Inhibiting solution and a method of suppressing pain, inflammation or spasm

 

(57) Abstract:

The invention relates to solutions for surgical irrigation and methods of use thereof, in particular to anti-inflammatory, analgesic and anticonvulsant solutions. The solution for continuous irrigation of the wound during a medical procedure includes at least two inhibitory agent of pain/inflammation or spasm in the physiological fluid. Physiological fluid acts as a carrier. Each agent in the solution is at a concentration of not more than 100,000 Nola. These inhibiting agents act through different molecular mechanisms in the target cells. Irrigating solution of the present invention is a dilute solution and provides suppression of pain, inflammation or spasm at low doses inhibiting agents. 4 C. and 26 C.p. f-crystals, 28 tab., 5 Il.

The invention relates to solutions for surgical irrigation and methods of use thereof, and particularly to anti-inflammatory, analgesic and anticonvulsant solutions for surgical irrigation.

Arthroscopy is a surgical procedure in which a camera attached to a remote source of the social incision in the overlying skin or joint capsule. Through a similar portal incisions surgical instruments can be placed into the joint, where their use is directed through arthroscopic visualization. As arthroscopic skills includes improved, increased the number of operational procedures, once performed "open" surgical technique, can now be accompanied by arthroscopy. Such procedures include, for example, meniscectomy and reconstruction of the ligaments in the knee, shoulder acromioplasty and purifications wounds cuff cooks shoulder and elbow synovectomy. As a result, advanced surgical indications and the development of arthroscopic small diameter, arthroscopes hand and knee were also routine.

During each arthroscopy physiological irrigating fluid (e.g., normal saline or aktirovannye ringer's solution) is continuously flushed through the joint, inflating the joint capsule and removing operational sludge, thereby providing more precise intra-articular visualization. U.S. patent 4505493 Marshall reveals smolyary solution of glycerin in water for non-conductive and optically pure irrigation solution for arthroscopy.

Irrigation is also used in other and the treatment of burns and any surgical wounds. Each case is a physiological fluid for irrigation of a wound or cavity in the body or pass. Normal physiological irrigating fluid do not provide a painkiller or anti-inflammatory action.

Relief of pain and suffering in postoperative patients is an area of special attention in clinical medicine, especially in light of the growing number of operations outpatients, held every year. The most widely used agents, cyclo-oxygenase inhibitors (eg, ibuprofen), and synthetic drugs (e.g. morphine, fentanyl) have significant side effects including gastrointestinal irritation/bleeding and respiratory depression. Strong spread of nausea and vomiting associated with drugs is particularly problematic in the postoperative period. Therapeutic agents for the treatment of postoperative pain, avoiding at the same time harmful side effects that are not easily developed, because the molecular targets for these agents are widely distributed throughout the body and mediate a variety of physiological actions. Although C is s, methods for relief from pain, inflammation and suppress spasm at effective doses at the same time with minimal harmful systemic side effects have not been developed. As an example, a normal (i.e., intravenous, oral or intramuscular) routes of administration of opiate agonists in therapeutic doses are often associated with significant adverse side effects, including severe respiratory depression, changes in relation to fatigue and mental disorder, and severe nausea and vomiting.

Previous studies have demonstrated the ability of endogenous agents, such as serotonin (5-hydroxytryptamine, which is sometimes referred to as "5-HT"), bradykinin and histamine to produce pain and inflammation. Sicutery, F. , et al. , Serotonin-Bradykinin Potentiation in the Pain Receptors in Man, Life Sci., 4, pp. 309-316 (1965), Rosenthal, S. R., Histamine as the Chemical Mediator for Cutaneous Pain, J. Invest. Dermat. 69, pp. 98-105 (1977), Richardson, C. R. , et al., Identification of serotonin M-Receptor Subtypes and their Specific Blockade by a New Class of Drugs, Nature 316, pp. 126-131 (1985), Whalley, E. T., et al., The effect of Kinin Agonists and Antagonists, Naunyn-Schmiedeb Arch. Pharmacjl. 36, pp. 652-57 (1987), Lang, E. et al., Chemo-Sensitivity of Fine Afferents from Rat Skin in Vitro, J. Neurophysiol. 63, pp. 887-901 (1990).

