large amounts, resulting in plasma 5-HT levels that are 20-fold higher than the resting levels (Ashton, J.H.et. al., 5-hydroxytryptamine as a mediator of the circulatory flow rate changes in the coronary arteries of dogs with vascular stenosis, Circulation 73, pp.572-578(1986)), it is possible that endogenous 5-HT may play a role in the development of post-operative pain, hyperalgesia and inflammation. In fact, it has been demonstrated that activated platelets can stimulate peripheral nociceptors in vitro. Ringkamp, m., et al, activated human plasma platelets stimulate rat skin nociceptors in vitro, neuroscience communications (neurosci. lett.)170, pp.103-106 (1994). Similarly, histamine and bradykinin are also released into tissues during tissue injury. Kimura, e.et.al, experimental coronary artery occlusion post-coronary sinus blood bradykinin level changes, journal of american heart disease (AmHeart J.)85, pp.635-647 (1973); douglas, 1985; dray et al, (1993).

In addition, prostaglandins are known to cause pain and inflammation. Cyclooxygenase inhibitors such as ibuprofen are commonly used to block the production of prostaglandins, thereby reducing prostaglandin-mediated pain and inflammation. Flower, r.j., et.al, analgesic and antipyretic, and anti-inflammatory; the medicines used in the treatment of gout are shown as follows: goodman, L.S., et al, eds., pharmacological Basis for therapy (the pharmacological Basis of Therapeutics), MacMillan publishing company, New York, pp.674-715 (1985). Cyclooxygenase inhibitors are associated with certain deleterious systemic side effects when used in a conventional manner. For example, indomethacin or ketorolac have been recognized to have gastrointestinal and renal adverse effects.

As discussed, 5-HT, histamine, bradykinin and prostaglandins can cause pain and inflammation. The various receptors by which these substances mediate effects on their surrounding tissues have been recognized and discussed for 20 years. Most studies have been performed in rats or other animal models. However, there are differences in pharmacology and receptor sequences between humans and animals. To date, no study has conclusively demonstrated the importance of 5-HT, bradykinin or histamine in the production of postoperative pain in the human hand.

Moreover, antagonists of these mediators are not currently used for the treatment of post-operative pain. A class of drugs known as 5-HT and norepinephrine uptake antagonists, including amitriptyline, has been used orally for chronic pain with moderate efficacy. However, it is believed that the mechanisms of chronic and acute pain states differ considerably. In fact, the perioperative use of amitriptyline for the treatment of acute pain in two studies did not demonstrate that amitriptyline has pain-reducing effects. Levine, j.d., et.al, Depression enhances the analgesic effect of opiates on postoperative pain. Pain (Pain)27, pp.45-49 (1986); kerrick, J.M., et.al., low dose amitriptyline as an adjuvant to opioid therapy to correct post-surgical pain: placebo-controlled clinical trial, Pain (Pain)52, pp.325-30 (1993). The drugs were administered orally in both studies. The second study indicated that oral amitriptyline actually reduced systemic sensation in postoperative patients, probably due to the affinity of this drug for polyamine receptors in the brain.

Amitriptyline, in addition to blocking the uptake of 5-HT and norepinephrine, is a potent 5-HT receptor antagonist. Therefore, the lack of efficacy in reducing postoperative pain in the aforementioned studies seems to be in conflict with the implications of endogenous 5-HT play in acute pain. There are several reasons why amitriptyline was found in these two studies to be unable to alleviate acute pain. (1) Amitriptyline was used starting one week before surgery until the end of the evening before surgery in the first study, while amitriptyline was used only after surgery in the second study. Amitriptyline is therefore not present in the surgical site tissue during the actual tissue damage phase, i.e., the period when 5-HT is said to be released. (2) Amitriptyline is generally thought to be metabolized completely by the liver. With oral administration, the concentration of amitriptyline in the surgical site tissue may not be maintained at a sufficiently high level for a significant period of time to inhibit the post-operative release of 5-HT in the second study. (3) Since studies have demonstrated a synergistic effect between various inflammatory mediators, blocking only one inflammatory mediator (5-HT) is not sufficient to inhibit the inflammatory response to tissue damage, given the presence of multiple inflammatory mediators.

Several studies have demonstrated very high concentrations (1% -3% solution, i.e., 10-30mg/ml) of histamine 1 (H)₁) Receptor antagonists have the ability to act as a surgical local anesthetic. It is generally believed that this anesthetic effect is not via H₁The receptor is mediated, but as a result of non-specific interactions with neuronal membrane sodium channels (similar to the effects of lidocaine). Because of the side effects (e.g., sedation) associated with these high "anesthetic" concentrations of histamine receptor antagonists, topical application of histamine receptor antagonists is not currently used in perioperative treatment.

Summary of the invention

The present invention provides a low concentration (i.e., dilute) solution composed of a mixture of components aimed at locally inhibiting pain and inflammatory mediators in physiological electrolyte-bearing fluids. The present invention also provides a method of use for perioperative administration of an irrigation fluid containing these ingredients directly to a surgical site where it acts locally at the neuroreceptor level to provide a pre-controlled pain and inflammation at the site. In the solutionThe anti-pain/anti-inflammatory agent of (a) includes drugs selected from the following classes of receptor antagonists, receptor agonists and enzyme inhibitors, wherein each class of drugs exerts pain and inflammation inhibitory effects through different molecular mechanisms of action: (1) 5-hydroxytryptamine receptor antagonists; (2) a 5-hydroxytryptamine receptor agonist; (3) a histamine receptor antagonist; (4) bradykinin receptor antagonists; (5) a kallikrein inhibitor; (6) tachykinin receptor antagonists including neurokinin 1 and neurokinin 2 receptor subtype antagonists; (7) a Calcitonin Gene Related Peptide (CGRP) receptor antagonist; (8) an interleukin receptor antagonist; (9) an enzyme inhibitor acting on the pathway of arachidonic acid metabolite synthesis, comprising: (a) phosphatase inhibitors including PLA₂Isotype inhibitors and PLCr isotype inhibitors, (b) cyclooxygenase inhibitors, and (c) lipoxygenase (lipoxygenase) inhibitors; (10) prostanoid receptor antagonists including eicosanoid EP-1 and EP-4 receptor subtype antagonists and thromboxane receptor subtype antagonists; (11) leukotriene receptor antagonists include leukotriene B₄Receptor subtype antagonists and leukotriene D₄A receptor subtype antagonist; (12) opioid receptor agonists including mu-opiates, delta-opiates and kappa-opiate receptor subtype agonists; (13) purine receptor (purinoceptor) agonists and antagonists, including P_2XReceptor antagonists and P_2YA receptor agonist; (14) adenosine Triphosphate (ATP) -sensitive potassium channel openers; calcium channel antagonists. Each of the above drugs acts as an anti-inflammatory agent and an anti-nociceptive, i.e., anti-pain or analgesic agent. To meet a particular application, it is necessary to select a drug from these types of compounds.

Several preferred embodiments of the solutions of the present invention also include antispasmodics for particular applications. For example, antispasmodics may be included in solutions used in vascular procedures to control vasospasm, and in solutions used in urinary tract surgery to control spasticity of the urinary tract and bladder walls. For such applications, the antispasmodic agent is utilized in the form of a solution of the present invention. For example, the solution may contain an anti-pain/anti-inflammatory agent which may also act as an anti-spasmodic agent. Suitable anti-inflammatory/anti-pain agents which may also act as antispasmodics include 5-hydroxytryptamine receptor antagonists, tachykinin receptor antagonists, ATP-sensitive potassium channel openers and calcium channel antagonists. Other anti-pain/anti-inflammatory agents that may be specifically utilized in the solution form of the present invention based on their anti-spasmodic properties include endothelin receptor antagonists and nitric oxide donors (enzyme activators).

The invention also provides methods of preparing a medicament formulated as a dilute rinse solution for use in continuous irrigation of a surgical site or wound during a surgical procedure. The method comprises dissolving a plurality of anti-pain/anti-inflammatory agents in a physiological electrolyte carrier fluid, and for some applications, an anti-spasmodic agent, preferably at a concentration of no more than 100,000nM, most preferably no more than 10,000nM for each pharmaceutical agent.

The method of the invention can be used to treat wounds, such as joint tissue during arthroscopy, by applying a low concentration of a complex solution of antagonists to various anti-pain, inflammation and spasm mediators and an inhibitory receptor agonist directly to the wound. Since the active ingredients of the solution are applied directly to the surgical tissue in a continuous manner, these agents can be effectively used in extremely low concentrations compared to those required to produce the therapeutic effect of the same agents when administered orally, intramuscularly and intravenously. The advantages of low dose drugs are three. The most important point is that there are no systemic side effects that often limit the use of these drugs. The low therapeutic dose of the drug used in the solution of the present invention minimizes intravascular absorption of the ingested drug, thereby minimizing systemic side effects. Secondly, the drug selected for a particular application in the solution of the invention is highly specific to the (pain and inflammation) mediator on which it is intended to act. This specificity is maintained by the low dose of drug used. Finally, the cost per liter of these active drugs is extremely low.

Local administration of these drugs via irrigation also ensures a concentration at the peripheral target site regardless of differences in metabolism, blood flow, etc. between patients. Because of the direct mode of administration, a constant therapeutic concentration can be achieved. In this way, dose control is improved. The direct topical application of these pharmacologically active agents to a wound or surgical site also significantly reduces the degradation of these agents by extracellular processes such as first and second pass effects that may occur if the agents are administered by oral, intravenous and intramuscular routes. This is particularly true for peptide drugs that have (analgesic and anti-inflammatory) activity, which are rapidly metabolized. For example, some of the following classes of drugs are peptides: bradykinin receptor antagonists; tachykinin receptor antagonists; opioid receptor agonists; CGRP receptor antagonists; and interleukin receptor antagonists. The continuous topical application to the wound or surgical site minimizes degradation, or otherwise continually renews the portion of the drug that may be degraded, to ensure that a local therapeutic concentration sufficient to maintain receptor occupancy is maintained throughout the surgical procedure.

According to the invention, the topical application of the solution throughout the surgical procedure produces a "preemptive analgesic" effect. The drug in the solution of the invention can modulate signal transmission by locally occupying the target receptor or inactivating the target enzyme before significant surgical trauma occurs, to preemptively inhibit the pathological process at the target site. If inflammatory mediators and pathological processes are inhibited before they can cause tissue damage, the benefit is more pronounced than if the administration is done after the damage has already begun.

By applying the solution containing various medicaments, more than one inflammatory mediator is inhibited, and the degree of inflammation and pain can be obviously reduced. The irrigation fluid of the present invention comprises a pharmaceutical composition, each of which is effective against a variety of anatomical receptors or enzymes. Thus, multiple drugs are simultaneously effective against multiple pathological processes, including pain and inflammation, vasospasm and smooth muscle spasm. The effects of these mediators are generally considered to be synergistic in nature, since the various receptor antagonists and inhibitory agonists of the invention are used in combination, exhibiting a disproportionate potentiation compared to the effects of the individual drugs. The synergistic effect of several of the agents of the present invention is discussed by way of example, and a detailed description of these agents follows.

In addition to arthroscopes, the solutions of the present invention may also be applied topically to other body cavities or passages, surgical wounds, traumatic wounds (e.g., burns) or any surgical or interventional procedure capable of being irrigated. These procedures include, but are not limited to, urological procedures, interventional cardiovascular diagnostic procedures and/or therapeutic procedures, and oral, dental, and periodontal procedures. As used throughout this document, the term "wound" is intended to include surgical wounds, surgical/interventional sites, trauma wounds and burns, unless otherwise indicated.

If the solution of the present invention is used intraoperatively, the solution should result in a clinically significant reduction in pain and inflammation at the surgical site as compared to irrigation solutions currently used, thereby reducing the need for post-operative pain relievers (e.g., opiates) in the patient and, where appropriate, allowing the patient to move the surgical site earlier. The solution according to the invention can be applied without additional effort compared to classical irrigation solutions on the part of surgical and operating room staff.

The invention relates in particular to the following.

Use of a mixture for perioperatively inhibiting pain, inflammation and/or spasm in a wound by topically applying the mixture to the wound during an arthroscopic, urological, oral/dental, general surgical, open surgical or body cavity procedure, wherein the medicament is for irrigating the wound, i.e., irrigating the wound with the solution during a medical procedure, wherein each drug in the mixture is at a concentration of no more than 100,000nM, or is at a concentration or dose sufficient to provide a therapeutically effective level at the wound when topically applied thereto and a resulting plasma concentration that is lower than the plasma concentration required to achieve the same therapeutically effective level at the wound when systemically administered, and wherein the mixture comprises a solution of a plurality of inhibitory drugs selected from the group consisting of pain/inflammation inhibitory drugs and spasm inhibitory drugs in a physiological fluid, these drugs are selected from a wide variety of classes of drugs that act, through different molecular mechanisms, on unique target molecules that may mediate pain, inflammation, or spasm, and are generally effective in inhibiting pain, inflammation, and/or spasm at the wound site.

An irrigation solution for perioperative suppression of pain and inflammation and/or spasticity during arthroscopic, urological, oral/dental, general surgery, open surgery or body cavity procedures, for topical application to a wound during the procedure, the solution comprising a dilute solution of a plurality of inhibitory drugs selected from the group consisting of pain/inflammation inhibitory drugs and spasm inhibitory drugs in a physiological fluid carrier, wherein each drug is present at a concentration of no more than 100,000nM, or at a concentration or dose sufficient to provide a therapeutically effective level at the wound when topically applied thereto and a plasma concentration produced that is lower than that required to achieve the same therapeutically effective level at the wound when administered systemically, the plurality of drugs being selected from a plurality of drug types that act, by different molecular mechanisms, on unique target molecules that mediate pain, inflammation or spasticity, these drugs are generally selected to be effective in inhibiting pain, inflammation and/or spasm at the wound site.

Use of a mixture for perioperatively inhibiting pain and inflammation and/or spasticity at a vascular structure by topically applying the mixture to the site of the vascular structure during an intravascular procedure during the procedure, wherein the medicament is for irrigating the vascular structure, i.e., irrigating a wound with the solution during a medical procedure, and wherein the mixture comprises a dilute solution of a plurality of inhibitory drugs selected from the group consisting of pain/inflammation inhibitory drugs and spasm inhibitory drugs, each drug being present in a concentration of no more than 100,000nM, or in a concentration or dose sufficient to provide a therapeutically effective level at the wound when topically applied thereto and a plasma concentration that is less than the plasma concentration required to achieve the same therapeutically effective level at the wound when systemically administered, the drugs being selected from the group consisting of multiple types of drugs, it acts through a unique molecular mechanism of action, where each class of drugs is selected from receptor antagonists, receptor agonists, enzyme inhibitors, enzyme activators, ion channel openers and receptor-manipulated ion channel antagonists, which are generally effective in inhibiting pain and inflammation and/or spasm at vascular structures.

An irrigation solution for perioperatively inhibiting pain and/or inflammation at a vascular structure by locally applying the solution to the vascular structure during a procedure during an intravascular procedure; the solution comprises a dilute solution of a plurality of inhibitory drugs selected from the group consisting of pain/inflammation inhibitory drugs and spasm inhibitory drugs in a physiological fluid carrier, wherein each drug is at a concentration and dose sufficient to provide a therapeutically effective level at the wound site when administered locally to the wound site, and produces a plasma concentration that is lower than that required to achieve the same therapeutically effective level at the wound site when administered systemically, the drugs being selected from a plurality of classes of drugs that act through distinct molecular mechanisms of action, wherein each class of drug is selected from the group consisting of receptor antagonists, receptor agonists, enzyme inhibitors, enzyme agonists, ion channel openers, and receptor-manipulated ion channel antagonists, which are collectively selected to be effective in inhibiting pain and inflammation and/or spasm at the vascular structure.

