OPHTHALMOLOGIC IRRIGATION SOLUTIONS AND METHOD

Abstract

Solutions for perioperative intraocular application by continuous irrigation during ophthalmologic procedures are provided. These solutions include multiple agents that act to inhibit inflammation, inhibit pain, effect mydriasis (dilation of the pupil), and/or decrease intraocular pressure, wherein the multiple agents are selected to target multiple molecular targets to achieve multiple differing physiologic functions, and are included in dilute concentrations in a balanced salt solution carrier.

Claims

1. A composition for use in perioperatively inhibiting ocular inflammation and maintaining mydriasis during an intraocular ophthalmologic procedure, comprising an anti-inflammatory agent and a mydriatic agent in a physiologic irrigation solution for intraocular delivery, wherein the anti-inflammatory agent comprises a non-steroidal anti-inflammatory drug (NSAID) and the mydriatic agent comprises an alpha-1 adrenergic receptor agonist, wherein the NSAID and the alpha-1 adrenergic receptor agonist are included at concentrations less than that used for conventional topical or systemic delivery and in a therapeutically effective amount for the maintenance of mydriasis during the procedure and the reduction of postoperative pain when delivered intraocularly during the intraocular ophthalmologic procedure.

2. The composition of claim 1, wherein the NSAID is selected from the group consisting of flurbiprofen, suprofen, diclofenac, ketoprofen, ketorolac, indomethacin, naproxen, ibuprofen.

3. The composition of claim 1, wherein the NSAID is selected from the group consisting of flurbiprofen, suprofen, diclofenac, ketoprofen and ketorolac.

4. The composition of claim 2, wherein the alpha-1 adrenergic receptor agonist is selected from the group consisting of phenylephrine, epinephrine, and oxymetazoline.

5. The composition of claim 1, wherein the alpha-1 adrenergic receptor agonist is selected from the group consisting of phenylephrine, epinephrine, and oxymetazoline.

6. The composition of claim 1, wherein the alpha-1 adrenergic receptor agonist is selected from the group consisting of phenylephrine and epinephrine.

7. The composition of claim 1, wherein the NSAID is included in the solution at a concentration of no more than 100,000 nanomolar and the alpha-1 adrenergic receptor agonist is included in the solution at a concentration of no more than 500,000 nanomolar.

8. The composition of claim 1, wherein the physiologic solution comprises a balanced salt solution liquid irrigation.

9. The composition of claim 8, wherein the balanced salt solution liquid irrigation carrier further comprises an adjuvant selected from a cellular energy source, a buffering agent, a free-radical scavenger and mixtures thereof.

10. The composition of claim 1, wherein the solution further comprises an analgesic agent selected from the group consisting of local anesthetics and opioids.

11. The composition of claim 10, wherein: the local anesthetic, if selected, is selected from the group consisting of lidocaine, tetracaine, bupivacaine, and proparacaine; and the opioid, if selected, is selected from the group consisting of morphine, fentanyl and hydromorphone.

12. A composition for use in perioperatively inhibiting ocular inflammation and maintaining mydriasis during an intraocular ophthalmologic procedure, comprising an anti-inflammatory agent and a mydriatic agent in a physiologic irrigation solution for intraocular delivery, wherein the anti-inflammatory agent comprises a non-steroidal anti-inflammatory drug (NSAID) and the mydriatic agent comprises an alpha-1 adrenergic receptor agonist, wherein the NSAID and the alpha-1 adrenergic receptor agonist are included at concentrations less than that used for conventional topical or systemic delivery and in a therapeutically effective amount for the maintenance of pupil dilation and inhibition of miosis during the procedure and the reduction of postoperative pain when delivered intraocularly during the intraocular ophthalmologic procedure.

Description

V. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0030] The present invention provides irrigation solutions for perioperative local application to ocular tissues, including intraocular and topical application, which include multiple agents that act to inhibit inflammation, inhibit pain, effect mydriasis (dilation of the pupil), and/or to decrease or control intraocular pressure, wherein the multiple agents are selected to act on multiple, differing molecular targets to achieve multiple differing physiologic functions. The irrigation solutions of the present invention are dilute solutions of multiple pain/inflammation inhibitory agents, IOP reducing agents, and/or mydriatic agents in a physiologic liquid irrigation carrier. The carrier is suitably an aqueous solution that may include physiologic electrolytes, such as normal saline or lactated Ringer's solution. More preferably, the carrier includes sufficient electrolytes to provide a physiological balanced salt solution, a cellular energy source, a buffering agent and a free-radical scavenger.

[0031] A solution in accordance with the present invention can include (a) one or more anti-inflammatory agents in combination with one or more analgesic agents, and optionally may also include one or more agents that act to reduce intraocular pressure (IOP reducing agents) and/or mydriatic agents; (b) one or more anti-inflammatory agents in combination with one or more IOP reducing agents, and optionally one or more analgesic and/or mydriatic agents; (c) one or more anti-inflammatory agents in combination with one or more mydriatic agents, and optionally one or more analgesic agents and/or IOP reducing agents; (d) one or more analgesic agents in combination with one or more IOP reducing agents, and optionally one or more anti-inflammatory agents and/or mydriatic agents; (e) one or more analgesic agents in combination with one or more mydriatic agents, and optionally one or more anti-inflammatory agents and/or IOP reducing agents; or (f) one or more mydriatic agents in combination with one or more IOP reducing agents, and optionally one or more anti-inflammatory and/or analgesic agents.

[0032] Any of these solutions of the present invention may also include one or more antibiotic agents. Suitable antibiotics for use in the present invention include ciprofloxacin, gentamicin, tobramycin and ofloxacin. Other antibiotics that are suitable for perioperative intraocular use are also encompassed by the present invention. Suitable concentrations for one antibiotic suitably included in the irrigation solutions of the present invention, ciprofloxacin, are 0.01 millimolar to 10 millimolar, preferably 0.05 millimolar to 3 millimolar, most preferably 0.1 millimolar to 1 millimolar. Different antibiotics will be applied at different concentrations, as may be readily determined.

[0033] In each of the surgical solutions of the present invention, the agents are included in low concentrations and are delivered locally in low doses relative to concentrations and doses required with conventional methods of drug administration to achieve the desired therapeutic effect. It is impossible to obtain an equivalent therapeutic effect by delivering similarly dosed agents via systemic (e.g., intravenous, subcutaneous, intramuscular or oral) routes of drug administration since drugs given systemically are subject to first- and second-pass metabolism.

[0034] The concentration of each agent may be determined in part based on its dissociation constant, K.sub.d. As used herein, the term dissociation constant is intended to encompass both the equilibrium dissociation constant for its respective agonist-receptor or antagonist-receptor interaction and the equilibrium inhibitory constant for its respective activator-enzyme or inhibitor-enzyme interaction. Each agent is preferably included at a low concentration of 0.1 to 10,000 times K.sub.d, except for cyclooxygenase inhibitors, which may be required at larger concentrations depending on the particular inhibitor selected. Preferably, each agent is included at a concentration of 1.0 to 1,000 times K.sub.d and most preferably at approximately 100 times K.sub.d. These concentrations are adjusted as needed to account for dilution in the absence of metabolic transformation at the local delivery site. The exact agents selected for use in the solution, and the concentration of the agents, varies in accordance with the particular application.

[0035] The surgical solutions constitute a novel therapeutic approach by combining multiple pharmacologic agents acting at distinct receptor and enzyme molecular targets. To date, pharmacologic strategies have focused on the development of highly specific drugs that are selective for individual receptor subtypes and enzyme isoforms that mediate responses to individual signaling neurotransmitters and hormones. This standard pharmacologic strategy, although well accepted, is not optimal since many other agents simultaneously may be responsible for initiating and maintaining a physiologic effect. Furthermore, despite inactivation of a single receptor subtype or enzyme, activation of other receptor subtypes or enzymes and the resultant signal transmission often can trigger a cascade effect. This explains the significant difficulty in employing a single receptor-specific drug to block a pathophysiologic process in which multiple transmitters play a role. Therefore, targeting only a specific individual receptor subtype is likely to be ineffective.

[0036] In contrast to the standard approach to pharmacologic therapy, the therapeutic approach of the present surgical solutions is based on the rationale that a combination of drugs acting simultaneously on distinct molecular targets is required to inhibit the full spectrum of events that underlie the development of a pathophysiologic state. Furthermore, instead of targeting a specific receptor subtype alone, the surgical solutions are composed of drugs that target common molecular mechanisms operating in different cellular physiologic processes involved in the development of pain and inflammation, the reduction in intraocular pressure, and the promotion of mydriasis. In this way, the cascading of additional receptors and enzymes in the nociceptive, inflammatory, and intraocular-pressure-increasing pathways is minimized by the surgical solutions. In these pathophysiologic pathways, the surgical solutions can inhibit the cascade effect both upstream and downstream (i.e., both at points of divergence and convergence of pathophysiologic pathways).

[0037] Preferred solutions of the present invention for use during ophthalmologic surgical procedures include one or more anti-inflammatory agents in combination with one or more mydriatic agents. Such preferred solutions may also include one or more analgesic agents and/or one or more IOP reducing agents, depending on whether a given procedure or condition treated thereby is associated with a high incidence of pain or increased intraocular procedure, respectively.

[0038] These agents are included at dilute concentrations in a physiologic aqueous carrier, such as any of the above-described carriers, e.g., a balanced salt solution. The solution may also include a viscosity increasing agent, e.g., a biocompatible and biodegradable polymer, for longer intraocular retention. The concentrations of the agents are determined in accordance with the teachings of the invention for direct, local application to ocular tissues during a surgical procedure. Application of the solution is carried out perioperatively, i.e.: intra-operatively; pre- and intra-operatively; intra- and post-operatively; or pre-, intra- and post-operatively. The agents may be provided in a stable one-part or two-part solution, or may be provided in a lyophilized form to which a one-part or two-part carrier liquid is added prior to use.

[0039] Functional classes of ophthalmologic agents that would be advantageous for use in perioperative ophthalmologic irrigation solutions of the present invention are now further described.

A. Anti-Inflammatory Agents

[0040] Preferred anti-inflammatory agents for use in the ophthalmologic solutions of the present invention include topical steroids, topical non-steroidal anti-inflammatory drugs (NSAIDs) and specific classes of anti-inflammatory agents that are suitably used intraocularly, such as topical anti-histamines, mast cell inhibitors and inhibitors of inducible nitric oxide synthase (iNOS). Other anti-inflammatory agents described below as pain/inflammation inhibitory agents, and other anti-inflammatory agents not disclosed herein, which are suitable for ocular use, are also intended to be encompassed by the present invention.

[0041] Examples of steroids that are believed to be suitable for use in the present invention include dexamethasone, fluorometholone and prednisolone. Examples of NSAIDS that are believed to be suitable include flurbiprofen, suprofen, diclofenac, ketoprofen and ketorolac. Selection of an NSAID will depend in part on a determination that excessive bleeding will not result. Examples of anti-histamines that are believed to be suitable include levocabastine, emedastine and olopatadine. Examples of mast cell inhibitors that are believed to be suitable include cromolyn sodium, lodoxamide and nedocromil. Examples of agents that act as both anti-histamine agents and mast cell inhibitors, and which are suitable for use in the present invention, include ketotifen and azelastine. Inhibitors of iNOS that are believed to be suitable include N.sup.G-monomethyl-L-arginine, 1400 W, diphenyleneiodium, S-methyl isothiourea, S-(aminoethyl) isothiourea, L-N.sup.6-(1-iminoethyl)lysine, 1,3-PBITU, and 2-ethyl-2-thiopseudourea.

B. Analgesic Agents

[0042] The term analgesic agent as used herein with reference to ophthalmologic solutions and methods is intended to encompass both agents that provide analgesia and agents that provide local anesthesia. Preferred analgesic agents for use in the ophthalmologic solutions of the present invention include topical local anesthetics and topical opioids. Other analgesic agents described below as pain/inflammation inhibitory agents, and other analgesic agents not disclosed herein, which are suitable for ocular use, are also intended to be encompassed by the present invention.

[0043] Examples of local anesthetics that are believed to be suitable for use in the present invention include lidocaine, tetracaine, bupivacaine and proparacaine. Examples of opioids that are believed to be suitable for use in the present invention include morphine, fentanyl and hydromorphone.

C. Mydriatic Agents

[0044] Preferred mydriatic agents for use in the ophthalmologic solutions of the present invention, to dilate the pupil during surgery, include sympathomimetics, including alpha-1 adrenergic receptor agonists, and anticholinergic agents, including anti-muscarinics. Anticholinergic agents may be selected when longer action is desired, because they provide both cycloplegia (paralysis of the ciliary muscle) and mydriasis, e.g., tropicamide exhibits a half-life of approximately 4-6 hours. However, for many procedures, alpha-1 adrenergics will be preferred because they provide mydriasis but not cycloplegia. Alpha-1 adrenergics are thus shorter acting, causing mydriasis during a surgical procedure and allowing the pupil to return to its normal state shortly after completion of the procedure. Examples of suitable adrenergic receptor agonists active at alpha-1 receptors include phenylephrine, epinephrine and oxymetazoline. Examples of suitable anticholinergic agents include tropicamide, cyclopentolate, atropine and homatropine. Other agents that cause mydriasis, and particularly short-acting mydriatic agents, are also intended to be encompassed by the present invention.

D. Agents that Decrease Intraocular Pressure

[0045] Preferred agents that decrease intraocular pressure for use in the ophthalmologic solutions of the present invention include beta adrenergic receptor antagonists, carbonic anhydrase inhibitors, alpha-2 adrenergic receptor agonists and prostaglandin agonists. Examples of suitable beta adrenergic receptor antagonists are believed to include timolol, metipranolol and levobunolol. Examples of suitable carbonic anhydrase inhibitors are believed to include brinzolamide and dorzolamide. Examples of suitable alpha-2 adrenergic receptor agonists are believed to include apraclonidine, brimonidine and oxymetazoline. Other alpha-2 adrenergic receptor agonists suitable for ocular use and described below as inflammatory/pain inhibitory agents may also suitably function as IOP reducing agents within the solutions of the present invention. Suitable prostaglandin agonists are believed to include latanoprost, travoprost and bimatoprost. When inflammation inhibition is a primary desired effect of the solution, and IOP control is needed, an IOP reducing agent other than a prostaglandin agonist may suitably be selected; to avoid the possibility that prostaglandin may enhance post-surgical inflammation. Other agents that decrease intraocular pressure are also intended to be encompassed by the present invention.

E. Pain/Inflammation Inhibitory Agents

[0046] The following agents, referred to herein as pain/inflammation inhibitory agents, may be suitable for use in the ophthalmologic solutions and methods of the present invention as analgesic and/or anti-inflammatory agents. The particular class(es) of agent, and individual agent(s) within a class, to be utilized for a particular ophthalmologic application can be readily determined by those of skill in the art in accordance with the present invention.

[0047] For example, ocular inflammation models in the rabbit have been studied by comparison of the inflammation response induced by the topical application of several irritating agents, specifically carrageenan, Freund's adjuvant, alkali and croton oil. The methods involve measurement of the following parameters which can be determined after the application of each irritant to the eyes of female, white, New Zealand rabbits: corneal edema and the Tyndall effect (slitlamp biomicroscopy), corneal thickness (biometer-pachometer) and aqueous humor levels of the prostaglandin E2 (R.I.A), total protein (Weichselbaum technique), albumin, albumin/globulin (Doumas technique) and leukocytes (coulter counter).