Brief description of the drawings IV

The invention will now be explained in more detail by way of example and with reference to the accompanying drawings, in which:

figures 1, 2A and 2B provide results of the animal study described in example VII herein showing the percentage of vasoconstriction experienced in the control artery, the proximal segment of the artery in the test animal, and the distal segment of the artery in the test animal, respectively. This study demonstrates the effect of histamine antagonist and 5-hydroxytryptamine antagonist perfusion used in the solutions of the present invention on vasoconstriction during balloon angioplasty.

Figures 3 and 4 provide graphs relating plasma extravasation in the knee joint and amitriptyline dose in the animal studies described in example VIII, which had been caused by the introduction of 5-hydroxytryptamine, under conditions of intravenous and intra-knee administration, respectively, of amitriptyline used in solutions of the present invention.

Detailed description of the preferred embodiments

The irrigation solution of the present invention is a dilute solution containing a variety of pain/inflammation inhibiting drugs and antispasmodics in a physiological carrier. The carrier is a liquid containing physiological electrolyte, such as physiological saline or ringer's solution with lactate. The carrier is preferably a liquid, but for certain applications, such as burns, it may be formulated as a paste or ointment.

These anti-inflammatory/anti-pain drugs are selected from the group consisting of: (1) 5-hydroxytryptamine receptor antagonists; (2) a 5-hydroxytryptamine receptor agonist; (3) a histamine receptor antagonist; (4) bradykinin receptor antagonists; (5) a kallikrein inhibitor; (6) tachykinin receptor antagonists including neurokinin 1 and neurokinin 2 receptor subtype antagonists; (7) a Calcitonin Gene Related Peptide (CGRP) receptor antagonist; (8) an interleukin receptor antagonist; (9) an inhibitor of an active enzyme in the arachidonic acid metabolite synthesis pathway, comprising: (a) inhibitors of phospholipases, including PLA₂Heterogeneous reforming inhibitor and PLC_rAn inhibitor of isomeric reforming, (b) a cyclooxygenase inhibitor and (c) a lipoxygenase inhibitor; (10) prostanoid receptor antagonists including eicosanoid EP-1 and EP-4 receptor subtype antagonists and thromboxane receptor subtype antagonists; (11) leukotriene receptor antagonists include leukotriene B₄Receptor subtype antagonists and leukotriene D₄A receptor subtype antagonist; (12) opioid receptor agonists including mu-opiates, delta-opiates and kappa-opiate receptor subtype agonists; (13) purine receptor agonists and antagonists, including P_2XReceptor antagonists and P_2YA receptor agonist; (14) adenosine Triphosphate (ATP) -sensitive potassium channel openers; calcium channel antagonists. Suitable anti-inflammatory and anti-pain agents which may also be used as anticonvulsants include 5-hydroxytryptamine receptor antagonists, tachykinin receptorsAntagonists, ATP-sensitive potassium channel openers and calcium channel antagonists. Other drugs that may be specifically used in the solutions of the present invention, depending on their antispasmodic properties, include endothelin receptor antagonists and nitric oxide donors (enzyme activators).

In each of the surgical solutions of the present invention, low concentrations of the drug are incorporated for topical application in low doses compared to the drug concentrations and doses required to achieve the desired therapeutic effect in conventional methods of administration. Similar doses of drug administered by other routes of administration (e.g., intravenous, intramuscular, or oral) may not achieve equivalent therapeutic effects, as systemic administration is susceptible to first-pass and second-pass effects. In addition to the cyclooxygenase inhibitors, which may be required in higher concentrations depending on the particular inhibitor chosen, each drug is preferably incorporated into the solution at a concentration of 0.1 to 10,000 nanomolar. As will be elucidated below, the exact drugs selected for use in the solutions of the present invention, and the concentrations of these drugs, will vary depending on the particular application.

The solutions of the present invention may contain, in low concentrations, only one or more drugs having pain/inflammation inhibitory effects, only one or more anti-spasmodic drugs, or a combination of anti-spasmodic and pain/inflammation inhibitory drugs selected from a wide variety of drugs. However, in view of the aforementioned synergistic effects of various drugs and the desire to broadly block pain and inflammation, it is preferable to employ multiple drugs.

The surgical solution constitutes a novel therapeutic approach for the administration of a variety of pharmacologically active drugs that act on unique receptor and enzyme molecule targets. To date, the strategic focus of pharmacology has focused on the development of highly specific drugs that selectively act on individual receptor subtypes or enzyme isoforms that mediate responses to single neurotransmitter and hormone transport signals. As an example, endothelin peptides are part of the most potent vasoconstrictors known. Several pharmaceutical companies are currently seeking selective antagonists specific for the Endothelin (ET) receptor subtype for the treatment of diseases involving elevated levels of endothelin in vivoVarious diseases. Due to the recognition of the receptor subtype ET_AFor the enhancement of hypertension, these pharmaceutical companies are focusing their goals on the development of selective ET_AA receptor subtype antagonist for use in the prior treatment of coronary vasospasm. This standard pharmacological strategy, while well established, is not as elegant as various vasoconstrictors (e.g., 5-hydroxytryptamine, prostaglandins, eicosanoids, etc.) may cause both the initiation and maintenance of vasospasm. Moreover, regardless of the inactivation of individual receptor subtypes or enzymes, activation of other receptor subtypes or enzymes and the resulting signaling often triggers a linkage reaction. This may explain the fact that it is very difficult to block the pathological processes in which multiple transmitters act using a single receptor-specific drug. Therefore, targeting is only to specific individual receptor subtypes such as ET_AThe above appears to be ineffective.

In contrast to standard pharmacological treatments, the treatment of the surgical solutions of the invention is based on the principle that a combination of drugs acting simultaneously on distinct molecular targets requires inhibition of all the various links constituting the development of the pathophysiological state. Moreover, the surgical solutions of the present invention are composed of drugs that target general molecular mechanisms rather than just a specific receptor subtype, i.e., control different cellular physiological processes involved in the development of pain, inflammation, vasospasm and smooth muscle spasm. In this way, the surgical solution of the present invention minimizes the interaction of extraneous receptors and enzymes in nociceptive, inflammatory and spastic pathways. In these pathophysiological pathways, the surgical solutions of the present invention inhibit the interlocking effects of both "ascending" and "descending".

An example of "up-flow" inhibition is the effect of cyclooxygenase antagonists in eliminating pain and inflammation. Cyclooxygenase (COX)₁And COX₂) Catalyzes the conversion of arachidonic acid to prostaglandin H, an intermediate in the biosynthesis of inflammatory and nociceptive mediators including prostaglandins, leukotrienes and thromboxanes. Cyclooxygenase inhibitors "Ascending "blocks the formation of these inflammatory and nociceptive mediators. This strategy eliminates the necessity of blocking the interaction of the 7 reported prostanoid receptor subtypes with their natural ligands. A similar "up" inhibitor contained in the surgical solution of the present invention is aprotinin, which is a kallikrein inhibitor. Kallikrein, a serine protease, cleaves high molecular weight kininogen in plasma to produce bradykinin, an important mediator of pain and inflammation. By inhibiting kallikrein, aprotinin can effectively inhibit the synthesis of bradykinin, thereby producing effective 'up' inhibition of these inflammatory mediators.

The present surgical solutions also utilize "down-flow" inhibitors to control these pathophysiological pathways. In vascular smooth muscle specimens pre-contracted with various neurotransmitters involved in coronary vasospasm (e.g., 5-hydroxytryptamine, histamine, endothelin, and thromboxane), ATP-sensitive potassium channel openers (KCOs) produce concentration-dependent smooth muscle relaxation (Quast et al, 1994; Kashiwabara et al, 1994). KCOs provide significant benefits to the surgical solutions of the present invention in relieving vasospasm and smooth muscle spasm by producing a "down-going" antispasmodic effect that is independent of the physiologically associated agonist that initiates spasm. Similarly, nitric oxide donors and voltage-gated calcium channel antagonists can reduce various vasospasm and smooth muscle spasm that are initiated by mediators known to act early on the pathological process of spasm. These same calcium channel antagonists can also provide a "down-stream" inflammatory blocking effect. Montade, s., Flower, r. and Vane, j. see: goodman and Gilman, Inc. (7 th edition), MacMillan publishing Co., pp 660-5 (1995).

The following is a description of suitable medicaments of the invention and their use in solution at appropriate concentrations within the aforementioned classes of anti-inflammatory/anti-pain agents. While not wishing to be bound by theory, the reason for selecting various drug types is also illustrated, which is believed to make the drugs effective.

A.5-hydroxytryptamine receptor antagonists

It is believed that 5-hydroxytryptamine is produced by stimulation of 5-hydroxytryptamine 2 (5-HT) on peripheral nociceptive neurons₂) And/or 5-hydroxytryptamine 3 (5-HT)₃) The receptor is painful. Most researchers agree that 5-HT receptors on peripheral nociceptors mediate the direct sensation of pain produced by 5-HT (Richardson et al, 1985). 5-HT receptor antagonists can inhibit neurogenic inflammation by inhibiting nociceptor activation in addition to pain caused by 5-HT. Barnes p.j.et.al., regulation of neurogenic inflammation, pharmacologic trends, 11, pp.185-189 (1990). However, the study of the ankle joints of rats claims 5-HT₂The receptor is responsible for the activation of nociceptors by 5-HT. Grubb, B.D., et al, Studies of 5-HT receptors associated with afferent nerves localized to normal and inflammatory rat ankles, drug Action (Agents Action)25, pp.216-18(1988), and thus, 5-HT₂Activation of receptors may also play a role in peripheral pain and neurogenic inflammation.

One of the purposes of the solutions of the present invention is to block pain and various inflammatory processes. Thus, as will be discussed later, 5-HT is suitably employed in the solutions of the present invention₂And 5-HT₃Receptor antagonists, either alone or in combination. Amitriptyline (Elavil)^TM) Which is a suitable 5-HT receptor antagonist, is employed in the present invention. Amitriptyline has been used clinically for many years as an antidepressant and has been found to have a good gastric effect on certain chronic pain patients (Reglan)^TM) It is clinically used as an antiemetic, but it is against 5-HT₃The receptor exhibits moderate affinity and is therefore capable of inhibiting the action of 5-HT on this receptor, and it is possible to inhibit pain caused by the release of 5-HT from platelets.

Other suitable 5-HT₂Receptor antagonists including imipramine, trazodone, Depressin and ketanserin have been used clinically for their antihypertensive effects. Hedner, T.et.al., Effect of novel 5-hydroxytryptamine antagonist ketanserin on experimental and clinical hypertension, J.Am.hypertension (Am J)Hypertension, pp.317s-23s (Jul.1988)). Other suitable 5-HT₃Receptor antagonists include cisapride and ondansetron. Suitable 5-hydroxytryptamine_1BThe receptor antagonist comprises yohimbine, N- [ methoxy-3- (4-methyl-1-piperazinyl) phenyl]-2 '-methyl-4' - (5-methyl) -1, 2, 4-oxadiazol-3-yl) [1, 1-biphenyl]-4-carboxamide ("GR 127935") and methiothepin. The therapeutic and preferred concentrations for these agents in the solutions of the present invention are listed in Table 1.

TABLE 1

Therapeutic and preferred concentrations of pain/inflammation inhibiting drugs

Therapeutic concentration preferred concentration

Medicine(nM) (nM)

5-hydroxytryptamine ₂ Receptor antagonists：

Amitriptyline 0.1-1, 00050-

Imipramine 0.1-1,00050-

Trazodone 0.1-1,00050-500-

Nomepromidine 0-1-1,00050-

Ketanserin 0.1-1,00050-

5-hydroxytryptamine ₃ Receptor antagonists：

Metoclopramide 10-10,000200-

Cisapride 0.1-1,00020-

Oondansetron 0.1-1,00020-

_{5-hydroxytryptamine 1B} (human 1D) _β ) Antagonists：

Yohimbine 0.1-1, 00050-

GR 127935 0.1-1,000 10-500

Methylthiothiaheptazine 0.1-5001-100-

B.5-hydroxytryptamine receptor agonists

It is thought that 5-HT_1A，5-HT_1BAnd 5-HT_1DThe receptor inhibits adenylate cyclase activity. Therefore, the solution of the invention is added with low dosage of 5-hydroxytryptamine_1A5-hydroxytryptamine_1BAnd 5-hydroxytryptamine_1DReceptor agonists are supposed to inhibit pain and inflammation mediated by neurons. From 5-hydroxytryptamine_1BAnd 5-hydroxytryptamine_1FReceptor agonists are expected to achieve the same effect as this, since these receptors also inhibit adenylate cyclase.

Buspirone is a suitable 1A receptor agonist for use in the present invention. Sumatriptan is a suitable 1A, 1B, 1D and 1F receptor agonist. A suitable 1B and 1D receptor agonist is dihydroergotamine. A suitable 1E receptor agonist is ergometrine. Therapeutic and preferred concentrations of these receptor agonists are listed in table 2.

TABLE 2

Therapeutic and preferred concentrations of pain/inflammation inhibiting drugs

Therapeutic concentration preferred concentration

Medicine(nM) (nM)

5-hydroxytryptamine _1A Agonists：

Buspirone 1-1,00010-

sumatriptan 1-1,000 10-200

5-hydroxytryptamine _1B Agonists：

Dihydroergotamine 0.1-1,00010-

sumatriptan 1-1,000 10-200

5-hydroxytryptamine _1D Agonists：

Dihydroergotamine 0.1-1,00010-

sumatriptan 1-1,000 10-200

5-hydroxytryptamine _1E Agonists：

Ergometrine 10-2,000100-

5-hydroxytryptamine _1F Agonists：

sumatriptan 1-1,000 10-200

C. Histamine receptor antagonists

Histamine receptors are generally classified as histamine 1 (H)₁) And histamine 2 (H)₂) The subtype is. The typical inflammatory response caused by peripheral histamine administration is via H₁Is receptor-mediated. Douglas, 1985. Therefore, the solution of the invention is preferably histamine H₁A receptor antagonist. Promethazine (trade name Phenergan)^TM) Is a commonly used effective block of H₁Receptor anti-emetic agents and are therefore suitable for use in the present invention. Interestingly, the drug has also been shown to have local anesthetic effects, but the concentration ratio required to produce this effect is blocking H₁The receptors are orders of magnitude larger and therefore these effects are thought to occur by different mechanisms. The concentration of histamine receptor antagonist used in the solution of the invention is sufficient to inhibit H involved in nociceptor activation₁The receptor, but not the "local anesthetic" effect, thus abrogating some of the associated systemic side effects.

Histamine receptors have also been claimed to have the ability to modulate vascular tension in coronary arteries. In vitro studies of isolated human hearts demonstrate that the histamine 1 receptor subtype mediates contraction of coronary smooth muscle. Ginsburg, r., et al, the challenge of histamine to clinical coronary spasm: the pathogenesis of various angina pectoris in association with complications is described in the journal of American Heart disease (American Heart J.), V.102, pp.819-822 (1980). Some studies have shown that histamine-induced excessive constriction of the human coronary system is most pronounced in proximal arteries where atherosclerosis and associated denudation of the arterial epithelium occur. Keitoku, M.et al, the differential effects of histamine on human proximal and distal coronary arteries in vitro, Cardiovascular study (Cardiovascular Research)24, pp.614-622 (1990). Therefore, histamine receptor antagonists can be added to cardiovascular irrigation fluids.

Other suitable H₁Receptor antagonists include terfenadine, diphenhydramine and amitriptyline. Amitriptyline has dual functionality for use in the present invention because it is also effective as a 5-hydroxytryptamine receptor antagonist. These H₁Suitable therapeutic and preferred concentrations of each of the receptor antagonists are listed in table 3.

TABLE 3

Therapeutic and preferred concentrations of pain/inflammation inhibiting drugs

Therapeutic concentration preferred concentration

Medicine (nM) (nM)

Histamine receptor antagonists：

Promethazine 0.1-1,00050-

Diphenhydramine 0.1-1,00050-

Amitriptyline 0.1-1, 00050-

0.1-1,00050 of terfenadine 500-

D. Bradykinin receptor antagonists

Bradykinin receptors are generally classified as bradykinin 1 (B)₁) And bradykinin 2 (B)₂) The subtype is. Studies have shown that acute peripheral pain and inflammation produced by bradykinin are caused by B₂Subtype-mediated, whereas bradykinin-induced pain in chronic inflammatory development is via B₁Subtype-mediated. Perkins, m.n.et.al, bradykinin B in two models of persistent hyperalgesia in rats₁And the B2 receptor antagonist des-Arg⁹，[Leu⁸]-BK and HOE140 anti-nociceptive activity. Pain (Pain)53, pp.191-97 (1993); dray, a., et al, bradykinin and inflammatory pain, neuroscience movement (Trends Neurosci)16, pp.99-104(1993), both of which are incorporated herein by reference.

Bradykinin receptor antagonists are not currently in clinical use. These drugs are all peptides (small molecular weight proteins) and therefore cannot be administered orally because they may be digested. anti-B2 receptor antagonists block acute pain and inflammation caused by bradykinin. Dray et al, 1993, B under chronic inflammatory conditions₁Receptor antagonists inhibit pain. Perkins et al, 1993; dray et al, 1993. Therefore, depending on the application, the solutions according to the invention preferentially incorporate B₁And B₂One or both of the receptor antagonists. For example, both acute and chronic joint pain and inflammation require arthroscopy, and the irrigating fluid used for arthroscopy should include B₁And B₂Two receptor antagonists.

Suitable comfort agents for use in the present inventionBradykinin receptor antagonists include the following bradykinin 1 receptor antagonists: D-Arg- (Hyp)³-Thi⁵-D-Tic⁷-Oic⁸) [ des-Arg ] of-BK¹⁰]Derivative (des-Arg of HOE 140)¹⁰]Derivatives, commercially available from Hoechst pharmaceutical manufacturers); and [ Leu⁸]des-Arg⁹-BK. Suitable bradykinin 2 receptor antagonists include: [ D-Phe ]⁷]-BK；D-Arg-(Hyp³-Thi^5，8-D-Phe⁷)-BK(“NPC 349”)；D-Arg-(Hyp³-D-Phe⁷) -BK ("NPC 567"); and D-Arg- (Hyp)³-Thi⁵-D-Tic⁷-Oic⁸) -BK ("HOE 140"). These compounds are more fully described in the aforementioned Perkins et al (1993) and Dray et al (1993). Suitable treatments and preferred concentrations are shown in table 4.

TABLE 4

Therapeutic and preferred concentrations of pain/inflammation inhibiting drugs

Therapeutic concentration preferred concentration

Medicine (nM) (nM)

Bradykinin ₁ Receptor antagonists：

[Leu⁸]des-Arg⁹-BK 1-1,000 50-500

[ des-Arg ] of HOE140¹⁰]Derivatives 1-1,00050-500-

Bradykinin ₂ Receptor antagonismAnti-agents：

[D-Phe⁷]-BK 100-10,000 200-5,000

NPC 349 1-1,000 50-500

NPC 567 1-1,000 50-500

HOE 140 1-1,000 50-500

E. Kallikrein inhibitors

As indicated previously, the peptide bradykinin is an important mediator of pain and inflammation. Bradykinin is produced as a cleavage product by the action of kallikrein on high molecular weight kininogen in plasma. Kallikrein is therefore considered to be of therapeutic value in inhibiting bradykinin production and the pain and inflammation that results therefrom. Kallikrein inhibitors suitable for use in the present invention are aprotinins. Suitable concentrations of the drug for use in the solutions of the present invention are listed in table 5 below.

TABLE 5

Therapeutic and preferred concentrations of pain/inflammation inhibiting drugs

Therapeutic concentration preferred concentration

Medicine (nM) (nM)

Kallikrein inhibitors：

0.1-1,00050-500 of aprotinin

Preferably: 200

F. Tachykinin receptor antagonists

Tachykinin (TKs) are a group of structurally related peptides including substance P, neurokinin A (NKA) and neurokinin B (NKB). Neurons are a major source of peripheral TKs. One important systemic effect of TKs is neuronal stimulation, while other effects include epithelium-dependent vasodilation, plasma protein extravasation, mast cell degranulation and recruitment, and stimulation of inflammatory cells. Maggi, c.a., general pharmacology (gen. pharmacol.)22, pp.1-24 (1991). In view of the above-mentioned complex physiological effects mediated by TK receptor activation, the TK receptor has been targeted for promoting analgesia and treating neurogenic inflammation.

1. Neurokinin 1 receptor subtype antagonists

Substance P activates a neurokinin receptor subtype known as NK-1. Substance P is an undecapeptide found in the sensory nerve end plate. Substance P is thought to have a variety of effects that produce peripheral inflammation and inflammation upon C-fiber activation, including vasodilation, plasma extravasation and mast cell degranulation. Levine, j.d., et.al., peptide and primitive afferent nociceptors, journal of neuroscience (j.neurosci)13, p.2273 (1993). A suitable substance P is ([ D-Pro)⁹[spiro-gamma-lactam]Leu¹⁰，Trp¹¹]physioaemin- (1-11)) ("GR 82334"). Other antagonists useful in the present invention that act on the NK-1 receptor are: 1-imino-2- (2-methoxy-phenyl) -ethyl) -7, 7-biphenyl-4-perhydroisoindolone (3aR, 7aR) ("RP 67580"); and 2s, 3 s-cis-3- (2-methoxybenzylamino) -2-benzhydrylquinuclidine ("CP 96,345"). Suitable concentrations of these agents are listed in table 6.

TABLE 6

Therapeutic and preferred concentrations of pain/inflammation inhibiting drugs

Therapeutic concentration preferred concentration

Medicine (nM) (nM)

Neurokinin 1 receptor subtype antagonists：

GR 82334 1-1,000 10-500

CP 96,345 1-10,000 100-1,000

RP 67580 0.1-1,000 100-1,000

2. Neurokinin 2 receptor subtype antagonists

Neurokinin a is a peptide that, together with substance P, accumulates in sensory neurons and contributes to inflammation and pain. Neurokinin a activates a specific neurokinin receptor called NK 2. Edmonds-Alt, s., et al, a potent selective non-peptide neurokinin a (NK2) receptor antagonist, Life science (Life Sci) 50: PL 10 (1992). In the urinary tract, TKs are potent spasmologens acting exclusively through NK-2 receptors in the human bladder and in the urethra and ureters. Maggi, c.a., general pharmacology (gen. pharmacol)22, pp.1-24 (1991). Thus, a desired drug in a surgical solution for use in a surgical procedure should contain an NK-2 receptor antagonist to relieve spasm. Examples of suitable NK-2 antagonists include: ((S) -N-methyl-N- [4- (4-acetamido-4-phenylpiperidino) -2- (3, 4-dichlorobenzene) benzamide ("(+ -) -SR 48968"); Met-Asp-Trp-Phe-Dap-Leu ("MEN 10,627"); and cyc (Gln-Trp-Phe-Gly-Leu-Met) ("L659,877"). The appropriate concentrations of these drugs are listed in Table 7.

TABLE 7

Therapeutic and preferred concentrations of pain/inflammation inhibiting drugs

Therapeutic concentration preferred concentration

Medicine (nM) (nM)

Neurokinin 2 receptor subtype antagonists：

MEN 10,627 1-1,000 10-1,000

L 659,877 10-10,000 100-10,000

(±)-SR 48968 10-10,000 100-10,000

CGRP receptor antagonists

Calcitonin gene-related peptide (CGRP) is a peptide that also accumulates in sensory neurons with substance P, acting as a vasodilator and enhancing the effect of substance P. Brain, s.d., et al, inflammatory edema caused by the synergistic effect of calcitonin gene-related peptide (CGRP) and a mediator that increases vascular permeability. British journal of pharmacology (br.j. pharmacol.)99, p.202 (1985). Examples of suitable CGRP receptor antagonists are α -CGRP- (8-37), a shortened form of CGRP. This polypeptide inhibits the activation of CGRP receptors. Suitable concentrations of the drug are listed in table 8.

TABLE 8

Therapeutic and preferred concentrations of pain/inflammation inhibiting drugs

Therapeutic concentration preferred concentration

Medicine (nM) (nM)

CGRP receptor antagonists：

α-CGRP-(8-37) 1-1,000 10-500

H. Interleukin receptor antagonists

Interleukins are a family of peptides, classified as cytokines, produced by leukocytes and other cells that are sensitive to inflammatory mediators. Interleukins (IL) may be potent peripheral hyperalgesics. Ferriiera, s.h., et al, interleukin 1 β is a potent hyperalgesic agent that can be combated by a tripeptide analog, Nature 334, p.698 (1988). An example of a suitable IL-1 β receptor antagonist is Lys-D-Pro-Thr, which is a shortened form of IL-1 β. Suitable concentrations of the drug are listed in table 9.

TABLE 9

Therapeutic and preferred concentrations of pain/inflammation inhibiting drugs

Therapeutic concentration preferred concentration

Medicine (nM) (nM)

Interleukin receptor antagonists：

Lys-D-Pro-Thr 1-1,000 10-500

I. Inhibitors of enzymatic activity in the arachidonic acid metabolite synthesis pathway

1. Phospholipase inhibitors

Via phospholipase A₂(PLA₂) Arachidonic acid produced by the action results in a cascade of reactions that produce a variety of inflammatory mediators, known as eicosanoids. Throughout this pathway, many stages may be inhibited, thereby reducing the production of these inflammatory mediators. Examples of inhibition at these various stages are listed below.

PLA₂The inhibitory action of the isoenzyme inhibits the release of arachidonic acid from the cell membrane and therefore the production of prostaglandins and leukotrienes, thus exhibiting the anti-inflammatory and analgesic properties of these compounds, Glaser, K.B., phospholipase A₂Regulation of the enzymes: selective inhibitors and their pharmacological potentiation, pharmacological evolution (adv. pharmacol.32, p.31 (1995)). Suitable PLA₂An example of a homotypic enzyme agonist is monoamide. The appropriate use concentrations of the drug are listed in table 10. PLC (programmable logic controller)_rInhibition of the isoenzyme also results in reduced production of prostanoids and leukotrienes, and therefore also results in reduced pain and inflammation. PLC (programmable logic controller)_rAn example of an isozyme inhibitor is 1- [6- ((17 beta-3-methoxyestra-1, 3, 5(10) -trien-17-yl) amino) hexyl]-1H-pyrrole-2, 5-dione.

Watch 10

Therapeutic and preferred concentrations of pain/inflammation inhibiting drugs

Therapeutic concentration preferred concentration

Medicine (nM) (nM)

PLA2 homotypic enzyme inhibitors:

manoalide 100-100,000 500-10,000

2. cyclooxygenase inhibitors

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used as anti-inflammatory, anti-pyretic, anti-thrombotic and analgesic agents. Lewis, r.a., prostaglandins and leukotrienes, see: textbook for rheumatology, third edition (Kelley w.n., et al eds.) p.258 (1989). The target molecules for these drugs are type I and type II cyclooxygenase (COX-1 and COX-2). These enzymes, also known as prostaglandin H synthase 1 (constitutive enzyme) and 2 (inducible enzyme) (PGHS), catalyze the conversion of arachidonic acid to prostaglandin H, an intermediate in the biosynthesis of prostaglandins and thromboxanes. COX-2 enzymes have been identified in endothelial cells, macrophages and fibroblasts. The enzyme is induced by IL-1 and endotoxin, and its expression is up-regulated at the site of inflammation. Both the constitutive enzymatic activity of COX-1 and the inducible enzymatic activity of COX-2 result in the synthesis of prostaglandins that can produce pain and inflammation.

Currently marketed NSAIDs (diclofenac, naproxen, indomethacin and ibuprofen, etc.) are generally non-selective inhibitors of the two COX isoforms, but may show greater selectivity for COX-1 than for COX-2, although the ratios vary from compound to compound. Blocking prostaglandin formation with COX-1 and 2 inhibitors represents a preferred therapeutic strategy compared to attempting to block the interaction of the natural ligand with the 7 illustrated prostanoid receptor subtypes. Antagonists of the reported prostanoid receptors (EP1, EP2 and EP3) are rare, and only specific, high affinity thromboxane a2 receptor antagonists have been reported. Wallace, j. and Cirino, g. pharmacologic Trends (Trends in pharm. sci), 15, pp.405-406 (1994).

The use of cyclooxygenase inhibitors is contraindicated in patients with ulcers, gastritis or nephropathy. The only injectable form of this drug available in the United states is ketorolac (under the Torad. TM. trade name)^TM) Commercially available from the Syntex pharmaceutical manufacturer, which is usually administered by intramuscular or intravenous injection to a patient after surgery, but is also contraindicated for the above-mentioned classes of patients. The use of ketorolac or other cyclooxygenase inhibitors in the solutions of the present invention is significantly lower than currently used perioperatively, which may allow the use of the drug in patients with other contraindications. The addition of a cyclooxygenase inhibitor in the solution of the present invention adds a unique mechanism to the inhibition of pain and inflammation production during arthroscopy or other surgical or interventional procedures.

Preferred cyclooxygenase inhibitors for use in the present invention are ketorolac and indomethacin. Of these two drugs, indomethacin is less preferred because it requires a relatively high dose. The therapeutic and preferred concentrations for use in the solutions of the present invention are listed in table 11.

TABLE 11

Therapeutic and preferred concentrations of pain/inflammation inhibiting drugs

Therapeutic concentration preferred concentration

Medicine (nM) (nM)

Cyclooxygenase inhibitors：

Ketorolac 100-

Indomethacin 1,000-

(most preferred concentration:

10,000-100,000)

3. lipoxygenase inhibitors

Inhibition of lipoxygenase inhibits leukotrienes such as leukotriene B, which are considered important mediators of inflammation and pain₄And (4) generating. Lewis, r.a., prostaglandins and leukotrienes, see: textbook on rheumatology, third edition (Kelley w.n., eds., et al), p.258 (1989). An example of a lipoxygenase antagonist is 2, 3, 5 trimethyl-6- (12-hydroxy-5, 10 dodecacarbynyl) -1, 4-benzoquinone (AA 861), suitable concentrations of which are set forth in Table 12.

TABLE 12

Therapeutic and preferred concentrations of pain/inflammation inhibiting drugs

Therapeutic concentration preferred concentration

Medicine (nM) (nM)

Lipoxygenase inhibitors：

AA 861 100-10,000 500-5,000

J. Prostanoid receptor antagonists

Certain prostanoids produced as arachidonic acid metabolites mediate their inflammatory effects by activating prostanoid receptors. Examples of various types of specific prostanoid antagonists are: eicosanoid EP-1 and EP-2 receptor subtypes and thromboxane receptor subtype antagonists. One suitable prostaglandin E2 receptor antagonist is 8-chlorodibenzo [ b, f ] [1, 4] oxazoxazine-10 (11H) -carboxylic acid, 2-acetylhydrazide ("SC 19220"). One suitable thromboxane receptor subtype antagonist is [15- [1 α, 2 β (5Z), 3 β,4 α ] -7- [3- [2- (phenylamino) -carbonyl ] hydrazino ] methyl ] -7-oxobicyclo- [2, 2, 1] -hept-2-yl ] -5-heptanoic acid ("SQ 29548"). Suitable concentrations of these drugs are listed in table 13.