[0048] Validation studies have found that Croton oil 1-4% (40 l) produced edema and a Tyndall effect that showed a proportional increase with croton oil concentration. Ultrasonic pachometer measurement of the variation in corneal thickness (3-168 h) showed a dose-dependent response (p<0.01) from the 8th to the 168th hour. Uveitis and considerable increases in the levels of the prostaglandin E2 (4.500.40 pg/0.1 ml vs. 260.032.03 pg/0.1 ml), total protein (0.250.05 g/l vs. 2.100.08 g/l), albumin, albumin/globulin and leukocytes were observed in the aqueous humor 24 hours after topical application of croton oil 3% (40 l). All the values obtained were statistically significant (p<0.01).

[0049] The topical application of 3% croton oil (40 l) is most appropriate for the evaluation of the inflammatory process in the anterior chamber and for the determination of the effects of intraocular penetration. The inflammatory mechanism in this model is thought to involve the activation of the arachidonic acid pathway accompanied by the breakdown of the blood-aqueous barrier permitting high molecular weight proteins to enter the aqueous humor.

[0050] The above models can be used to test the efficacy of drugs applied topically, such as by irrigation, in inhibiting inflammatory processes and effecting other ocular functions. A given agent or combination of agents to be evaluated is applied to the eyes of rabbits after the application of each irritant to the eyes.

[0051] The solution may suitably include agents selected from the following classes of receptor antagonists and agonists and enzyme activators and inhibitors, each class acting through a differing molecular mechanism of action for pain and inflammation inhibition: (1) serotonin receptor antagonists; (2) serotonin receptor agonists; (3) histamine receptor antagonists; (4) bradykinin receptor antagonists; (5) kallikrein inhibitors; (6) tachykinin receptor antagonists, including neurokinin) and neurokinin.sub.2 receptor subtype antagonists; (7) calcitonin gene-related peptide (CGRP) receptor antagonists; (8) interleukin receptor antagonists; (9) inhibitors of enzymes active in the synthetic pathway for arachidonic acid metabolites, including (a) phospholipase inhibitors, including PLA.sub.2 isoform inhibitors and PLC.sub. isoform inhibitors, (b) cyclooxygenase inhibitors, and (c) lipooxygenase inhibitors; (10) prostanoid receptor antagonists including eicosanoid EP-1 and EP-4 receptor subtype antagonists and thromboxane receptor subtype antagonists; (11) leukotriene receptor antagonists including leukotriene B.sub.4 receptor subtype antagonists and leukotriene D.sub.4 receptor subtype antagonists; (12) opioid receptor agonists, including -opioid, -opioid, and -opioid receptor subtype agonists; (13) purinoceptor agonists and antagonists including P.sub.2X receptor antagonists and P.sub.2Y receptor agonists; (14) adenosine triphosphate (ATP)-sensitive potassium channel openers; (15) local anesthetics; and (16) alpha-2 adrenergic receptor agonists. Each of the above agents functions either as an anti-inflammatory agent and/or as an analgesic, i.e., anti-pain, agent. The selection of agents from these classes of compounds is tailored for the particular application.

1. Serotonin Receptor Antagonists

[0052] Serotonin (5-HT) is thought to produce pain by stimulating serotonin.sub.2 (5-HT.sub.2) and/or serotonin.sub.3 (5-HT.sub.3) receptors on nociceptive neurons in the periphery. Most researchers agree that 5-HT.sub.3 receptors on peripheral nociceptors mediate the immediate pain sensation produced by 5-HT. In addition to inhibiting 5-HT-induced pain, 5-HT.sub.3 receptor antagonists, by inhibiting nociceptor activation, also may inhibit neurogenic inflammation. Activation of 5-HT.sub.2 receptors also may play a role in peripheral pain and neurogenic inflammation. One goal of the solution of the present invention is to block pain and a multitude of inflammatory processes. Thus, 5-HT.sub.2 and 5-HT.sub.3 receptor antagonists may both be suitably used, either individually or together, in the solution of the present invention. Amitriptyline (Elavil) is believed to be a potentially suitable 5-HT.sub.2 receptor antagonist for use in the present invention. Metoclopramide (Reglan) is used clinically as an anti-emetic drug, but displays moderate affinity for the 5-HT.sub.3 receptor and can inhibit the actions of 5-HT at this receptor, possibly inhibiting the pain due to 5-HT release from platelets. Thus, it may also be suitable for use in the present invention.

[0053] Other potentially suitable 5-HT.sub.2 receptor antagonists include imipramine, trazodone, desipramine, ketanserin. Other suitable 5-HT.sub.3 antagonists include cisapride and ondansetron. Therapeutic and preferred concentrations for use of these drugs in the solution of the present invention are set forth in Table 1.

TABLE-US-00001 TABLE 1 Therapeutic and Preferred Concentrations of Pain/Inflammation Inhibitory Agents Therapeutic Preferred Concentrations Concentrations Class of Agent (Nanomolar) (Nanomolar) Serotonin.sub.2 Receptor Antagonists: amitriptyline 0.1-1,000 50-500 imipramine 0.1-1,000 50-500 trazodone 0.1-2,000 50-500 desipramine 0.1-1,000 50-500 ketanserin 0.1-1,000 50-500 Serotonin.sub.3 Receptor Antagonists: tropisetron 0.01-100 0.05-50 metoclopramide .sup.10-10,000 200-2,000 cisapride 0.1-1,000 20-200 ondansetron 0.1-1,000 20-200

2. Serotonin Receptor Agonists

[0054] 5-HT.sub.1A, 5-HT.sub.1B and 5-HT.sub.1D receptors are known to inhibit adenylate cyclase activity. Thus including a low dose of these serotonin.sub.1A, serotonin.sub.1B and serotonin.sub.1D receptor agonists in the solution should inhibit neurons mediating pain and inflammation. The same action is expected from serotonin.sub.1E and serotonin.sub.1F receptor agonists because these receptors also inhibit adenylate cyclase.

[0055] Buspirone is a potentially suitable 1A receptor agonist for use in the present invention. Sumatriptan is a potentially suitable 1A, 1B, 1D and 1F receptor agonist. A potentially suitable 1B and 1D receptor agonist is dihydroergotamine. A suitable 1E receptor agonist is ergonovine. Therapeutic and preferred concentrations for these receptor agonists are provided in Table 2.

TABLE-US-00002 TABLE 2 Therapeutic and Preferred Concentrations of Pain/Inflammation Inhibitory Agents Therapeutic Preferred Concentrations Concentrations Class of Agent (Nanomolar) (Nanomolar) Serotonin.sub.1A Agonists: 5-carboxyamidotryptamine 1-1,000 10-200 sumatriptan 1-1,000 10-200 Serotonin.sub.1B Agonists: CP93129 0.1-1,000.sup. 10-100 sumatriptan 1-1,000 10-200 Serotonin.sub.1D Agonists: naratriptan 0.1-1,000.sup. 10-100 sumatriptan 1-1,000 10-200 Serotonin.sub.1E Agonists: ergonovine 10-2,000 100-1,000 Serotonin.sub.1F Agonists: sumatriptan 1-1,000 10-200

3. Histamine Receptor Antagonists

[0056] Histamine receptor antagonists may potentially be included in the irrigation solution. Promethazine (Phenergan) is a commonly used anti-emetic drug that potently blocks H.sub.1 receptors, and is potentially suitable for use in the present invention. Other potentially suitable H.sub.1 receptor antagonists include terfenadine, diphenhydramine, amitriptyline, mepyramine and tripolidine. Because amitriptyline is also effective as a serotonin.sub.2 receptor antagonist, it has a dual function as used in the present invention. Suitable therapeutic and preferred concentrations for each of these H.sub.1 receptor antagonists are set forth in Table 3.

TABLE-US-00003 TABLE 3 Therapeutic and Preferred Concentrations of Pain/Inflammation Inhibitory Agents Therapeutic Preferred Class of Agent Concentrations Concentrations Histamine.sub.1 Receptor Antagonists: (Nanomolar) (Nanomolar) promethazine 0.1-1,000 50-200 diphenhydramine 0.1-1,000 50-200 amitriptyline 0.1-1,000 50-500 terfenadine 0.1-1,000 50-500 mepyramine (pyrilamine) 0.1-1,000 5-200 tripolidine 0.01-100 5-20

4. Bradykinin Receptor Antagonists

[0057] Bradykinin receptors generally are divided into bradykinin.sub.1 (B.sub.1) and bradykinin.sub.2 (B.sub.2) subtypes. These drugs are peptides (small proteins), and thus they cannot be taken orally, because they would be digested. Antagonists to B.sub.2 receptors block bradykinin-induced acute pain and inflammation. B.sub.1 receptor antagonists inhibit pain in chronic inflammatory conditions. Depending on the application, the solution of the present invention may suitably include either or both bradykinin B.sub.1 and B.sub.2 receptor antagonists. Potentially suitable bradykinin.sub.1 receptor antagonists for use in the present invention include: the [des-Arg.sup.10] derivative of D-Arg-(Hyp.sup.3-Thi.sup.5-D-Tic.sup.7-Oic.sup.8)-BK (the [des-Arg.sup.10] derivative of HOE 140, available from Hoechst Pharmaceuticals); and [Leu.sup.8] des-Arg.sup.9-BK. Potentially suitable bradykinin.sub.2 receptor antagonists include: [D-Phe.sup.7]-BK; D-Arg-(Hyp.sup.3-Thi.sup.5,8-D-Phe.sup.7)-BK (NPC 349); D-Arg-(Hyp.sup.3-D-Phe.sup.7)-BK (NPC 567); and D-Arg-(Hyp.sup.3-Thi.sup.5-D-Tic.sup.7-Oic.sup.8)-BK (HOE 140). Suitable therapeutic and preferred concentrations are provided in Table 4.

TABLE-US-00004 TABLE 4 Therapeutic and Preferred Concentrations of Pain/Inflammation Inhibitory Agents Therapeutic Preferred Concentrations Concentrations Class of Agent (Nanomolar) (Nanomolar) Bradykinin.sub.1 Receptor Antagonists: [Leu.sup.8] des-Arg.sup.9-BK 1-1,000 50-500 [des-Arg.sup.10] derivative of HOE 140 1-1,000 50-500 [leu.sup.9] [des-Arg.sup.10] kalliden 0.1-500 10-200 Bradykinin.sub.2 Receptor Antagonists: [D-Phe.sup.7]-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

5. Kallikrein Inhibitors

[0058] 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 kininogens in plasma. Therefore, kallikrein inhibitors are believed to be therapeutic in inhibiting bradykinin production and resultant pain and inflammation. A potentially suitable kallikrein inhibitor for use in the present invention is aprotinin. Potentially suitable concentrations for use in the solutions of the present invention are set forth below in Table 5.

TABLE-US-00005 TABLE 5 Therapeutic and Preferred Concentrations of Pain/Inflammation Inhibitory Agents Therapeutic Preferred Class of Agent Concentrations Concentrations Kallikrein Inhibitor: (Nanomolar) (Nanomolar) aprotinin 0.1-1,000 50-500

6. Tachykinin Receptor Antagonists

[0059] Tachykinins (TKs) are a family of structurally related peptides that include substance P, neurokinin A (NKA) and neurokinin B (NKB). Neurons are the major source of TKs in the periphery. An important general effect of TKs is neuronal stimulation, but other effects include endothelium-dependent vasodilation, plasma protein extravasation, mast cell recruitment and degranulation and stimulation of inflammatory cells. Due to the above combination of physiological actions mediated by activation of TK receptors, targeting of TK receptors is a reasonable approach for the promotion of analgesia and the treatment of neurogenic inflammation.

a. Neurokinin.SUB.1 .Receptor Subtype Antagonists

[0060] Substance P activates the neurokinin receptor subtype referred to as NK.sub.1. A potentially suitable Substance P antagonist is ([D-Pro.sup.9[spiro-gamma-lactam]Leu.sup.10,Trp.sup.11]physalaemin-(1-11)) (GR 82334). Other potentially suitable antagonists for use in the present invention which act on the NK.sub.1 receptor are: 1-imino-2-(2-methoxy-phenyl)-ethyl)-7,7-diphenyl-4-perhydroisoindolone(3aR,7aR) (RP 67580); and 2S,3S-cis-3-(2-methoxybenzylamino)-2-benzhydrylquinuclidine (CP 96,345). Suitable concentrations for these agents are set forth in Table 6.

TABLE-US-00006 TABLE 6 Therapeutic and Preferred Concentrations of Pain/Inflammation Inhibitory Agents Class of Agent Therapeutic Preferred Neurokinin.sub.1 Receptor Concentrations Concentrations Subtype Antagonists (Nanomolar) (Nanomolar) GR 82334 1-1,000 10-500 CP 96,345 1-10,000 100-1,000 RP 67580 0.1-1,000.sup. 100-1,000

b. Neurokinin.SUB.2 .Receptor Subtype Antagonists

[0061] Neurokinin A is a peptide which is colocalized in sensory neurons with substance P and which also promotes inflammation and pain. Neurokinin A activates the specific neurokinin receptor referred to as NK.sub.2. Examples of potentially suitable NK.sub.2 antagonists include: ((S)N-methyl-N-[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl]benzamide (()-SR 48968); Met-Asp-Trp-Phe-Dap-Leu (MEN 10,627); and cyc(Gln-Trp-Phe-Gly-Leu-Met) (L 659,877). Suitable concentrations of these agents are provided in Table 7.

TABLE-US-00007 TABLE 7 Therapeutic and Preferred Concentrations of Pain/Inflammation Inhibitory Agents Class of Agent Therapeutic Preferred Neurokinin.sub.2 Receptor Concentrations Concentrations Subtype Antagonists: (Nanomolar) (Nanomolar) 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

7. CGRP Receptor Antagonists

[0062] Calcitonin gene-related peptide (CGRP) is a peptide which is also colocalized in sensory neurons with substance P, and which acts as a vasodilator and potentiates the actions of substance P. An example of a potentially suitable CGRP receptor antagonist is I-CGRP-(8-37), a truncated version of CGRP. This polypeptide inhibits the activation of CGRP receptors. Suitable concentrations for this agent are provided in Table 8.

TABLE-US-00008 TABLE 8 Therapeutic and Preferred Concentrations of Pain/Inflammation Inhibitory Agents Therapeutic Preferred Class of Agent Concentrations Concentrations CGRP Receptor Antagonist: (Nanomolar) (Nanomolar) I-CGRP-(8-37) 1-1,000 10-500

8. Interleukin Receptor Antagonist

[0063] Interleukins are a family of peptides, classified as cytokines, produced by leukocytes and other cells in response to inflammatory mediators. Interleukins (IL) may be potent hyperalgesic agents peripherally. An example of a potentially suitable IL-1 receptor antagonist is Lys-D-Pro-Thr, which is a truncated version of IL-1. This tripeptide inhibits the activation of IL-1 receptors. Suitable concentrations for this agent are provided in Table 9.

TABLE-US-00009 TABLE 9 Therapeutic and Preferred Concentrations of Pain/Inflammation Inhibitory Agents Therapeutic Preferred Class of Agent Concentrations Concentrations Interleukin Receptor Antagonist: (Nanomolar) (Nanomolar) Lys-D-Pro-Thr 1-1,000 10-500

9. Inhibitors of Enzymes Active in the Synthetic Pathway for Arachidonic Acid Metabolites

a. Phospholipase Inhibitors

[0064] The production of arachidonic acid by phospholipase A.sub.2 (PLA.sub.2) results in a cascade of reactions that produces numerous mediators of inflammation, known as eicosanoids. There are a number of stages throughout this pathway that can be inhibited, thereby decreasing the production of these inflammatory mediators. Examples of inhibition at these various stages are given below.