Watch 13

Therapeutic and preferred concentrations of pain/inflammation inhibiting drugs

Therapeutic concentration preferred concentration

Medicine (nM) (nM)

Eicosanoid EP-1 antagonists：

SC 19220 100-10,000 500-5,000

K. Leukotriene receptor antagonists

Leukotrienes (LTB)₄，LTC₄And LTD₄) Is a product of the 5-lipoxygenase pathway in arachidonic acid metabolism, by enzymesIt has important biological properties. Leukotrienes are involved in pathological conditions including inflammation. Several pharmaceutical companies are currently seeking specific antagonists to intervene in these pathological conditions as powerful therapeutic approaches. Halushka, p.v., et.al., annual review of pharmacology and toxicology (annu.rev.pharmacol.toxicol.) 29: 213-239 (1989); Ford-Hutchinson, A. Immunological identification review (crit. Rev. lmmunol.10: 1-12(1990) LTB was found in certain immune cells including eosinophils and neutrophils₄A receptor. LTB₄Binding to these receptors results in chemotaxis and lysosomal release, which leads to inflammatory processes. And LTB₄The signaling processes involved in receptor activation include G-protein mediated stimulation of phospholipid group (P1) metabolism and increased intracellular calcium levels.

An appropriate leukotriene B₄An example of a receptor antagonist is SC (+) - (S) -7- (3- (2- (cyclopropylmethyl) -3-methoxy-4- [ (methylamino) -carbonyl]Phenoxy) propoxy) -3, 4-dihydro-8-propyl-2H-1-benzopyran-2-propionic acid ("SC 53228"). The concentrations of the agents suitable for use in the present invention are listed in Table 14. Other suitable leukotrienes B₄The receptor antagonist comprises [3- [2 (7-chloro-2-quinolyl) ethenyl]Phenyl radical][ 3-dimethylamino-3-oxopropyl) thio group]Methyl radical]Thiopropionic acid ("MK 057") and the drugs LY 66071 and ICI 20, 3219. MK 0571 may also be considered LTD₄A receptor subtype antagonist.

TABLE 14

Therapeutic and preferred concentrations of pain/inflammation inhibiting drugs

Therapeutic concentration preferred concentration

Medicine (nM) (nM)

Leukotriene B ₄ Antagonists：

SC 53228 100-10,000 500-5,000

Opioid receptor agonists

Opioid receptors have antinociceptive effects and agonists at these receptors are desirable. Opioid receptors include the mu, delta and kappa opioid receptor subtypes. mu receptors are localized on the end plates of peripheral sensory neurons, and activation of these receptors inhibits sensory neuron activity. Basbaum, a.i., et.al., opiate analgesics: how the Peripheral Target is Central (How the How Central is a Peripheral Target]-NH(CH₂)₂(DAMGO). An example of a suitable delta-opiate receptor agonist is (trans) -3, 4-dichloro-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl]-phenylacetamide ("U50,488"). Suitable concentrations of each of these drugs are listed in table 15.

Watch 15

Therapeutic and preferred concentrations of pain/inflammation inhibiting drugs

Therapeutic concentration preferred concentration

Medicine (nM) (nM)

Mu-opiate agonists：

DAMGO 0.1-100 0.5-20

Fentanyl 0.1-1000.5-20

Delta-opiate agonists：

DPDPE 0.1-500 1.0-100

Kappa-opiate agonists：

U 50,488 0.1-500 1.0-100

Purine receptor antagonists and agonists

Extracellular ATP passage with P₂Interaction of purine receptors, acting as signaling molecules. One major type of purine receptor is P_2XPurine receptors, which are capable of controlling Na permeability⁺，K⁺And Ca⁺⁺Of the ion channel is controlled by the ligand of the ion channel. P functioning in sensory neurons_2XReceptors are important for primary afferent neurotransmission and pain perception. ATP is known to depolarize sensory neurons and plays a role in nociceptor activation because ATP released from damaged cells stimulates P_2XThe receptors have nerve fiber endplate depolarizations that cause nociception. P_2X1Receptors have a highly restricted distribution (Chen, C.C., et al., Nature V.377, pp.428-431 (1995)) because this receptor is selectively expressed in sensory C-fiber nerves that enter the spinal cord, many of which are known to carry receptors that can be stimulated by painThis is, P_2X2This highly stringent site of expression of receptor subtypes makes these receptor subtypes excellent targets for analgesic action.

By way of example, P is suitable for the application of the invention_2Xthe/ATP purine receptor antagonists include suramin and pyridoxal-6-azobenzene-2, 4 disulfonic acid phosphate ("PPADS"). Suitable concentrations of these agents are listed in table 16.

P_2YAgonists of the receptor, i.e. the receptor coupled to the G protein, are known to affect smooth muscle relaxation by an increase in IP3 levels followed by an increase in intracellular calcium. P_2YAn example of a receptor agonist is 2-me-S-ATP.

TABLE 16

Therapeutic and preferred concentrations of pain/inflammation inhibiting drugs

Therapeutic concentration preferred concentration

Medicine (nM) (nM)

Purine receptor antagonists：

Suramin 100-

PPADS 100-100,000 10,000-100,000

Adenosine Triphosphate (ATP) -sensitive potassium channel openers

ATP-sensitive potassium channels have been found to be present in a variety of tissues, including the brain, and binding studies with radiolabeled ligands have confirmed their presenceAt this point. Opening of these channels causes potassium (K)⁺) Efflux and over-polarization of cell membranes. This over-polarization is achieved by suppressing voltage-dependent calcium (Ca)²⁺) Channel and receptor-manipulated Ca²⁺Channels, leading to a reduction in intracellular free calcium. This combined action forces the cells into a relaxed state, i.e., a state more resistant to activation. It has been demonstrated that K⁺Channel Openers (KCOs) prevent stimulation of coupled (Ca)²⁺) Secreted, it is thought that these KCOs act on presynaptic neuronal receptors, thereby inhibiting the effects due to neurostimulation and inflammatory mediator release. Quast, u.et.al, cytopharmacology of potassium channel openers in vascular smooth muscle, cardiovascular studies (Cardiovasc Res.) v.28, pp.805-810 (1994).

ATP-sensitive potassium channels have been found in vascular and non-vascular smooth muscle, the presence of which has been confirmed by binding studies with radiolabeled ligands. The opening of these channels hyperpolarizes the cell membrane, which results in the smooth muscle cells being forced into a relaxed state or a state more resistant to activation, thereby achieving vasodilation. K⁺Channel openers have been characterized by potent antihypertensive activity in vivo and vascular relaxation activity in vitro. There is no precedent in the medical literature to demonstrate the therapeutic utility of these drugs as anti-inflammatory, antinociceptive and bladder antispasmodic agents.

Endothelin (ET) in achieving vascular or smooth muscle relaxation_A) Synergistic interaction between antagonists and ATP-sensitive potassium channels (KCOs) is desirable. The principle of compatibility is based on the fact that these drugs have different molecular mechanisms of action in promoting smooth muscle relaxation and preventing vasospasm. From ET_AReceptor-induced elevation of early intracellular calcium in smooth muscle cells then triggers activation of voltage-dependent channels and entry of extracellular calcium required for contraction. ET_AReceptor antagonists specifically block the effects mediated by the receptor, but do not block calcium elevation by activation of other G-protein coupled receptors on muscle cells.

Potassium channels and the administration of drugs such as pinadil open these channels that cause K efflux and excessive cell membrane polarization. This over-polarization can reduce contraction mediated by other receptors through the following mechanisms: (1) induce a decrease in intracellular free calcium levels through inhibition of voltage-dependent calcium channels by decreasing the probability of opening of L-type and T-type calcium channels, (2) prevent endogenous release of agonist-induced (receptor-operated channels) Ca from the cell by inhibiting IP3 formation. (3) Reducing the effect of calcium as a contractile protein activator. Thus, the combined action of these two classes of drugs forces the target cells to a relaxed state or a state that is more resistant to activation.

ATP-sensitive K suitable for use in the present invention⁺The channel openers include: (-) pinacidil; cromakalin; nicorandil; minoxidil; N-cyano-N' - [1, 1-dimethyl [2, 2, 3, 3-³H]Propyl radical]-N "- (3-pyridyl) guanidine (" P1075 "); and N-cyano-N' - (2-nitroxylethyl) -3-pyridinecarboxamidine monomethanesulfonate ("KRN 239"). The concentrations of these drugs are listed in table 17.

TABLE 17

Therapeutic and preferred concentrations of pain/inflammation inhibiting drugs

Therapeutic concentration preferred concentration

Medicine (nM) (nM)

ATP-sensitive K ⁺ Channel openers：

cromakalin 10-10,000 100-10,000

Nicorandil 10-10,000100-

Minoxidil 10-10,000100-

P 1075 0.1-1,000 10-1,000

KRN 2391 1-10,000 100-1,000

(-) pinacidil 1-10,000100-

Calcium channel antagonists

Calcium channel antagonists are a special group of drugs that interfere with calcium ion transmembrane flux, which is required for activation of the cellular response that mediates neuroinflammation. Calcium entry into platelets and leukocytes is a critical step in mediating activation reactions in these cells. Furthermore, bradykinin receptors and neurokinin receptors (NK1 and NK2) have been implicated in mediating neuroinflammation, a role in signaling pathways involving increases in intracellular calcium, leading to activation of calcium channels on the serosa. In many tissues, calcium channel antagonists such as nifedipine reduce the release of arachidonic acid, prostaglandins and leukotrienes triggered by various stimuli. See Moncada, s., Flower, r. and van, j.: the pharmacological basis for Goodman and Gilman's treatment (seventh edition) MacMillan Publ.Inc.pp.660-5 (1995).

Calcium channel antagonists also interfere with the calcium ion transmembrane flux required for vascular smooth muscle contraction. This effect provides a theoretical basis for proposing the use of calcium antagonists in perioperative procedures aimed at relieving vasospasm and relaxing smooth muscle. Dihydropyridines, including nisoldipine, are specific inhibitors (antagonists) of voltage-dependent valves of calcium channels of the L-type subtype. Systemic administration of the calcium channel antagonist nifedipine perioperative in the heart has previously been used to prevent or reduce coronary vasospasm. Seiteberger, r., et al cycle (Circulation), 83: 460-468(1991). Still, there is no precedent in the medical literature to demonstrate the therapeutic utility of these drugs as anti-inflammatory, antinociceptive and bladder antispasmodic agents.

Calcium channel antagonists, which are anti-pain/inflammation/spasticity agents useful in the present invention, exhibit synergistic effects when used in combination with other agents of the present invention. Calcium (Ca)²⁺) Channel antagonists and Nitric Oxide (NO) donors are coordinated in achieving vascular relaxation or smooth muscle relaxation, i.e., in inhibiting spasmodic activity. The principle of joint application is based on the fact that: these drugs have different molecular mechanisms of action, and may not be fully effective in achieving relaxation when applied alone, and may have different periods of action. In fact, a number of studies have shown that calcium channel antagonists alone do not completely relax vascular muscles that have been previously contracted with a receptor agonist.

The effect of nisoldipine alone and in combination with nitroglycerin on the Internal Mammary Artery (IMA) was shown, and the use of two drugs in preventing contractions produced a significant positive synergistic effect (Liu et al, 1994). These studies provide scientific evidence for the most effective use of calcium channel antagonists in combination with nitric oxide donors (NO) for the prevention of vasospasm and for the relaxation of smooth muscle. Examples of such uses have been reported for systemic administration of nitroglycerin and nifedipine during cardiac surgery to prevent and treat myocardial ischemia or coronary vasospasm (Cohen et al, 1983; Seiteberger et al, 1991).

Calcium channel antagonists and endothelin receptor subtype A (ET)_A) Antagonists also show synergistic effects. Yanagisawa and colleagues observed that dihydropyridine antagonists, calcium channel antagonists, block the endogenous agonist ET-1₁For ET in coronary artery smooth muscle_AEffect of the receptor, from which ET is presumed₁Are endogenous agonists of voltage sensitive calcium channels. It has been found that ET is found in smooth muscle cells_AExtracellular calcium is required for the maintenance phase of intracellular calcium elevation induced by receptor activation, and this maintenance can be at least partially blocked by nicardipine. Thus, ET in surgical solution_AWhen the antagonists are used together, it is desirable to add calcium channel antagonists to synergistically enhance ET_AThe action of the antagonist.

Calcium channel antagonists and ATP-sensitive potassium channel openers also show synergistic effects. ATP-sensitive potassium channel (K)_ATP) The membrane potential of the cell is coupled to the metabolic state of the cell by sensitization to adenosine nucleotides. Intracellular ATP inhibition K_ATPThe channel is excited by intracellular dinucleotide diphosphate. The activity of these channels is controlled by the electrochemical driving force on potassium and intracellular signals (e.g., ATP or G-protein), but not by membrane potential per second. K_ATPThe channel hyperpolarizes the membrane, allowing it to control the resting potential of the cell. ATP-sensitive potassium flux has been found in skeletal muscle, brain, vascular and non-vascular smooth muscle, and binding studies with radiolabeled ligands have demonstrated the presence of these channels as receptor targets for potassium channel opener drugs such as pinadil. The opening of these channels causes potassium efflux and hyperpolarization of the cell membrane. This hyperpolarization (1) inhibits voltage-dependent calcium channels by reducing the probability of opening of both L-and T-type calcium channels, resulting in a reduction in intracellular free calcium levels, (2) prevents agonist-induced (receptor-operated channel) Ca by inhibiting inositol triphosphate (IP3) formation²⁺Endogenous release from the cell, (3) reduced efficacy of calcium as a contractile protein activator. These combined effects of these two classes of drugs force target cells to a relaxed state or a state that is more resistant to activation.

Finally, calcium channel antagonists and tachykinin antagonists and bradykinin antagonists exhibit synergistic effects in mediating neuroinflammation. The role of neurokinins in mediating neuroinflammation has been identified. The neurokinin 1(NK1) and neurokinin 2(NK2) receptor (a member of the G protein-binding superfamily) signaling pathway involves intracellular calcium elevation, leading to activation of calcium channels on the serosa. Similarly, activation of the bradykinin 2(BK2) receptor is associated with increased intracellular calcium levels. Thus, calcium channel antagonist interference involves the general mechanism of elevated intracellular calcium levels that are partly accessible via L-type channels. This is the basis for a synergistic interaction between calcium channel antagonists and antagonists at these receptors.

Calcium channel antagonists suitable for use in the present invention include nisoldipine, nifedipine, nimodipine, lacidipine and isradipine. Suitable concentrations of these agents are listed in Table 18

Watch 18

Therapeutic and preferred concentrations of pain/inflammation inhibiting drugs

Therapeutic concentration preferred concentration

Medicine (nM) (nM)

Calcium channel antagonists：

Nisoldipine 1-10,000100-

Nifedipine 1-10,000100-

Nimodipine 1-10,000100-

Lacidipine 1-10,000100-

Isradipine 1-10,000100-

P. anticonvulsant

1. Multifunctional medicine

Several of the above-mentioned anti-pain and anti-inflammatory agents also have the effect of inhibiting vasoconstriction or smooth muscle spasm. Because of this, these drugs also function as antispasmodics and are therefore advantageously applied to vascular and urinary tract indications. Anti-inflammatory and anti-pain agents which may also act as anticonvulsants include 5-hydroxytryptamine receptor antagonists, especially 5-hydroxytryptamine 2 receptor antagonists; tachykinin receptor antagonists, ATP-sensitive potassium channel openers, and calcium channel antagonists.