[0065] Inhibition of the enzyme PLA.sub.2 isoform inhibits the release of arachidonic acid from cell membranes, and therefore inhibits the production of prostaglandins and leukotrienes resulting in decreased inflammation and pain. An example of a potentially suitable PLA.sub.2 isoform inhibitor is manoalide. Suitable concentrations for this agent are included in Table 10. Inhibition of the phospholipase C (PLC) isoform also will result in decreased production of prostanoids and leukotrienes and, therefore, will result in decreased pain and inflammation. An example of a PLC isoform inhibitor is 1-[6-((17-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione.

TABLE-US-00010 TABLE 10 Therapeutic and Preferred Concentrations of Pain/Inflammation Inhibitory Agents Therapeutic Preferred Class of Agent Concentrations Concentrations PLA.sub.2 Isoform Inhibitor: (Nanomolar) (Nanomolar) manoalide 100-100,000 500-10,000

b. Cyclooxygenase Inhibitors

[0066] Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used as anti-inflammatory and analgesic agents. The molecular targets for these drugs are type I and type II cyclooxygenases (COX-1 and COX-2). Constitutive activity of COX-1 and induced activity of COX-2 both lead to synthesis of prostaglandins that contribute to pain and inflammation.

[0067] NSAIDs currently on the market (diclofenac, naproxen, indomethacin, ibuprofen, etc.) are generally nonselective inhibitors of both isoforms of COX, but may show greater selectively for COX-1 over COX-2, although this ratio varies for the different compounds. Use of COX-1 and COX-2 inhibitors to block formation of prostaglandins represents a better therapeutic strategy than attempting to block interactions of the natural ligands with the seven described subtypes of prostanoid receptors.

[0068] Potentially suitable cyclooxygenase inhibitors for use in the present invention are ketoprofen, ketorolac and indomethacin. Therapeutic and preferred concentrations of these agents for use in the solution are provided in Table 11. For some applications, it may also be suitable to utilize a COX-2 specific inhibitor (i.e., selective for COX-2 relative to COX-1) as an anti-inflammatory/analgesic agent. Potentially suitable COX-2 inhibitors include rofecoxib (MK 966), SC-58451, celecoxib (SC-58125), meloxicam, nimesulide, diclofenac, NS-398, L-745,337, RS57067, SC-57666 and flosulide.

TABLE-US-00011 TABLE 11 Therapeutic and Preferred Concentrations of Pain/Inflammation Inhibitory Agents Therapeutic Preferred Class of Agent Concentrations Concentrations Cyclooxygenase Inhibitors: (Nanomolar) (Nanomolar) ketorolac 100-10,000 500-5,000 ketoprofen 100-10,000 500-5,000 indomethacin 1,000-500,000 10,000-200,000

c. Lipooxygenase Inhibitors

[0069] Inhibition of the enzyme lipooxygenase inhibits the production of leukotrienes, such as leukotriene B.sub.4, which is known to be an important mediator of inflammation and pain. An example of a potentially suitable 5-lipooxygenase antagonist is 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (AA 861), suitable concentrations for which are listed in Table 12.

TABLE-US-00012 TABLE 12 Therapeutic and Preferred Concentrations of Pain/Inflammation Inhibitory Agents Therapeutic Preferred Class of Agent Concentrations Concentrations Lipooxygenase Inhibitor: (Nanomolar) (Nanomolar) AA 861 100-10,000 500-5,000

10. Prostanoid Receptor Antagonists

[0070] Specific prostanoids produced as metabolites of arachidonic acid mediate their inflammatory effects through activation of prostanoid receptors. Examples of classes of specific prostanoid antagonists are the eicosanoid EP-1 and EP-4 receptor subtype antagonists and the thromboxane receptor subtype antagonists. A potentially suitable prostaglandin E.sub.2 receptor antagonist is 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-acetylhydrazide (SC 19220). A potentially suitable thromboxane receptor subtype antagonist is [15-[1,2(5Z),3,4]-7-[3-[2-(phenylamino)-carbonyl] hydrazino] methyl]-7-oxobicyclo-[2,2,1]-hept-2-yl]-5-heptanoic acid (SQ 29548). Suitable concentrations for these agents are set forth in Table 13.

TABLE-US-00013 TABLE 13 Therapeutic and Preferred Concentrations of Pain/Inflammation Inhibitory Agents Therapeutic Preferred Class of Agent Concentrations Concentrations Eicosanoid EP-1 Antagonist: (Nanomolar) (Nanomolar) SC 19220 100-10,000 500-5,000

11. Leukotriene Receptor Antagonists

[0071] The leukotrienes (LTB.sub.4, LTC.sub.4, and LTD.sub.4) are products of the 5-lipooxygenase pathway of arachidonic acid metabolism that are generated enzymatically and have important biological properties. Leukotrienes are implicated in a number of pathological conditions including inflammation. An example of a potentially suitable leukotriene B.sub.4 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-propanoic acid (SC 53228). Concentrations for this agent that are potentially suitable for the practice of the present invention are provided in Table 14. Other potentially suitable leukotriene B.sub.4 receptor antagonists include [3-[-2(7-chloro-2-quinolinyl)ethenyl]phenyl] [[3-(dimethylamino-3-oxopropyl)thio] methyl]thiopropanoic acid (MK 0571) and the drugs LY 66,071 and ICI 20,3219. MK 0571 also acts as a LTD.sub.4 receptor subtype antagonist.

TABLE-US-00014 TABLE 14 Therapeutic and Preferred Concentrations of Pain/Inflammation Inhibitory Agents Therapeutic Preferred Class of Agent Concentrations Concentrations Leukotriene B.sub.4 Antagonist: (Nanomolar) (Nanomolar) SC 53228 100-10,000 500-5,000

12. Opioid Receptor Agonists

[0072] Activation of opioid receptors results in anti-nociceptive effects and, therefore, agonists to these receptors are desirable. Opioid receptors include the -, - and -opioid receptor subtypes. Examples of potentially suitable -opioid receptor agonists are fentanyl and Try-D-Ala-Gly-[N-MePhe]-NH(CH.sub.2)OH (DAMGO). An example of a potentially suitable -opioid receptor agonist is [D-Pen.sup.2,D-Pen.sup.5]enkephalin (DPDPE). An example of a potentially suitable -opioid receptor agonist is (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidnyl)cyclohexyl]-benzene acetamide (U50,488). Suitable concentrations for each of these agents are set forth in Table 15.

TABLE-US-00015 TABLE 15 Therapeutic and Preferred Concentrations of Pain/Inflammation Inhibitory Agents Therapeutic Preferred Concentrations Concentrations Class of Agent (Nanomolar) (Nanomolar) -Opioid Agonist: DAMGO 0.1-100 0.5-20 sufentanyl 0.01-50 1-20 fentanyl 0.1-500 10-200 PL 017 0.05-50 0.25-10 -Opioid Agonist: DPDPE 0.1-500 1.0-100 -Opioid Agonist: U50,488 0.1-500 1.0-100

13. Purinoceptor Antagonists and Agonists

[0073] Extracellular ATP acts as a signaling molecule through interactions with P.sub.2 purinoceptors. One major class of purinoceptors are the P.sub.2X purinoceptors which are ligand-gated ion channels possessing intrinsic ion channels permeable to Na.sup.+, K.sup.+, and Ca.sup.2+. Potentially suitable antagonists of P.sub.2X/ATP purinoceptors for use in the present invention include, by way of example, suramin and pyridoxylphosphate-6-azophenyl-2,4-disulfonic acid (PPADS). Suitable concentrations for these agents are provided in Table 16. Agonists of the P.sub.2Y receptor, a G-protein coupled receptor, are known to effect smooth muscle relaxation through elevation of inositol triphosphate (IP.sub.3) levels with a subsequent increase in intracellular calcium. An example of a P.sub.2Y receptor agonist is 2-me-S-ATP.