2. Nitric oxide donors

The nitric oxide donor may be added to the solution of the invention, especially with respect to its anti-spasmodic activity. Nitric Oxide (NO) plays an important role as a molecular mediator of a variety of physiological processes, including vasodilation and control of normal vascular tone. Within endothelial cells, one enzyme, termed NO synthase (NOS), catalyzes the conversion of L-arginine to NO, which acts as a diffusible second messenger mediating reactions in adjacent smooth muscle cells. Under the basic conditions of inhibiting constriction and controlling basal coronary tone, NO is continuously formed and released by vascular endothelial cells and can be produced in endothelial cells that are sensitive to various antagonists (e.g., acetylcholine) and other endothelial cell-dependent vasodilatory stimuli. Thus, regulation of NO synthase activity and the resulting NO levels are key molecular targets for controlling vascular tone. Muramatsu, et al, coronary artery disease (corona. artey. dis.), 5: 815-820(1994.).

Synergistic interaction between NO donors and ATP-sensitive potassium channels (KCOs) is desirable to achieve vascular relaxation or smooth muscle relaxation. The principle of joint application is based on the fact that: these drugs have different molecular mechanisms of action in promoting smooth muscle relaxation and preventing vasospasm. Evidence obtained from cultured coronary smooth muscle cells suggests that various vasoconstrictors, including vasopressin, angiotensin II and endothelin, inhibit K by inhibiting protein kinase A_ATPAnd (4) streaming. In addition, K in bladder smooth muscle is reported_ATPFlow quiltInhibition by a toxic base agonist. The role of NO in mediating smooth muscle relaxation is achieved through a separate molecular pathway involving protein kinase G (described above). This indicates that the combination of the two drugs is more effective than the single drug in relaxing smooth muscle.

Nitric oxide donors suitable for use in the present invention include nitroglycerin, sodium nitroferricyanide, the drug FK 409, 3-morpholino sydnonimine, or lisimine hydrochloride ("SIN-I"): and S-nitroso-N-acetylpenicillamine ("SNAP"). Suitable concentrations of these agents are listed in table 19.

Watch 19

Therapeutic and preferred concentrations of pain/inflammation inhibiting drugs

Therapeutic concentration preferred concentration

Medicine (nM) (nM)

Nitric oxide donors：

Nitroglycerin 10-10,000100-

Sodium nitrosoferricyanide 10-10,000100-

SIN-I 10-10,000 100-1,000

SNAP 10-10,000 100-1,000

FK 409 1-1,000 10-100

3. Endothelin receptor antagonists

Endothelin is a polypeptide consisting of 21 amino acids, one of the strongest vasoconstrictors known. Three different human endothelin polypeptides, designated ET1, ET2 and ET3, respectively, have been reported by designating at least two as ET_AAnd ET_BReceptor subtypes of the receptor mediate their physiological effects. Cardiac and vascular smooth muscle contains a dominant ET_AReceptors, the receptor subtype governs the contraction of these tissues. Thus, for ET_AAntagonists of the receptor should be therapeutically beneficial in inhibiting perioperative coronary spasm and, in addition, may be useful in inhibiting smooth muscle contraction in urological applications. Miller, r.c., et al, pharmacologic scientific initiative (Trends in pharmacol.sci), 14: 54-60(1990).

Suitable endothelin receptor antagonists include: ring (D-Asp-Pro-D-Val-Leu-D-Trp) ("BQ 123"); (N, N-hexamethylene) -carbamoyl-Leu-D-Trp- (CHO) -D-Trp-OH ("BQ 610"); (R)2- ([ R-2[ (S) -2- ([ 1-hexahydro-1H-azepinyl ] -carbonyl ] amino-4-methyl-pentanoyl) amino-3- (3[ 1-methyl-1H-indolyl) propionylamino-3- (2-pyridyl) propanoic acid ("FR 139317"), (D-Asp-Pro-D-Ile-Leu-D-Trp) ("JKC 301"), (D-Ser-Pro-D-Val-Leu-D-Trp) ("JK 302"), (D-Asp-Pro-Leu-D-Trp) ("JK 302"), (5- (dimethylamino) -N- (3, 4-dimethyl-5-isoxazolyl) -1-naphthalenesulfonamide ("BMS 182874"). The concentrations of two representative drugs are listed in the Table 20.

Watch 20

Therapeutic and preferred concentrations of pain/inflammation inhibiting drugs

Therapeutic concentration preferred concentration

Medicine (nM) (nM)

Endothelin receptor antagonists：

BQ 123 0.01-1,000 10-1,000

FR139317 1-100,000 100-10,000

Method of application

The solutions of the present invention have a variety of applications for use in a variety of surgical and interventional procedures, including surgical, diagnostic and therapeutic techniques. These applications include application as irrigation fluids during endoscopic examination of anatomically related joints, urological procedures, and intravascular diagnostic and therapeutic procedures. As used throughout this document, the term "perioperative" is intended to mean the use of the solutions of the present invention during a surgical or medical interventional procedure, which term also requires, for many procedures, the application of the solutions of the present invention preferably prior to the beginning of the procedure. Such procedures typically employ a physiological irrigation solution, such as saline or lactated ringer's solution, applied to the surgical site by those skilled in the art. The method of the present invention involves replacing the normal irrigation fluid with the anti-pain/anti-inflammatory/anti-spasm irrigation fluid of the present invention. The irrigating fluid is applied to the wound or surgical site prior to the beginning of the surgical procedure, preferably prior to tissue trauma, and continues until the end of the procedure to preemptively block pain and inflammation and/or spasm. As used throughout this document, the term "irrigation fluid" is intended to mean a fluid stream used to irrigate a wound or anatomical structure. As used throughout this document, the term "continuously" is intended to take into account repeated frequent intermediate washes of the wound with a frequency sufficient to maintain a predetermined local therapeutic concentration of the drug used, as well as intermediate stops of the wash fluid wash which may be required by the surgical procedure itself.

Arthroscopic techniques that may use the solutions of the present invention include, by way of non-limiting example, knee semilunar valve resection and ligament reconstruction, shoulder and shoulder arthroplasty, rotator cuff debridement, elbow synovectomy, and wrist and ankle endoscopy. The solution of the present invention is continuously supplied to the intra-operatively articulated joint at a flow rate sufficient to distend the joint cavity to dislodge surgical debris and enable an unobstructed view within the joint.

An irrigation solution suitable for controlling pain and edema during such arthroscopy is provided in example 1 below. For arthroscopy, the preferred solutions include combinations of the following, preferably all in combination, or alone: 5-hydroxytryptamine 2 receptor antagonists, 5-hydroxytryptamine 3 receptor antagonists, histamine 1 receptor antagonists, 5-hydroxytryptamine receptor agonists acting at the 1A, 1B, 1D, 1F and/or 1E receptors, bradykinin 1 receptor antagonists, bradykinin 2 receptor antagonists, and cyclooxygenase inhibitors, preferably in combination in their entirety.

Since these pain/inflammation-inhibiting drugs are applied topically to the surgical site directly perioperatively, the solutions are used at very low concentrations of these drugs. For example, less than 0.05mg amitriptyline (a suitable dual receptor antagonist of 5-hydroxytryptamine 2 and histamine 1) per liter of wash solution is required to provide inhibition of 5-HT₂And H₁Local tissue of the recipient is at a relatively high drug concentration. This dose is very low compared to the 10-25mg starting dose commonly used for oral administration of amitriptyline.

In each of the surgical solutions of the present invention, the various drugs are added at low concentrations and are administered locally at low doses compared to the drug concentrations and doses required to achieve the desired therapeutic effect using conventional methods of administration. It is not possible to achieve equivalent therapeutic effects by administering similar doses of the drug via other routes of administration (e.g., intravenous, intramuscular, or oral), since the administered drug undergoes systemic first and second passes.

For example, using the rat arthroscopic model, the present inventors examined 5-HT according to the present invention₂The antagonist amitriptyline inhibits 5-HT-induced plasma extravasation in rat knee joints. This study, described in more detail in example VIII below, compares the local application of amitriptyline at the knee (e.g., intra-articular) and the therapeutic dose administered intravenously. The results demonstrate that the dose level required for the intra-articular administration of amitriptyline is about 200 times less than the dose required for the same therapeutic effect when administered intravenously. Since only a small fraction of the intra-articular administered drug is absorbed by synovial tissue, the difference in plasma drug levels between the two routes of administration is much greater than the difference in total amitriptyline dose levels.

The practice of the present invention should be distinguished from the conventional practice of injecting opiates and/or local anesthetics into joints at the end of arthroscopic or "open" joint procedures (e.g., knee, shoulder, etc.). The solutions of the present invention are used for continuous perfusion throughout the surgical procedure to preemptively inhibit pain and inflammation. In contrast, the high concentrations necessary for a local anesthetic such as lidocaine (0.5-2% solution) to achieve therapeutic effects by constant infusion can cause significant systemic toxicity.

Once the procedure of the present invention is completed, it is desirable to inject or otherwise supply a high concentration of the same pain and inflammation suppressant used in the irrigation fluid of the present invention at the surgical site, as an alternative or adjunct to the opiates.

The solutions of the present invention also have application in intravascular diagnostic and therapeutic procedures to effectively reduce vascular wall spasm, platelet aggregation and nociceptor activation resulting from vascular injury. Suitable solutions for such manipulation techniques are disclosed herein below in example II. The intravascular solution preferably comprises any combination of the following drugs, preferably all: 5-hydroxytryptamine 2 receptor antagonists (Saxena, et al, inhibition of cardiovascular effects of agonists and antagonists of 5-hydroxytryptamine, J.Cardiovasc Pharmacol)15 (suppl.7): S17-S34 (1990); Douglas, 1985); 5-hydroxytryptamine 3 receptor antagonists to block activation of sympathetic neurons and C-fiber nociceptive neurons in the vessel wall at these receptors, which have been shown to produce bradycardia and tachycardia (Saxena, et al 1990); bradykinin 1 receptor antagonists; and cyclooxygenase inhibitors to block the production of prostaglandins at the site of tissue injury, thus reducing pain and inflammation. In addition, the intravascular solution preferably also contains a 5-hydroxytryptamine 1B (also known as 5-hydroxytryptamine 1D β) antagonist, since it has been demonstrated that 5-hydroxytryptamine produces significant vasospasm by activating the human 5-hydroxytryptamine 1B receptor. Kaumann, a.t. et al, 5-hydroxytryptamine 1-like receptor and 5-hydroxytryptamine 2 receptor are involved in 5-hydroxytryptamine induced isolated human coronary artery constriction to varying degrees, Circulation (Circulation) 90: 1141-53(1994). Agonism of the 5-hydroxytryptamine 1B receptor on the vessel wall leads to vasoconstriction, which is in contrast to the previously discussed inhibitory effect of the 5-hydroxytryptamine receptor in neurons. For the purpose of this intravascular solution, the term "pain/inflammation-inhibiting drug" is intended to also include drugs that inhibit vascular wall spasm and platelet aggregation.

The solutions of the present invention are also useful for reducing pain and inflammation associated with urological procedures such as laser transurethral prostatectomy and similar urological procedures. Studies have demonstrated that 5-hydroxytryptamine, histamine and bradykinin produce inflammation in lower urinary tract tissues. Schwartz, m.m., et al, renal and lower urinary vascular leakage: the effects of histamine, 5-hydroxytryptamine and bradykinin, and the society for experimental biomedicine (proc.soc.exp.biol Med) 140: 535-539(1972). Suitable irrigants for use in urological procedures are discussed in example III herein below. The washing liquid preferably comprises the following compatible application of medicines, and preferably adopts the following medicines in total: histamine 1 receptor antagonists to inhibit histamine-induced pain and inflammation; 5HT₃Receptor antagonists to block the activation of these receptors on peripheral C-fiber nociceptive neurons; bradykinin 1 antagonists; bradykinin 2 antagonists; and cyclooxygenase inhibitors to reduce pain and inflammation at the site of tissue injury caused by prostaglandins. The lotion is preferably added with antispasmodicTo prevent urethral spasms and bladder wall spasms.

The solutions of the present invention may also be used perioperatively to inhibit pain and inflammation in surgical wounds, and to reduce pain and inflammation associated with burns. Burns cause the release of a large amount of biogenic amines which not only cause pain and inflammation, but also cause significant plasma extravasation (loss of body fluids) and are often a life-threatening factor for severe burns. Hollliman c.j., et al, Ketanserin, the effect of a specific 5-hydroxytryptamine antagonist on the hemodynamic parameters of burn shock in a pig burn model, journal of trauma (j. trauma) 23: 867-871(1983). The solution for arthroscopy disclosed in example 1 can also be applied to wounds or burns for the control of pain and inflammation. Alternatively, the drug in the solution of example I may also be incorporated into a paste or ointment at the same concentration, supplied for use on a burn or wound.

VII. examples

The following is a summary of two clinical studies using the drug of the present invention followed by an irrigation fluid formulation developed in accordance with the present invention, suitable for use in certain surgical procedures.

A. Example 1

Washing liquid for arthroscopy

The following formulations are suitable for irrigation of anatomical joints during arthroscopy. As with the other rinses set forth in the examples below, each drug is dissolved in a carrier solution containing physiological electrolytes, such as physiological saline or ringer's solution with lactate.

Type of drug MedicineConcentration (nM):

treatment of Preference is given to Most preferably

5-hydroxytryptamine 2 antagonist amitriptyline 0.1-1,00050-

5-hydroxytryptamine 3 antagonist metoclopramide 10-10,000200-

Histamine 1 antagonist amitriptyline 0.1-1,00050-

5-hydroxytryptamine 1A, 1B, sumatriptan 1-1, 00010-

1D, 1F inhibitory agonists

1-1,00050-500200 of bradykinin 1 antagonist HOE140

[des-Arg¹⁰]

Derivatives of the same

Bradykinin 2 antagonist HOE 1401-

B. Example II

Flushing fluid for intravascular therapeutic procedures

The following drugs and their concentrations in the physiological carrier solution are suitable for irrigating the surgical site during intravascular procedures.

Type of drug MedicineConcentration (nM):

treatment of Preference is given to Most preferably

5-hydroxytryptamine 2 antagonist trazodone 0.1-1,00050-

5-hydroxytryptamine 3 antagonist metoclopramide 10-10,000200-

5-hydroxytryptamine 1B antagonist yohimbine 0.1-1,00050-500200

1-1,00050-500200 of bradykinin 1 antagonist HOE140

[des-Arg¹⁰]

Derivatives of the same

10,000800 ketorolac 5,0003,000 cyclooxygenase inhibitors

C. Example III

Flushing fluid for urological operation

The following drugs and their concentrations in physiological carrier solutions are suitable for irrigating the surgical site during urological procedures.