TABLE-US-00016 TABLE 16 Therapeutic and Preferred Concentrations of Pain/Inflammation Inhibitory Agents Therapeutic Preferred Class of Agent Concentrations Concentrations Purinoceptor Antagonists: (Nanomolar) (Nanomolar) suramin 100-100,000 10,000-100,000 PPADS 100-100,000 10,000-100,000

14. Adenosine Triphosphate (ATP)-Sensitive Potassium Channel Openers

[0074] Potentially suitable ATP-sensitive K.sup.+ channel openers for the practice of the present invention include: ()pinacidil; cromakalim; nicorandil; minoxidil; N-cyano-N-[1,1-dimethyl-[2,2,3,3-.sup.3H]propyl]-N-(3-pyridinyl)guanidine (P 1075); and N-cyano-N-(2-nitroxyethyl)-3-pyridinecarboximidamide monomethansulphonate (KRN 2391). Concentrations for these agents are set forth in Table 17.

TABLE-US-00017 TABLE 17 Therapeutic and Preferred Concentrations of Pain/Inflammation Inhibitory Agents Therapeutic Preferred Class of Agent Concentrations Concentrations ATP-Sensitive K.sup.+ Channel Opener: (Nanomolar) (Nanomolar) cromakalim 10-10,000 100-10,000 nicorandil 10-10,000 100-10,000 minoxidil 10-10,000 100-10,000 P 1075 0.1-1,000.sup. 10-1,000 KRN 2391 1-10,000 100-1,000 ()pinacidil 1-10,000 100-1,000

15. Local Anesthetics

[0075] The solution of the present invention is preferably used for continuous infusion throughout the surgical procedure to provide preemptive inhibition of pain and inflammation. Local anesthetics (e.g., lidocaine, bupivacaine, etc.) are used clinically as analgesic agents and are known to reversibly bind to sodium channels in the membrane of neuronal axons, thereby inhibiting axonal conduction and the transmission of pain signals from the periphery to the spinal cord. The local delivery of extremely low or sub-clinical concentrations of lidocaine, a local anesthetic, has been shown to inhibit nerve injury discharge (Bisla K and Tanalian D L, Concentration-dependent Effects of Lidocaine on Corneal Epithelial Wound Healing, Invest Ophthalmol Vis Sci 33(11), pp. 3029-3033, 1992). Therefore, in addition to decreasing pain signals, local anesthetics, when delivered in extremely low concentrations, also have anti-inflammatory properties.

[0076] The inclusion of a local anesthetic in extremely low or sub-anesthetic concentrations in the irrigation solution provides a beneficial anti-inflammatory effect without exposing the patient to the systemic toxicity associated with currently used clinical doses of local anesthetics. Thus, in extremely low concentrations, a local anesthetic is suitable for use in the present invention. Examples of representative local anesthetics useful in the practice of the present invention include, without limitation, benzocaine, bupivacaine, chloroprocaine, cocaine, etiodocaine, lidocaine, mepivacaine, pramoxine, prilocaine, procaine, proparacaine, ropivacaine, tetracaine, dibucaine, QX-222, ZX-314, RAC-109, HS-37 and the pharmacologically active enantiomers thereof. Although not wishing to be bound by any particular theory, some local anesthetics are believed to act by inhibiting voltage-gated sodium channels. (See Guo, X. et al., Comparative inhibition of voltage-gated cation channels by local anesthetics, Ann. N.Y. Acad. Sci. 625: 181-199 (1991)). Particularly useful pharmacologically active enantiomers of local anesthetics include, for example, the R-enantiomer of bupivacaine. For purposes of the present invention, useful concentrations of anesthetic agents delivered locally are generally in the range of about 125 to about 100,000,000 nanomolar, more preferably about 1,000 to about 10,000,000 nanomolar, and most preferably about 225,000 to about 1,000,000 nanomolar. In one embodiment, the solutions of the invention comprise at least one local anesthetic agent delivered locally at a concentration of no greater than 750,000 nanomolar. In other embodiments, the solutions of the invention comprise at least one local anesthetic agent delivered locally at a concentration of no greater than 500,000 nanomolar. Useful concentrations of representative specific local anesthetic agents are set forth below.

TABLE-US-00018 TABLE 18 Therapeutic and Preferred Concentrations of Specific Local Anesthetic Agents Local Concentrations (Nanomolar) Anesthetics: Therapeutic Preferred More Preferred lidocaine 500-1,600,000 4,000-1,200,000 900,000-1,100,000 bupivacaine 125-400,000.sup. 1,000-300,000.sup. 225,000-275,000.sup.

16. Alpha-2 Adrenergic Receptor Agonists

[0077] All the individual nine receptors that comprise the adrenergic amine receptor family belong to the G-protein linked superfamily of receptors. The classification of the adrenergic family into three distinct subfamilies, namely .sub.1 (alpha-1), .sub.2 (alpha-2), and (beta), is based upon a wealth of binding, functional and second messenger studies. Each adrenergic receptor subfamily is itself composed of three homologous receptor subtypes that have been defined by cloning and pharmacological characterization of the recombinant receptors. Among adrenergic receptors in different subfamilies (alpha-1 vs. alpha-2 vs. beta), amino acid identities in the membrane spanning domain range from 36-73%. However, between members of the same subfamily (.sub.1A vs. .sub.1B) the identity between membrane domains is usually 70-80%. Together, these distinct receptor subtypes mediate the effects of two physiological agonists, epinephrine and norepinephrine.

[0078] Distinct adrenergic receptor types couple to unique sets of G-proteins and are thereby capable of activating different signal transduction effectors. The classification of alpha-1, alpha-2, and beta subfamilies not only defines the receptors with regard to signal transduction mechanisms, but also accounts for their ability to differentially recognize various natural and synthetic adrenergic amines. In this regard, a number of selective ligands have been developed and utilized to characterize the pharmacological properties of each of these receptor types. Functional responses of alpha-1 receptors have been shown in certain systems to stimulate phosphatidylinositol turnover and promote the release of intracellular calcium (via G.sub.q), while stimulation of alpha-2 receptors inhibits adenylyl cyclase (via G.sub.i). In contrast, functional responses of beta receptors are coupled to increases in adenylyl cyclase activity and increases in intracellular calcium (via G.sub.s).

[0079] It is now accepted that there are three different alpha-1 receptor subtypes which all exhibit a high affinity (subnanomolar) for the antagonist, prazosin. The subdivision of alpha-1 adrenoceptors into three different subtypes, designated .sub.1A, .sub.1B, and .sub.1D, has been primarily based on extensive ligand binding studies of endogenous receptors and cloned receptors. Pharmacological characterization of the cloned receptors led to revisions of the original classification such that the clone originally called the .sub.1C subtype corresponds to the pharmacologically defined .sub.1A receptor. Agonist occupation of .sub.1A-D receptor subtypes results in activation of phospholipase C, stimulation of PI breakdown, generation of the IP.sub.3 as second messenger and an increase in intracellular calcium.

[0080] Three different .sub.2-receptor subtypes have been cloned, sequenced, and expressed in mammalian cells, referred to as .sub.2A (.sub.2-C10), .sub.2B (.sub.2-C2), .sub.2C (.sub.2-C4). These subtypes not only differ in their amino acid composition but also in their pharmacological profiles and distributions. An additional .sub.2-receptor subtype, .sub.2D (gene rg20), was originally proposed based on radioligand binding studies of rodent tissues but is now considered to represent a species homolog to the human .sub.2A receptor.

[0081] Functionally, the signal transduction pathways are similar for all three .sub.2A receptor subtypes; each is negatively coupled to adenylate cyclase via G.sub.i/o. In addition, the .sub.2A and .sub.2B receptors have also been reported to mediate activation of a G-protein coupled potassium channel (receptor-operated) as well as inhibition of a G-protein associated calcium channel.