Type of drug MedicineConcentration (nM):

treatment of Preference is given to Most preferably

Histamine 1 antagonist terfenadine 0.1-100050-500200

5-hydroxytryptamine 3 antagonist metoclopramide 10-10000200-

1-100050-500200 of bradykinin 1 antagonist HOE140

[des-Arg¹⁰]

Derivatives of the same

Bradykinin 2 antagonists HOE 1401-100050-500200

Cycloxygenases inhibitor ketorolac 100-10000800-50003000

D. Example IV

Irrigation solution for arthroscopic, general surgical wound and oral/dental applications

The following drugs are preferred for use in arthroscopy and irrigation of anatomical sites during oral/dental procedures, as well as treatment of burns and general surgical wounds. While the solutions listed in example 1 are suitable for use in the present invention, the following solutions are preferred for their intended high potency.

Concentration (nM):

type of drug Medicine Treatment of Preference is given to Most preferably

5-hydroxytryptamine 2 antagonist amitriptyline 0.1-1,00050-

5-hydroxytryptamine 3 antagonist metoclopramide 10-10,000200-

Histamine 1 antagonist amitriptyline 0.1-1,00050-

5-hydroxytryptamine 1A, 1B, sumatriptan 1-1, 00010-

1D, 1F inhibitory agonists

10,000800 ketorolac 5,0003,000 cyclooxygenase inhibitors

Neurokinin 1 antagonist GR 823341-500200, 00010-500200

Neurokinin 2 antagonist (+/-) SR 489681-1,00010-500200

Purine 2X antagonist PPADS 100-

100,000

ATP-sensitive K⁺(-) pinacidil 1-10,000100 and 1,000500

Channel agonists

Ca²⁺Channel antagonist nifedipine 1-10,000100-

Kallikrein aprotinin 0.1-1,00050-500200

E. Example V

Flushing liquid for intravascular treatment and operation

The following drugs and concentration ranges in the physiological carrier solution are preferred for use in irrigating the surgical site during intravascular procedures. Also, this solution is preferred due to its higher potency compared to the solutions listed in example II above.

Concentration (nM):

type of drug Medicine Treatment of Preference is given to Most preferably

5-hydroxytryptamine 2 antagonist trazodone 0.1-1,00050-

10,000800 ketorolac 5,0003,000 cyclooxygenase inhibitors

Endothelin antagonist BQ 1230.01-1, 00010-1, 000500

ATP-sensitive K⁺(-) pinacidil 1-10,000100 and 1,000500

Channel agonists

Ca²⁺Channel antagonist nisoldipine 1-10,000100-

Nitrogen monoxide donor SIN-110-10, 000100-1, 000500

F. Example VI

Washing liquid for urological operation

The following drugs and concentration ranges in the physiological carrier solution are preferred for use in irrigating the surgical site during urological procedures. This solution is believed to be more cost effective than the solution listed in example III above.

Concentration (nM):

type of drug Medicine Treatment of Preference is given to Most preferably

5-hydroxytryptamine 2 antagonist LY 538570.1-5001-10050

Histamine 1 antagonist terfenadine 0.1-1,00050-

10,000800 ketorolac 5,0003,000 cyclooxygenase inhibitors

Neurokinin 2 antagonist SR 489681-

Purine 2X antagonist PPADS 100-

100,000

ATP-sensitive K⁺(-) pinacidil 1-10,000100 and 1,000500

Channel agonists

Ca²⁺Channel antagonist nifedipine 1-10,000100-5,0001,000-

Kallikrein inhibitor aprotinin 0.1-1,00050-500200

Nitrogen monoxide donor SIN-110-10, 000100-1, 000500

G. Example VII

Balloon dilatation of the normal Iliac artery and histamine and 5-hydroxytryptamine receptors in new zealand big ear white rabbits Effect of somatic blockade on balloon dilatation response

The objective of this study was two-fold, first, a new in vivo model was used for studying arterial tone. The time course of the change in the artery diameter before and after balloon angioplasty is described below. Second, the role of histamine and 5-hydroxytryptamine in combination in regulating arterial tone in this experimental setup was then investigated by selectively perfusing the arteries with histamine and 5-hydroxytryptamine receptor blockers before and after angioplasty.

1. Design basis

This study was to demonstrate the time course of arterial lumen diameter changes in one set of arteries and to evaluate the effect of histamine and 5-hydroxytryptamine receptor blockade on these changes in a second set of similar arteries. To facilitate comparison between the two different groups, both groups were treated in the same way during the experiment, except that the perfusate used was of a different composition. In control animals (arteries), the perfusate was normal saline (as vehicle for test solution). Histamine and 5-hydroxytryptamine receptor blockade treated arteries received saline containing a blocking agent at the same rate and in the same protocol section as control animals. In particular, the test solutions include: (a) the 5-hydroxytryptamine 3 antagonist metoclopramide, the concentration is 16.0 μ M; (b) 5-hydroxytryptamine 2 antagonist trazodone, at a concentration of 1.6 μ M; and (c) the histamine antagonist promethazine, at a concentration of 1.0 μ M. All these blockers were dissolved in physiological saline. The study was conducted in a prospective, randomized and blinded fashion. The assignment of the particular animal groups was randomized and the composition of the perfusion solution (saline alone or containing histamine and 5-hydroxytryptamine receptor antagonist) was kept secret from the investigator until the vessel image analysis was complete.

2. Animal protocol

The scheme is approved by the animal application committee of the Seattle refund military human affairs medical center, and the experimental facilities are completely approved by the American society for laboratory animal management and identification. Iliac arteries of male new zealand white rabbits fed 3-4kg weight with normal rabbit feed were used for the study. Animals were sedated by intravenous xylazine (5mg/kg) and ketamine (35mg/kg) and the carotid artery was isolated by cutting the ventral midline of the neck. The distal end of the artery is ligated, arteriotomized, and a catheter labeled French No. 5 is inserted into the descending aorta. Baseline blood pressure and heart rate were recorded, then 76% iopamidol (Squibb Diagnostics, Princeton, NJ) was injected into the descending aorta by manual injection, and angiographies of the distal aorta and bilateral iliac arteries were recorded on 35mm cine film (15 frames per second). For each vessel image, a correction objective lens is placed within the field of view of the radiograph for magnification correction when making vessel diameter measurements. An infusion catheter (Advanced Cardiovascular Systems, Santa Clara, Calif.) with a French scale number 2.5 is placed through the carotid sheath and fixed 1-2cm above the aortic bifurcation. The test solution-saline alone or saline containing histamine and 5-hydroxytryptamine receptor antagonist-was initially perfused at a rate of 5ml per minute for 15 minutes. At 5 minutes into perfusion, a second angiogram was performed using the technique described above, and then a 2.5mm balloon angioplasty catheter (the Lightning, Cordis Corp., Miami, FL) was inserted rapidly into the left and then the right iliac artery under fluoroscopic guidance. In each iliac artery, a balloon catheter was carefully positioned between the proximal and distal deep femoral branches using bony landmarks, and the balloon was inflated for 30 seconds to a pressure of 12 ATM. The balloon catheter is filled with a dilute solution of radiographic contrast so that the inflated balloon diameter can be recorded on the motion picture film. On average at 8 minutes after the start of perfusion, the angioplasty catheter was removed quickly and another angiogram was recorded on the cine film. Perfusion continued until the 15 minute time point and another angiogram was taken (4 th). The perfusion was then stopped (total perfused amount was 75ml solution) and the perfusion catheter was removed. At the 30 minute time point (i.e., 15 minutes after perfusion cessation), the last angiogram was recorded as before. Blood pressure and heart rate were recorded immediately 15 and 30 minutes prior to the angiographic picture. After the last angiogram, the animals were sacrificed by intravenous injection of excess anesthetic, the iliac arteries removed and fixed in formalin solution for histological analysis.

3. Angiographic analysis

Angiograms were recorded on 35mm motion picture film at a film rate of 15 films per second. For analysis, vessel projections were projected from a Vanguard projector at a distance of 5.5 feet, and iliac artery diameters at pre-specified locations relative to the balloon angioplasty site were recorded based on measurements made by measuring the calibrant for the hand-held compass after magnification correction. Measurements were taken at time points at baseline (before the start of perfusion of the test solution), 5 minutes into perfusion, immediately after balloon angioplasty (8 minutes on average after the start of perfusion of the test solution), 15 minutes (just before the end of perfusion) and 30 minutes (15 minutes after the end of perfusion). Vascular diameter measurements were made at three different sites of each iliac artery: a proximal end of a balloon inflation location, and a distal end of the balloon inflation location.

The diameter measurement is then converted to an area measurement according to the following formula:

area (Pi) (diameter)²)/4

To calculate vasoconstriction, a baseline value is used to represent the maximum arterial area and the percent vasoconstriction is calculated as follows:

vasoconstriction (%) - (area of baseline-area of later time point) ÷

Base line area ]. times.100

4. Statistical method

All data are expressed as mean ± 1 standard error of the mean. The time course of the control arterial vascular motor response was evaluated using a univariate analysis of variance (one wayanalysis of variance) with repeated measurement corrections. After this time a Scheffe test was used to compare the data between the specific time points. Once the time point at which significant vasoconstriction occurred in the control artery was determined, the control artery and the artery treated with the histamine/5-hydroxytryptamine receptor antagonist were compared using the multiple-group analysis of variance with the treatment group as the independent variable at the time point at which significant vasoconstriction occurred in the control artery. To negate the previously proposed undifferentiated assumption, p values < 0.01 are considered significantly different. Statistical processing was performed using Windows version 4.5 statistical software (Statsoft, Tulsa, UK).

5. Results

The time course of the change in arterial diameter before and after normal arterial balloon angioplasty receiving saline perfusion was evaluated in 16 arteries of 8 animals (Table 21). Each artery was studied in three sections: a proximal section immediately upstream from the balloon inflation section, a balloon inflation section, and a distal section immediately downstream from the balloon inflation section. The proximal and distal segments demonstrate similar arterial diameter variation maps: at each segment, there was a significant change in arterial diameter when compared at each time point (proximal segment, p 0.0002; distal segment, p < 0.001, ANOVA). The results of the Post hoc test indicate that at the time point immediately after angioplasty, the vessel diameter is significantly smaller than the vessel diameter at the baseline or at the 30 minute time point for each segment. On the other hand, the arterial diameter of each segment was similar to the baseline diameter at the 5 minute, 15 minute and 30 minute time points. The balloon-inflated section has a smaller change in arterial diameter than the proximal and distal sections. The base line diameter of the section is 1.82 +/-0.05 mm; the nominal straight line after inflation of the balloon used for angioplasty was 2.5mm, and the actual measured inflated balloon diameter was 2.20 ± 0.03mm (p < 0.0001 compared to the baseline diameter of the balloon treated segment). Thus, the inflated balloon causes circumferential stretching of the balloon-inflated segment vessel, but only a slight increase in vessel lumen diameter from baseline to the 30 minute time point (1.82 ± 0.05mm to 1.94 ± 0.07mm, p ═ NS according to Post hoc measurements).

TABLE 21

Before and after normal iliac artery balloon inflation at specific time points

Lumen diameter measured from angiogram

5min PTA at segment baseline immediately followed by 15min 30min

Proximal end¹ 2.18±0.7 2.03±0.7 1.81±0.08^* 2.00±0.08 2.23±0.08

Air bag² 1.82±0.05 1.77±0.03 1.79±0.05 1.70±0.04 1.94±0.07

Distal end³ 1.76±0.04 1.68±0.04^** 1.43±0.04^* 1.54±0.03 1.69±0.06

All measurements are expressed in mm, mean ± standard error (Means ± SEM), PTA:

percutaneous transluminal angioplasty.¹p ═ 0.0002(ANOVA, intra group comparison).

²p-0.03 (ANOVA, intra-group comparison).³p < 0.0001(ANOVA, intra-group comparison), with n-16 at each time point.

^*p < 0.01, to baseline and to the diameter measurement ratio at the 30 minute time point (Scheffe test for post hoc test comparison).

^**p < 0.01, compared to the ratio measured immediately after PTA (Scheffe test for post hoc detection). All other post hoc comparisons were made with a probability level of p < 0.01, with no significant change。

The luminal area was calculated using the arterial luminal diameter and then the percent vasoconstriction was calculated by comparing the area measurements at 5 minutes, immediately after angioplasty, at 15 and 30 minute time points with the baseline measurements. Data for the proximal and distal segments expressed as percent vasoconstriction are shown in figure 1; the change in vasoconstriction over time was significant (p ═ 0.0008 in the proximal segment; p ═ 0.0001 in the distal segment, ANOVA). post hoc experiments found that vasoconstriction at the time point immediately after angioplasty differed significantly (p < 0.01 in both segments) compared to the constriction at the 30 minute time point. In the distal segment, vasoconstriction immediately after angioplasty was also significantly less than the 5 minute time point (p < 0.01); with the post hoc test, no significant difference was observed in the comparison between the other time points.

Lumen changes of the control arteries can be summarized as follows: (1) vasoconstriction occurs in the proximal and distal arterial sections at a level of basal luminal area that is about 30% less than the balloon-expandable section loss upon balloon inflation. There is a tendency that: before dilation and at the 15 minute time point (about 7 minutes after dilation), the proximal and distal segments were less vasoconstrictive, but by the 30 minute time point (about 22 minutes after dilation), the tendency of the vessel to dilate has replaced the previous vasoconstriction; (2) in the balloon-expanded section, there is only a small change in the lumen area of the vessel, and although the expanded vessel diameter is significantly larger than the base diameter of the section due to the balloon application, the lumen diameter of the expanded section is not significantly increased. These findings lead to the conclusion that: the effect of this putative histamine/5-hydroxytryptamine treatment may only be detectable at the proximal and distal segments at the time point when vasoconstriction is present.

This histamine/5-hydroxytryptamine receptor blocking solution was perfused into 16 arteries (8 animals). Angiographic image data were acquired at all time points of the 12 arteries. Heart rate and systolic pressure were measured at each time point in the experimental animals (table 22). When two groups of animals were compared at a specific time point, there was no difference in heart rate and systolic blood pressure. The baseline systolic blood pressure of histamine/5-hydroxytryptamine treated animals tended to decrease compared to 30 minutes (-13 ± 5mmHg, p ═ 0.04), and the heart rate tended to decrease compared to 30 minutes (-26 ± 10, p ═ 0.05). Both heart rate and systolic blood pressure were unchanged throughout the experiment in the control animals.

TABLE 22

Control and histamine/5-hydroxytryptamine treated animal systolic blood pressure and heart rate determinations

Group baseline 5min 15min 30min

(n) (n) (n) (n)

Systolic pressure

Controls 83. + -. 4(8) 84. + -. 4(8) 82. + -. 6(8) 80. + -. 4(8)

Histamine/5-hydroxytryptamine 93 + -5 (6) 87 + -9 (4) 82 + -9 (6) 80 + -8 (6)^*

Heart rate

Controls 221. + -. 18(5) 234. + -. 18(4) 217. + -. 23(5) 227. + -. 22(5)

Histamine/5-hydroxytryptamine 232 + -8 (5) 209 + -14 (5) 206 + -12 (5)^**

Systolic blood pressure is expressed in mmHg and heart rate in beats per minute. Mean ± SEM. The ratio of the contraction pressure of the base line in the animal treated by the histamine/5-hydroxytryptamine to the contraction pressure of the base line in the animal treated by the histamine/5-hydroxytryptamine is 30min,^*p is 0.04, and shows a descending trend, the ratio of the baseline heart rate to 30min,^**p is 0.05, which is in the downward trend.

This parameter was measured as percent vasoconstriction and the histamine/5-hydroxytryptamine treated proximal and distal segments of the artery were compared to the control artery. Figure 2A shows the effect of histamine/5-hydroxytryptamine perfusion on proximal segment vasoconstriction compared to vasoconstriction present in control arteries. When the two treated animal groups were compared at baseline immediately after angioplasty and at the 15 minute time point, histamine/5-hydroxytryptamine perfusion resulted in a significant reduction in vasoconstriction compared to the saline control (p ═ 0.003, 2-way ANOVA). A comparison of distal segments of the two treated groups is illustrated in fig. 2B. Although differences in mean vessel diameter measurements in the distal segment were observed, the drug solution treated vessels showed less vasoconstriction than the saline treated control vessels at baseline, immediately after angioplasty and at the 15 minute time point, but this difference did not reach statistically significant levels (p ═ 0.32, 2-way ANOVA). The reason for the lack of statistically significant differences may be due to the fact that the degree of vasoconstriction in the control vessels is less than expected.

H. Example VIII

Inhibition of 5-hydroxytryptamine-induced knee plasma extravasation by amitriptyline-comparison of intraarticular administration with intravenous route

To compare the administration of the 5-hydroxytryptamine receptor antagonist amitriptyline by both routes, the following tests were performed: in the rat knee synovial fluid inflammation model, (1) continuous intra-articular perfusion, (2) as a comparison, intravenous injection was performed. The ability of amitriptyline to inhibit 5-HT-induced joint plasma extravasation was determined by comparing the potency of amitriptyline administered by both routes and the total dose administered.

1. Animal(s) production

These studies were approved by the animal care committee of the institute of university of california, san francisco, cisscones (san francisco). Male Sprague-Dawley rats (Bantin and Kingman, Fremont, CA) weighing 300-450g were used for these studies. Rats were housed under controlled light conditions (light from 6AM to 6PM) with no restriction on feed and water.

2. Extravasation of plasma

After anesthetizing the rats with phenobarbital sodium (65mg/kg), the tail vein was injected with Yiwenlan (50mg/kg, injection volume 2.5ml/kg), which served as a marker for plasma protein extravasation. Superficial skin was incised to expose the knee joint cavity and a 30 gauge needle was inserted into the joint for use as the perfusion fluid. The perfusion rate (250. mu.l/min) was controlled with a Sag Instruments Syring pump (model 341B, Orion Research, Boston, Mass.). A25 gauge needle was also inserted into the joint cavity and the perfusate was withdrawn at a rate of 250 μ l/min, controlled by a Sag Instruments Syringe pump (model 351).

Rats were randomized into three groups: (1) a portion of the rats received 5-HT (1 μ M) intra-articularly (IA), (2) a portion of the rats received amitriptyline Intravenously (IV) (at a dose ranging from 0.01 to 1.0mg/kg) followed by IA 5HT (1 μ M), and (3) a portion of the rats received amitriptyline intra-articularly (IA) (at a concentration ranging from 1 to 100nM) followed by IA 5HT (1 μ M) plus IA amitriptyline. Basal plasma extravasation level data were obtained for all groups, at the beginning of each experiment, by intra-articular infusion of 0.9% normal saline, and collection of three perfusate samples (one every 5 minutes) over a 15 minute period. The first group was then given 5-HT via IA, perfused for a total of 25 minutes. One perfusate sample was collected every 5 minutes for 25 minutes. The concentration of the Ile dye in the sample was then determined spectrophotometrically at 620nm, which is linear with the dye concentration (Carr and Wilhelm, 1964). IV amitriptyline group animals were given amitriptyline during tail vein injection of iturin. The knee joint was then perfused with physiological saline (basal) for 15 minutes followed by 5-HT (1. mu.M) for 25 minutes. Perfusate samples were collected every 5 minutes for 25 minutes. The sample was then analyzed spectrophotometrically. In the IA amitriptyline group, after 15 minutes of saline infusion, the joints were perfused with amitriptyline for 10 minutes, followed by a 25 minute joint infusion of amitriptyline with 5-HT. One tube of lavage fluid was collected every 5 minutes and analyzed as above.

Some rat knee joints were excluded from the study for the following reasons: physiological damage to the knee joint, or improper ratios of inflow and outflow (blood may be detected in the perfusate, high basal levels of plasma extravasation, or joint swelling due to improper needle placement).

a.5-HT induced plasma extravasation

Basal plasma extravasation values were determined in all tested knee joints (total n 22). The basal plasma extravasation level was low with a mean absorbance unit at 620nm of 0.022 ± 0.003 (mean ± standard error of the mean). This basal extravasation level is shown in figures 1 and 2, as indicated by the dashed line.

Infusion of 5-HT (1. mu.M) into the knee joints of rats produced a time-dependent increase in plasma extravasation above basal levels. Plasma extravasation was maximal at 15min during 25 min of 5-HT intra-articular perfusion and continued until the end of perfusion at 25 min (unpublished data). Therefore, the reported plasma extravasation levels by 5-HT are averages of three time points at 15, 20 and 25 minutes during each experiment. 5-HT caused plasma extravasation averaging 0.192. + -. 0.011, approximately 8-fold higher than the basal extravasation level. This data is represented graphically in figures 3 and 4, corresponding to the "0" dose of IV amitriptyline and the "0" dose of IA amitriptyline, respectively.

b. Effect of intravenous amitriptyline administration on 5-HT-induced plasma extravasation

As shown in FIG. 3, administration of amitriptyline by tail vein injection produced a dose-dependent reduction in plasma extravasation induced by 5-HT. IV IC of amitriptyline for inhibiting 5-HT induced plasma extravasation₅₀The value was about 0.025 mg/kg. Plasma extravasation induced by 5-HT was completely inhibited by an IV dose of 1mg/kg amitriptyline, with a mean plasma extravasation of 0.034 + -0.010.

c. Effect of Intra-articular amitriptyline administration on 5-HT-induced plasma extravasation

Amitriptyline alone, administered in a manner that increased intra-articular concentrations did not affect plasma extravasation levels compared to basal extravasation levels, with plasma extravasation averaging 0.018 ± 0.002 (data not shown). Amitriptyline as a medicamentThe increased concentration mode, combined with 5-HT perfusion, as shown in FIG. 4, produced a concentration-dependent reduction in 5-HT induced plasma extravasation. In the presence of 3nM of IA amitriptyline, 5-HT induced plasma extravasation was not significantly different from that induced by 5-HT alone, however, 30nM amitriptyline was more than 50% inhibited when infused in combination with 5-HT, whereas 100nM amitriptyline infused in combination with 5-HT completely inhibited 5-HT induced plasma extravasation. IC for inhibition of 5-HT-induced plasma extravasation by IA amitriptyline₅₀The value was approximately 20 nM.

The main findings of this study were: (1) intra-knee perfusion of 5-HT (1 μ M) in rats stimulated plasma extravasation in an amount of approximately 8-fold of basal levels. (2) The 5-HT receptor antagonist amitriptyline inhibits plasma extravasation induced by 5-HT, whether administered intravenously or intra-articularly. However, the total dose of amitriptyline administered is quite different between the two methods of administration. IV IC of amitriptyline for inhibition of 5-HT-induced plasma extravasation₅₀0.025mg/kg, or a 300g adult rat requires 7.5X 10^-3IC of mg, IA amitriptyline inhibits 5-HT-induced plasma extravasation₅₀Was 20 nM. Since the solution was infused every 5 minutes with 1ml for 25 minutes, the total dose infused into the knee joint was 7ml, corresponding to a total dose of 4.4X 10^-5mg amitriptyline was infused into the knee joint. The IA amitriptyline dose is about 200 times lower than the IV amitriptyline dose. Furthermore, it is possible that only a small fraction of the IA infused drug is absorbed systemically, resulting in an even greater difference in the total dose of drug administered (by both routes of administration).

Given that 5-HT may play an important role in surgical pain and inflammation, 5-HT antagonists such as amitriptyline may be beneficial if used perioperatively. A recent study attempted to determine the effect of oral amitriptyline on postoperative orthopedic pain (Kerrick et al, 1993). Oral doses as low as 50mg produce undesirable CNS side effects such as "reduced physical well-being". In addition, the study demonstrated that oral amitriptyline produced a higher pain score in postoperative patients than placebo (P0.05). It is not clear whether this is due to the total unpleasantness associated with oral administration of amitriptyline. In contrast, intra-articular routes of administration allow for very low drug doses to be applied locally to the site of inflammation, so that maximum efficacy with minimal side effects is possible.

While the preferred embodiments of the invention have been illustrated and described, it will be appreciated that various changes can be made in the solutions and methods disclosed without departing from the spirit and scope of the invention. For example, in light of the disclosure herein, it is possible to find alternative pain-suppressing drugs as well as anti-inflammatory and anti-spasmodic drugs. It is intended that the scope of the granted patent certificate be limited only by the detailed description of the appended claims.

Claims (48)

1. Use of a mixture for perioperatively inhibiting pain, inflammation and/or spasm in a wound by topically applying the mixture to the wound during an arthroscopic, urological, oral/dental, general surgical, open surgical or body cavity procedure, wherein the medicament is for irrigating the wound, i.e., irrigating the wound with the solution during a medical procedure, wherein each drug in the mixture is at a concentration of no more than 100,000nM, or is at a concentration or dose sufficient to provide a therapeutically effective level at the wound when topically applied thereto and a resulting plasma concentration that is lower than the plasma concentration required to achieve the same therapeutically effective level at the wound when systemically administered, and wherein the mixture comprises a solution of a plurality of inhibitory drugs selected from the group consisting of pain/inflammation inhibitory drugs and spasm inhibitory drugs in a physiological fluid, these drugs are selected from a wide variety of classes of drugs that act, through different molecular mechanisms, on unique target molecules that may mediate pain, inflammation, or spasm, and are generally effective in inhibiting pain, inflammation, and/or spasm at the wound site.

2. The use of claim 1, wherein the concentration of each agent in the mixture is no greater than 10,000 nM.

3. The use of claim 1, wherein the plurality of drug classes in the mixture comprises one or more pain/inflammation suppressing drug classes selected from the group consisting of: 5-hydroxytryptamine receptor antagonists; a 5-hydroxytryptamine receptor agonist; (ii) a histamine receptor antagonist; bradykinin receptor antagonists; (ii) a kallikrein inhibitor; neurokinin receptor antagonists, including neurokinin 1 receptor subtype antagonists and neurokinin 2 receptor subtype antagonists; calcitonin gene-related peptide receptor antagonists; an interleukin receptor antagonist; phospholipase inhibitors including PLA₂Alloenzyme and PLC γ alloenzyme inhibitors; a cyclooxygenase inhibitor; an lipoxygenase inhibitor; prostanoid receptor antagonists including eicosanoid EP-1 and EP-4 receptor subtype antagonists and thromboxane receptor subtype antagonists; leukotriene receptor antagonists, including leukotriene B₄And D₄A receptor subtype antagonist; opioid receptor agonists including mu-opioid receptor subtype agonists, delta-opioid receptor subtype agonists, and kappa-opioid receptor subtype agonists; purine receptor agonists and antagonists, including P_2YReceptor agonists and P_2XA receptor antagonist; and ATP-sensitive potassium channel openers.

4. The use as claimed in claim 3, wherein theThe concentrations of the selected pain/inflammation-inhibiting drugs in the mixture were as follows: 5-hydroxytryptamine receptor antagonist 0.1-10,000 nM; 5-hydroxytryptamine receptor agonist 0.1-2,000 nM; histamine receptor antagonist 0.1-1,000 nM; bradykinin antagonists 1-10,000 nM; kallikrein inhibitor 0.1-1000 nM; neurokinin 1 receptor subtype antagonists 0.1-10,000 nM; neurokinin 2 receptor subtype antagonists 1.0-10,000 nM; 1.0-1,000nM of calcitonin gene-related peptide antagonist; interleukin antagonist 1-1,000 nM; PLA (polylactic acid)₂100,000nM of the alloenzyme inhibitor; 100,000nM of cyclooxygenase inhibitor; lipoxygenase inhibitor 100-; the eicosanoid EP-1 receptor subtype antagonist 100-10,000 nM; leukotriene B₄Receptor subtype antagonist 100. about.10,000 nM; mu-opioid receptor subtype agonist 0.1-100 nM; delta-opioid receptor subtype agonist 0.1-500 nM; kappa-opioid receptor subtype agonist 0.1-500 nM; 100,000nM of purine receptor antagonist; ATP-sensitive potassium channel openers 0.1-10,000 nM.

5. The use of claim 1 or 3, wherein at least one drug in the mixture comprises a cyclooxygenase inhibitor and at least one other drug comprises a 5-hydroxytryptamine receptor antagonist and/or a histamine receptor antagonist.

6. The use of claim 5, wherein the mixture comprises a cyclooxygenase inhibitor and amitriptyline.

7. Use according to claim 1 or 3, wherein at least one drug in the mixture comprises a cyclooxygenase inhibitor and the at least one further drug comprises a calcium channel antagonist.

8. The use of claim 7, wherein the mixture comprises a cyclooxygenase inhibitor and nifedipine.

9. The use of claim 1 or 3, wherein the mixture comprises at least one pain/inflammation inhibiting drug and one spasm inhibiting drug, i.e. a calcium channel antagonist.

10. The use of claim 9, wherein the concentration of the calcium channel antagonist is no more than 10,000 nM.

11. The use of claim 1 or 3, wherein at least one selected drug type in the mixture comprises a spasm-inhibiting drug for inhibiting smooth muscle spasm.

12. The use of claim 11, wherein the one or more spasticity-inhibiting drugs is selected from the group consisting of: 5-hydroxytryptamine 2 receptor subtype antagonists, tachykinin receptor antagonists, nitric oxide donors, ATP-sensitive potassium channel openers, and endothelin receptor antagonists.

13. The use of claim 12, wherein the concentrations of the one or more spasticity-inhibiting drugs selected are as follows: 5-hydroxytryptamine 2 receptor antagonist 0.1-10,000 nM; tachykinin receptor antagonists 0.1-10,000 nM; nitric oxide donors 1.0-10,000 nM; 0.1-10,000nM of ATP-sensitive potassium channel opener; the endothelin receptor antagonist is 0.01-100,000 nM.

15. Use according to claim 1 or 3, wherein the plurality of drug types in the mixture are selected from the following types: a receptor agonist; a receptor antagonist; an enzyme inhibitor; an enzyme activator; an ion channel opener; and receptor-operated ion channel antagonists.

15. The use of claim 1, wherein the plurality of agents in the solution comprises one or more selected pain/inflammation suppressing agents selected from the group consisting of: a 5-hydroxytryptamine 2 receptor antagonist at a concentration of 50-500 nM; 5-hydroxytryptamine 3 receptor antagonist at a concentration of 200 and 2000 nM; histamine 1 receptor antagonist at a concentration of 50-500 nM; 5-hydroxytryptamine receptor agonist at a concentration of 10-200 nM; cyclooxygenase inhibitor, concentration 800-; neurokinin 1 receptor subtype antagonists at concentrations of 10-500 nM; neurokinin 2 receptor subtype antagonists at concentrations of 10-500 nM; a purine receptor antagonist at a concentration of 10,000 and 100,000 nM; ATP-sensitive potassium channel openers at a concentration of 100-1000 nM; kallikrein inhibitor at a concentration of 50-500 nM.

16. The use of claim 1, wherein said applying step comprises irrigating at least a portion of the urinary tract during a urological procedure, and said irrigating solution of pharmaceutical agent comprises at least one selected spasm-inhibiting drug and at least one selected pain/inflammation-inhibiting drug, the selected drugs comprising: a 5-hydroxytryptamine 2 receptor subtype antagonist at a concentration of 1-100 nM; histamine 1 receptor subtype antagonists at a concentration of 50-500 nM; cyclooxygenase inhibitor, concentration 800-; neurokinin 2 receptor subtype antagonists at concentrations of 10-500 nM; a purine receptor antagonist at a concentration of 10,000 and 100,000 nM; ATP-sensitive potassium channel openers at a concentration of 100-1000 nM; kallikrein inhibitor at a concentration of 50-500 nM; and nitric oxide donor at a concentration of 100-1000 nM.