[0082] Pharmacologically, alpha-2 adrenergic receptors are defined as highly sensitive to the antagonists yohimbine (Ki=0.5-25 M), atipamezole (Ki=0.5-2.5 M), and idazoxan (Ki=21-35 M) and with low sensitivity to the alpha-1 receptor antagonist prazosin. Agonists selective for the alpha-2 adrenergic receptor class relative to the alpha-1 adrenergic receptor class are UK14,304, BHT920 and BHT933. Oxymetazoline binds with high affinity and selectivity to the .sub.2A-receptor subtype (K.sub.D=3 M), but in addition binds with high affinity to alpha-1 adrenergic receptors and 5HT1 receptors. An additional complicating factor is that alpha-2 adrenergic receptor ligands which are imidazolines (clonidine, idazoxan) and others (oxymetazoline and UK14304) also bind with high affinity (nanomolar) to non-adrenoceptor imidazoline binding sites. Furthermore, species variation in the pharmacology of the .sub.2A-adrenoceptor exists. To date, subtype-selective alpha-2 adrenergic receptor ligands show only minimal selectivity or are nonselective with respect to other specific receptors, such that the therapeutic properties of subtype selective drugs are still under development.

[0083] A therapeutic field in which alpha-2 receptor agonists may be considered to have potential use is as an adjunct to anesthesia, for the control of pain and blockade of neurogenic inflammation. Sympathetic nervous system stimulation releases norepinephrine after tissue injury, and thus influences nociceptor activity. Alpha-2 receptor agonists, such as clonidine, can inhibit norepinephrine release at terminal nerve fibre endings and thus may induce analgesia directly at peripheral sites (without actions on the CNS). The ability of primary afferent neurons to release neurotransmitters from both their central and peripheral endings enables them to exert a dual, sensory and efferent or local effector function. The term, neurogenic inflammation, is used to describe the efferent function of the sensory nerves that includes the release of sensory neuropeptides that contribute, in a feed-forward manner, to the inflammatory process. Agents that induce the release of sensory neuropeptides from peripheral endings of sensory nerves, such as capsaicin, produce pain, inflammation and increased vascular permeability resulting in plasma extravasation. Drugs that block release of neuropeptides (substance P, CGRP) from sensory endings are predicted to possess analgesic and anti-inflammatory activity. This mechanism of action has been established for other drugs that exhibit analgesic and anti-inflammatory action in the periphery, such as sumatriptan and morphine, which act on 5HT1 and -opioid receptors, respectively. Both of these drugs are agonists that activate receptors that share a common mechanism of signal transduction with the alpha-2 receptors. UK14304, like sumatriptan, has been shown to block plasma extravasation within the dura mater through a prejunctional action on alpha-2 receptors.

[0084] Evidence supporting a peripheral analgesic effect of clonidine was obtained in a study of the effect of intra-articular injection of the drug at the end of an arthroscopic knee surgery ((Gentili, M et al (1996) Pain 64: 593-596)). Clonidine is considered to exhibit nonopiate anti-nociceptive properties, which might allow its use as an alternative for postoperative analgesia. In a study undertaken to evaluate the analgesic effects of clonidine administered intravenously to patients during the postoperative period, clonidine was found to delay the onset of pain and decrease the pain score. Thus, a number of studies have demonstrated intra- and postoperative analgesia effects from drugs acting either at alpha-2 adrenergic receptors, indicating these receptors are good therapeutic targets for new drugs to treat pain.

[0085] From the molecular and cellular mechanism of action defined for alpha-2 receptor agonists, such as UK14304, these compounds are expected to exhibit anti-nociceptive action on the peripheral terminals of primary afferent nerves when applied intraoperatively in an irrigation solution directly to tissues.

[0086] Alpha-2 receptor agonists are suitable for use in the current invention, delivered either as a single agent or in combination with other anti-pain and/or anti-inflammatory drugs, to inhibit pain and inflammation. Representative alpha-2 receptor agonists for the practice of the present invention include, for example: clonidine; dexmedetomidine; oxymetazoline; ((R)-()-3-(2-amino-1-hydroxyethyl)-4-fluoro-methanesulfoanilide (NS -49); 2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline (AGN-193080); AGN 191103 and AGN 192172, as described in Munk, S. et al., J. Med. Chem. 39: 3533-3538 (1996); 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK14304); 5,6,7,8-tetrahydro-6-(2-propenyl)-4H-thiazolo[4,5-d]azepin-2-amine (BHT920); 6-ethyl-5,6,7,8-tetrahydro-4H-oxaazolo[4,5-d]azepin-2-amine (BHT 933), 5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphyl-imidazoline (A-54741).

TABLE-US-00019 TABLE 19 Therapeutic and Preferred Concentrations of Alpha-2 Adrenergic Receptor Agonists Therapeutic Therapeutic Most Acceptable Efficient Preferred Preferred Concentrations Concentrations Concentrations Concentration Compounds (nM) (nM) (nM) (nM) clonidine 0.002-200,000 0.01-50,000 0.1-10,000 10-2,000 dexmedetomidine 0.002-200,000 0.01-50,000 0.1-10,000 10-2,000 UK14304 0.002-200,000 0.01-50,000 0.1-10,000 10-2,000 oxymetazoline 0.001-100,000 0.01-25,000 0.05-15,000 5-10,000 NS-49 0.002-200,000 0.01-50,000 0.1-10,000 10-2,000 AGN192172 0.005-100,000 0.1-25,000 1-5,000 10-1,000 AGN193080 0.005-100,000 0.1-25,000 1-5,000 10-1,000 AGN191103 0.002-200,000 0.1-25,000 1-5,000 10-1,000 A-54741 0.002-200,000 0.1-50,000 .sup.1-10,000 10-2,000 BHT920 0.003-200,000 0.3-50,000 .sup.3-30,000 30-5,000 BHT933 0.003-200,000 0.3-50,000 .sup.3-30,000 30-5,000

F. Multi-Function Agents

[0087] In a further aspect of the present invention, selection of preferred agents to include in an ophthalmologic irrigation solution takes into consideration particular agents that display efficacy in more than one of the above functional classes. The previously described alpha-2 adrenergic receptor agonists provide examples of this, as they may function as both IOP reducing agents and agents that inhibit inflammation and pain. For example, oxymetazoline inhibits ocular inflammation by inhibiting release of sensory neurotransmitters (Fuder H., J. Ocul. Pharmacol., 10:109-123 (1994)). Oxymetazoline also functions as a mydriatic agent via agonist activity at alpha-1-adrenergic receptors and also decreases IOP via agonist activity at alpha-2-adrenergic receptors (Chu T. et al, Pharmacology, 53:259-270 (1996)). NSAIDS, in addition to anti-inflammatory effects, also are indicated for inhibiting intra-operative miosis, thereby possessing mydriatic properties. Such multi-functional agents may suitably be used in the ophthalmologic solutions of the present invention when combined with an additional agent or agents that provide at least one additional ophthalmologic function not already provided by the multifunctional agent.

[0088] In addition to choosing multi-functional agents, avoiding toxic side-effects of these topically applied agents is also of importance. An advantage of topical delivery is a significant reduction in systemic side effects. However, local effects of these agents, such as reduced wound healing with high-concentration local anesthetics or steroids, must by considered. Therefore, local anesthetics at low concentrations that effectively inhibit neuronal discharge yet avoid wound-healing problems are preferred for use in the present invention (Bisla K, et al, Invest. Ophthalmol. Vis. Sci., 33:3029-3033 (1992).). Because NSAIDS have been demonstrated to be as effective as steroids for controlling inflammation following ocular surgery (Dadeya S. et al, J. Pediatr. Ophthalmol. Strabismus., 39:166-168 (2002)), NSAIDS are preferred to avoid the potential non-specific detrimental effects of steroids.

[0089] Depending on the specific requirements of various ophthalmologic surgical procedures, a variety of suitable irrigation solutions of the present invention including 2 or more agents may be formulated in accordance with the present invention, but each solution might not include agents drawn from all of the named functional categories (i.e., analgesic, anti-inflammatory, mydriati, and IOP reducing agents). For example, an irrigation solution formulated in accordance with the disclosure herein for use during cataract surgery may not require an analgesic, because this procedure is not as painful as a vitrectomy.

G. Irrigation Carriers

[0090] The active agents of the present invention are solubilized within a physiologic liquid irrigation carrier. The carrier is suitably an aqueous solution that may include physiologic electrolytes, such as normal saline or lactated Ringer's solution. More preferably, the carrier includes one or more adjuvants, and preferably all of the following adjuvants: sufficient electrolytes to provide a physiological balanced salt solution; a cellular energy source; a buffering agent; and a free-radical scavenger. One suitable solution (referred to in the examples below as a preferred balanced salt solution includes: electrolytes of from 50 to 500 millimolar sodium ions, from 0.1 to 50 millimolar potassium ions, from 0.1 to 5 millimolar calcium ions, from 0.1 to 5 millimolar magnesium ions, from 50 to 500 millimolar chloride ions, and from 0.1 to 10 millimolar phosphate; bicarbonate as a buffer at a concentration of from 10 to 50 millimolar; a cellular energy source selected from dextrose and glucose, at a concentration of from 1 to 25 millimolar; and glutathione as a free-radical scavenger (i.e., anti-oxidant) at a concentration of from 0.05 to 5 millimolar. The pH of the irrigation solution is suitable when controlled at between 5.5 and 8.0, preferably at a pH of 7.4.

VI. METHOD OF APPLICATION

[0091] The solution of the present invention has applications for a variety of operative/interventional procedures, including surgical, diagnostic and therapeutic techniques. The irrigation solution is applied perioperatively during ophthalmologic surgery. As defined above, the term perioperative encompasses application intraprocedurally, pre- and intraprocedurally, intra- and postprocedurally, and pre-, intra- and postprocedurally. Preferably, the solution is applied preprocedurally and/or postprocedurally as well as intraprocedurally. The irrigation solution is most preferably applied to the wound or surgical site prior to the initiation of the procedure, preferably before substantial tissue trauma, and continuously throughout a major portion or for the duration of the procedure, to preemptively block pain and inflammation, inhibit intraocular pressure increases, and/or cause mydriasis. As defined previously, continuous application of the irrigation fluid of the present invention may be carried out as an uninterrupted application, or repeated and frequent irrigation of wounds or procedural sites at a frequency sufficient to maintain a predetermined therapeutic local concentration of the applied agents, or an application in which there may be intermittent cessation of irrigation fluid flow necessitated by operating technique. At the conclusion of the procedure, additional amounts of the therapeutic agents may be introduced, such as by intraocular injection of an additional amount of the irrigation fluid including the same or a higher concentration of the active agents, or by intraocular injection or topical application of the agents in a viscoelastic gel.

[0092] The concentrations listed for each of the agents within the solutions of the present invention are the concentrations of the agents delivered locally, in the absence of metabolic transformation, to the operative site in order to achieve a predetermined level of effect at the operative site. This solution utilizes extremely low doses of these pain and inflammation inhibitors, due to the local application of the agents directly to the operative site during the procedure.

[0093] In each of the surgical solutions of the present invention, the agents are included in low concentrations and are delivered locally in low doses relative to concentrations and doses required with systemic methods of drug administration to achieve the desired therapeutic effect at the procedural site.

VII. EXAMPLES

[0094] The following are exemplary formulations in accordance with the present invention suitable for ophthalmologic procedures.

Example 1

[0095] Exemplary ophthalmologic solutions of the present invention for use during cataract removal surgery are described in Tables 20, 21 and 22. This solution, and the following solutions of Tables 23-25, are provided by way of example only, and are not intended to limit the invention. Anti-inflammatories are believed to be particularly useful in cataract solutions of the invention, to potentially reduce the post-operative incidence of, or hasten resolution of, cystoid macular edema (CME). These exemplary solutions and the other exemplary ophthalmologic irrigation solutions described herein below are provided in terms of the concentration of each agent included in the previously described preferred balanced-salt solution. The solution may suitably be supplied in 500 ml bags, this being the quantity of irrigation solution typically applied during a procedure, by way of non-limiting example.

TABLE-US-00020 TABLE 20 Exemplary Cataract Solution Concentration (Nanomolar): Most Class of Agent Drug Therapeutic Preferred Preferred anti- flurbiprofen 10-1,000,000 100-100,000 1,000-10,000 inflammatory IOP red. agent timolol 10-1,000,000 100-100,000 1,000-10,000 mydriatic phenylephrine 50-500,000.sup. 500-100,000 1,000-10,000

TABLE-US-00021 TABLE 21 Alternate Exemplary Cataract Solution Concentration (Nanomolar): Most Class of Agent Drug Therapeutic Preferred Preferred anti- ketoprofen 10-1,000,000 100-100,000 1,000-10,000 inflammatory IOP red. agent timolol 10-1,000,000 100-100,000 1,000-10,000 mydriatic tropicamide 10-1,000,000 100-100,000 1,000-10,000

TABLE-US-00022 TABLE 22 Alternate Exemplary Cataract Solution Concentration (Nanomolar): Most Class of Agent Drug Therapeutic Preferred Preferred mydriatic, IOP oxymetazoline 10-1,000,000 100-100,000 1,000-10,000 red. agent anti- flurbiprofen 10-1,000,000 100-100,000 1,000-10,000 inflammtory

Example 2

[0096] A similar irrigation solution including multiple agents for effective reduction of inflammation and to provide mydriasis for invasive ophthalmologic surgery, such as a trabeculectomy, is provided in Table 23.

TABLE-US-00023 TABLE 23 Exemplary Trabeculectomy Solution Concentration (Nanomolar): Most Class of Agent Drug Therapeutic Preferred Preferred anti- prednisolone 10-1,000,000 100-100,000 1,000-10,000 inflammatory anti- flurbiprofen 10-1,000,000 100-100,000 1,000-10,000 inflammatory IOP red. agent timolol 10-1,000,000 100-100,000 1,000-10,000 mydriatic phenylephrine 50-500,000.sup. 500-100,000 1,000-10,000

Example 3

[0097] Irrigation solutions suitably used for extensive ophthalmologic surgery or posterior ocular chamber procedures, such as vitrectomy, provide increased analgesia by the addition of a local anesthetic. Such solutions of the present invention including a local anesthetic are provided in Tables 24 and 25.

TABLE-US-00024 TABLE 24 Exemplary Local Anesthetic Ophthalmologic Solution Concentration (Nanomolar): Most Class of Agent Drug Therapeutic Preferred Preferred IOP red. agent timolol 10-1,000,000 100-100,000 1,000-10,000 anti- flurbiprofen 10-1,000,000 100-100,000 1,000-10,000 inflammatory mydriatic tropicamide 10-1,000,000 100-100,000 1,000-10,000 analgesic lidocaine 1,000-100,000,000 10,000-10,000,000 100,000-1,000,000

TABLE-US-00025 TABLE 25 Alternate Exemplary Local Anesthetic Ophthalmologic Solution Concentration (Nanomolar): Most Class of Agent Drug Therapeutic Preferred Preferred IOP red. agent timolol 10-1,000,000 100-100,000 1,000-10,000 anti- flurbiprofen 10-1,000,000 100-100,000 1,000-10,000 inflammatory mydriatic tropicamide 10-1,000,000 100-100,000 1,000-10,000 analgesic bupivacaine 125-400,000 1,000-300,000.sup. 225,000-275,000

[0098] While the preferred embodiment of the invention has been illustrated and described, it will be appreciated that various changes to the disclosed solutions and methods can be made therein without departing from the spirit and scope of the invention. For example, alternate pain inhibitors, inflammation inhibitors, IOP reducing agents and mydriatic agents may be discovered that may augment or replace the disclosed agents in accordance with the disclosure contained herein. It is therefore intended that the scope of letters patent granted hereon be limited only by the definitions of the appended claims.