17. The use of claim 1, wherein the solution comprises a 5-hydroxytryptamine receptor antagonist, an ATP-sensitive potassium channel opener, a calcium channel antagonist at a concentration of no more than 100,000 nM.

18. An irrigation solution for perioperative suppression of pain and inflammation and/or spasticity during arthroscopic, urological, oral/dental, general surgery, open surgery or body cavity procedures, for topical application to a wound during the procedure, the solution comprising a dilute solution of a plurality of inhibitory drugs selected from the group consisting of pain/inflammation inhibitory drugs and spasm inhibitory drugs in a physiological fluid carrier, wherein each drug is present at a concentration of no more than 100,000nM, or at a concentration or dose sufficient to provide a therapeutically effective level at the wound when topically applied thereto and a plasma concentration produced that is lower than that required to achieve the same therapeutically effective level at the wound when administered systemically, the plurality of drugs being selected from a plurality of drug types that act, by different molecular mechanisms, on unique target molecules that mediate pain, inflammation or spasticity, these drugs are generally selected to be effective in inhibiting pain, inflammation and/or spasm at the wound site.

19. The solution of claim 18 wherein the plurality of drug classes includes one or more pain/inflammation suppressing drug classes selected from the group consisting of: 5-hydroxytryptamine receptor antagonists; a 5-hydroxytryptamine receptor agonist; (ii) a histamine receptor antagonist; bradykinin receptor antagonists; (ii) a kallikrein inhibitor; neurokinin receptor antagonists, including neurokinin 1 receptor subtype antagonists and neurokinin 2 receptor subtype antagonists; calcitonin gene-related peptide receptor antagonists; an interleukin antagonist; phospholipase inhibitors including PLA₂Inhibitors of allozymes and PLC γ allozymes; a cyclooxygenase inhibitor; an lipoxygenase inhibitor; prostanoid receptor antagonists including EP-1 and EP-4 receptor subtype antagonists and thromboxane receptor subtype antagonists; leukotriene receptor antagonists, including leukotriene B₄And D₄A receptor subtype antagonist; opioid receptor agonists including mu-opioid receptor subtype agonists, delta-opioid receptor subtype agonists, and kappa-opioid receptor subtype agonists; purine receptor agonists and antagonists, including P_2YReceptor agonists and P_2XA receptor antagonist; and ATP-sensitive potassium channel openers.

20. The solution of claim 19 wherein the concentration of the pain/inflammation suppressing agent is as follows: 5-hydroxytryptamine receptor antagonist 0.1-10,000 nM; 5-hydroxytryptamine receptor agonist 0.1-2,000 nM; histamine receptor antagonist 0.1-1000 nM; bradykinin receptor antagonists 1-10,000 nM; kallikrein inhibitor 0.1-1000 nM; neurokinin 1 receptor subtype antagonists 0.1-10,000 nM; neurokinin 2 receptor subtype antagonists 1.0-10,000 nM; 1.0-1000nM of calcitonin gene-related peptide receptor antagonist; interleukin antagonist 1-1000 nM; 100,000nM of phospholipase inhibitor; 100,000nM of cyclooxygenase inhibitor; lipoxygenase inhibitor 100-; similar peanutAcid EP-1 receptor antagonist 100-10,000 nM; leukotriene B₄Receptor antagonist 100-; mu-opioid receptor subtype agonist 0.1-100 nM; delta-opioid receptor subtype agonist 0.1-500 nM; kappa-opioid receptor subtype agonist 0.1-500 nM; 100,000nM of purine receptor antagonist; and 0.1-10,000nM of ATP-sensitive potassium channel opener.

21. The solution of claim 18 or 19, wherein at least one of the selected drug types in the solution comprises a spasm-inhibiting drug for inhibiting smooth muscle spasm.

22. The solution of claim 21, wherein the spasm-inhibiting agent is selected from the group consisting of: 5-hydroxytryptamine 2 receptor subtype antagonists; tachykinin receptor antagonists; a nitric oxide donor; ATP-sensitive potassium channel openers; a calcium channel antagonist; and endothelin receptor antagonists.

23. The solution of claim 22, wherein the concentration of the spasm inhibition drug is as follows: 5-hydroxytryptamine 2 receptor subtype antagonist 0.1-10,000 nM; tachykinin receptor antagonists 0.1-10,000 nM; nitric oxide donors 1.0-10,000 nM; 0.1-10,000nM of ATP-sensitive potassium channel opener; the endothelin receptor antagonist is 0.01-100,000 nM.

24. The solution of claim 18 or 19, wherein the concentration of each agent is no more than 10,000 nM.

25. The solution of claim 18 or 19 wherein at least one drug in the mixture comprises a cyclooxygenase inhibitor and at least one other drug comprises a 5-hydroxytryptamine receptor antagonist and/or a histamine receptor antagonist.

26. The solution of claim 25 wherein the mixture comprises a cyclooxygenase inhibitor and amitriptyline.

27. The solution of claim 18 or 19 wherein at least one drug in the mixture comprises a cyclooxygenase inhibitor and the at least one other drug comprises a calcium channel antagonist.

28. The solution of claim 27, wherein the mixture comprises a cyclooxygenase inhibitor and nifedipine.

29. The solution of claim 18 or 19, wherein the drug type in the solution is selected from the group consisting of: a receptor agonist; a receptor antagonist; an enzyme inhibitor; an enzyme activator; an ion channel opener; and receptor-operated ion channel antagonists.

30. The solution of claim 18 or 19, wherein the solution comprises at least one pain/inflammation inhibiting drug and one spasm inhibiting drug, i.e., a calcium channel antagonist.

31. The solution of claim 30, wherein the solution comprises the calcium channel antagonist at a concentration of no more than 100,000 nM.

32. Use of a mixture for perioperatively inhibiting pain and inflammation and/or spasticity at a vascular structure by topically applying the mixture to the site of the vascular structure during an intravascular procedure during the procedure, wherein the medicament is for irrigating the vascular structure, i.e., irrigating a wound with the solution during a medical procedure, and wherein the mixture comprises a dilute solution of a plurality of inhibitory drugs selected from the group consisting of pain/inflammation inhibitory drugs and spasm inhibitory drugs, each drug being present in a concentration of no more than 100,000nM, or in a concentration or dose sufficient to provide a therapeutically effective level at the wound when topically applied thereto and a plasma concentration that is less than the plasma concentration required to achieve the same therapeutically effective level at the wound when systemically administered, the drugs being selected from the group consisting of multiple types of drugs, it acts through a unique molecular mechanism of action, where each class of drugs is selected from receptor antagonists, receptor agonists, enzyme inhibitors, enzyme activators, ion channel openers and receptor-manipulated ion channel antagonists, which are generally effective in inhibiting pain and inflammation and/or spasm at vascular structures.

33. The use of claim 32, wherein the concentration of each agent in the mixture does not exceed 10,000 nM.

34. The use of claim 32, wherein the drug classes include one or more pain/inflammation suppressing drug classes selected from the group consisting of: 5-hydroxytryptamine receptor antagonists; a 5-hydroxytryptamine receptor agonist; (ii) a histamine receptor antagonist; bradykinin receptor antagonists; (ii) a kallikrein inhibitor; neurokinin receptor antagonists, including neurokinin 1 receptor subtype antagonists and neurokinin 2 receptor subtype antagonists; calcitonin gene-related peptide receptor antagonists; an interleukin antagonist; phospholipase inhibitors including PLA₂Inhibitors of allozymes and PLC γ allozymes; a cyclooxygenase inhibitor; an lipoxygenase inhibitor; prostanoid receptor antagonists including EP-1 and EP-4 receptor subtype antagonists and thromboxane receptor subtype antagonists; leukotriene receptor antagonists, including leukotriene B₄And D₄A receptor subtype antagonist; opioid receptor agonists including mu-opioid receptor subtype agonists, delta-opioid receptor subtype agonists, and kappa-opioid receptor subtype agonists; purine receptor agonists and antagonists, including P_2YReceptor agonists and P_2XA receptor antagonist; and ATP-sensitive potassium channel openers.

35. The use of claim 34, wherein the concentrations of the pain/inflammation-inhibiting drugs are as follows: 5-hydroxytryptamine receptor antagonist 0.1-10,000 nM; 5-hydroxytryptamine receptor agonist 0.1-2,000 nM; histamine receptor antagonist 0.1-1000 nM; bradykinin receptor antagonists 1-10,000 nM; kallikrein inhibitor 0.1-1000 nM; spirit of the invention0.1-10,000nM of a kinin 1 receptor subtype antagonist; neurokinin 2 receptor subtype antagonists 1.0-10,000 nM; 1.0-1000nM of calcitonin gene-related peptide receptor antagonist; interleukin antagonist 1-1000 nM; 100,000nM of phospholipase inhibitor; 100,000nM of cyclooxygenase inhibitor; lipoxygenase inhibitor 100-; the eicosanoid EP-1 receptor antagonist 100-10,000 nM; leukotriene B₄Receptor antagonist 100-; mu-opioid receptor subtype agonist 0.1-100 nM; delta-opioid receptor subtype agonist 0.1-500 nM; kappa-opioid receptor subtype agonist 0.1-500 nM; 100,000nM of purine receptor antagonist; and 0.1-10,000nM of ATP-sensitive potassium channel opener.

36. The use of claim 32 or 34, wherein at least one selected drug type in said mixture comprises a class of spasm-inhibiting drugs for inhibiting spasm of blood vessels or smooth muscle, which class of drugs targets enzymes, receptors, ATP-sensitive potassium channels or receptor-operated ion channels.

37. The use of claim 32 or 34, wherein the one or more spasm-inhibiting drugs is selected from the group consisting of: 5-hydroxytryptamine 2 receptor subtype antagonists; tachykinin receptor antagonists; a nitric oxide donor; ATP-sensitive potassium channel openers; a calcium channel antagonist; and endothelin receptor antagonists.

38. The use of claim 37, wherein the concentration of the selected spasm-inhibiting drugs is as follows: 5-hydroxytryptamine 2 receptor antagonist 0.1-10,000 nM; tachykinin receptor antagonists 0.1-10,000 nM; nitric oxide donors 1.0-10,000 nM; 0.1-10,000nM of ATP-sensitive potassium channel opener; the endothelin receptor antagonist is 0.01-100,000 nM.

39. The use of claim 32, wherein the irrigation fluid used comprises at least one selected spasm-inhibiting drug and at least one selected pain/inflammation-inhibiting drug, the selected drugs comprising: a 5-hydroxytryptamine 2 receptor subtype antagonist at a concentration of 50-500 nM; cyclooxygenase inhibitor, concentration 800-; an endothelin receptor antagonist at a concentration of 10-1000 nM; ATP-sensitive potassium channel openers at a concentration of 100-1000 nM; and nitric oxide donor at a concentration of 100-1000 nM.

40. An irrigation solution for perioperatively inhibiting pain and/or inflammation at a vascular structure by locally applying the solution to the vascular structure during a procedure during an intravascular procedure; the solution comprises a dilute solution of a plurality of inhibitory drugs selected from the group consisting of pain/inflammation inhibitory drugs and spasm inhibitory drugs in a physiological fluid carrier, wherein each drug is at a concentration and dose sufficient to provide a therapeutically effective level at the wound site when administered locally to the wound site, and produces a plasma concentration that is lower than that required to achieve the same therapeutically effective level at the wound site when administered systemically, the drugs being selected from a plurality of classes of drugs that act through distinct molecular mechanisms of action, wherein each class of drug is selected from the group consisting of receptor antagonists, receptor agonists, enzyme inhibitors, enzyme agonists, ion channel openers, and receptor-manipulated ion channel antagonists, which are collectively selected to be effective in inhibiting pain and inflammation and/or spasm at the vascular structure.

41. The solution of claim 40 wherein the drug type comprises a pain/inflammation suppressing drug type selected from the following classes of drugs: 5-hydroxytryptamine receptor antagonists; a 5-hydroxytryptamine receptor agonist; (ii) a histamine receptor antagonist; bradykinin receptor antagonists; (ii) a kallikrein inhibitor; neurokinin receptor antagonists, including neurokinin 1 receptor subtype antagonists and neurokinin 2 receptor subtype antagonists; calcitonin gene-related peptide receptor antagonists; an interleukin antagonist; phospholipase inhibitors including PLA₂Inhibitors of allozymes and PLC γ allozymes; a cyclooxygenase inhibitor; an lipoxygenase inhibitor; prostanoid receptor antagonists including eicosanoid EP-1 and EP-4 receptor subtype antagonists and thromboxane receptor subtype antagonists; leukotriene receptor antagonists, including leukotriene B₄And D₄A receptor subtype antagonist; opioid receptor agonists including mu-opioid receptor subtype agonists, delta-opioid receptor subtype agonists, and kappa-opioid receptor subtype agonists; purine receptor agonists and antagonists, including P_2YReceptor agonists and P_2XA receptor antagonist; and ATP-sensitive potassium channel openers.

42. The solution of claim 41 wherein the concentration of pain/inflammation suppressing drug in the solution is as follows: 5-hydroxytryptamine receptor antagonist 0.1-10,000 nM; 5-hydroxytryptamine receptor agonist 0.1-2,000 nM; histamine receptor antagonist 0.1-1000 nM; bradykinin receptor antagonists 1-10,000 nM; kallikrein inhibitor 0.1-1000 nM; neurokinin 1 receptor subtype antagonists 0.1-10,000 nM; neurokinin 2 receptor subtype antagonists 1.0-10,000 nM; 1.0-1000nM of calcitonin gene-related peptide receptor antagonist; interleukin antagonist 1-1000 nM; 100,000nM of phospholipase inhibitor; 100,000nM of cyclooxygenase inhibitor; lipoxygenase inhibitor 100-; the eicosanoid EP-1 receptor antagonist 100-10,000 nM; leukotriene B₄Receptor antagonist 100-; mu-opioid receptor subtype agonist 0.1-100 nM; delta-opioid receptor subtype agonist 0.1-500 nM; kappa-opioid receptor subtype agonist 0.1-500 nM; 100,000nM of purine receptor antagonist; and 0.1-10,000nM of ATP-sensitive potassium channel opener.

43. The solution of claim 40 or 41 wherein at least one selected drug type in said solution comprises a class of spasm-inhibiting drugs for inhibiting vasospasm or smooth muscle spasm.

44. The use of claim 43, wherein the spasm-inhibiting drug is selected from the group consisting of: 5-hydroxytryptamine 2 receptor subtype antagonists; tachykinin receptor antagonists; a nitric oxide donor; ATP-sensitive potassium channel openers; and endothelin receptor antagonists.

45. The solution of claim 44, wherein the concentration of the spasm inhibition drug is as follows: 5-hydroxytryptamine 2 receptor subtype antagonist 0.1-10,000 nM; tachykinin receptor antagonists 0.1-10,000 nM; nitric oxide donors 1.0-10,000 nM; 0.1-10,000nM of ATP-sensitive potassium channel opener; and endothelin receptor antagonist 0.01-100,000 nM.

46. The solution of claim 40 or 41 wherein the concentration of each agent is no more than 100,000 nM.

47. The solution of claim 40 or 41 wherein the concentration of each agent is no more than 10,000 nM.

48. The solution of claim 40 or 41 wherein the drug type in the mixture comprises a pain/inflammation suppressing drug.