For example, it was demonstrated that 5-HT applied in case of processing the Foundation of the world is chardson et al., 1985. Similarly, peripheral-applied bradykinin was produced pain, which could block bradykinesia antagonists of the receptor. Sicutery, et al., 1965, Whalley, et al., 1987, Dray A. et al., Bradykinin and Inflammatory Pain, Trends Neurosci. 16, pp. 99-104 (1993). Peripheral-applied histamine was produced vasodilation, itching, and pain, which could be suppressed by antagonists of the histamine receptor. Rosenthal, 1997, Douglas, W. W., "Histamine and 5-Hydroxytryptamin (Serotonin) and their Antagonists", in Goodman, L. S., et al., ed. The Pharmacol, ogical Basis of Theraupeutics, Mac Millan Publishing Company, New York, pp. 6050638 (1985), Rumore, M. M. et al. , Analgesic Effects of Antihistaminics, Life Sci., 36, pp. 403-416 (1985). It was demonstrated that the combination of these three agonists (5-HT, bradykinin and histamine) are applied together detect the effect caused by the synergistic pain, producing longer and more intense the pain signal. Sicutery, et al., 1965, Richardson et al., 1985, Kessler, W. et al., Excitation of cutaneous Afferent Nerve Endings in Vitro by a Combination of Inflammatory Mediators and Conditioning Effect of Substance P., Exp. Brain Res. 91, pp. 467-476 (1992).

In the body of 5-HT is located in platelets and Central neurons, histidine is found in breast cells and bradykinin is produced from the molecules of the precursor to a larger size in the process of injured tissue, pH changes, temperature changes, etc. as 5-HT can byee levels of plasma 20 times higher than the levels at rest (Ashton, J. H., et al., Serotonin as Mediator of Cyclic Flow Variations in Stenosed Canine Coronary Arteries, Circulation 73, pp. 572-578 (1986), it is possible that endogenous 5-HT plays a role in the generation of post-operative pain, hyperalgesia and inflammation. In fact, it was shown that activated platelets stimulate peripheral nociceptors in vitro. Ringkamp, M. et al., Activated Human Platelets in Plasma Excite Nociceptors in Rat Skin, in Vitro, Neurosci. Lett. 170, pp. 103-106 (1994). Similarly, histamine and bradykinin also released into tissue in the process of injury. Kimura, E. et al., Changes in Bradykinin Level in Coronary Sinus Blood After the Experimental Occlusion of a Coronary Artery, Am Heart J. 85, pp. 635-647 (1973), Douglas, 1985, Dray et al. (1993).

In addition, it is known that prostaglandins also cause pain and inflammation. Cyclo-oxygenase inhibitors, such as ibuprofen, are commonly used to block the production of prostaglandins, thereby reducing the prostaglandin-mediated pain and inflammation. Flower, R. J., et al., Analgesic-Antiperetics and Anti-Inflammatory Agents, Drugs Employed in the Treatment of Gout, in Goodman, L. S. et al., ed. The Pharmacological Basis of Theraupeutics, Mac Millan Publishing Company, New York, pp. 674-715 (1985). Cyclo-oxygenase inhibitors are associated with certain harmful systemic side effects, which typically are applied. For example, indomethacin or Ketorolac well rant, histamine, bradykinin and prostaglandins cause pain and inflammation. A variety of receptors through which these agents mediate their effects on peripheral tissue were known and/or discussed in the last two decades. The majority of studies were conducted on rats or other animal models. However, there is a distinction in pharmacology and receptor sequences of humans and animals. No studies have definitively demonstrated the importance of 5-HT, histamine or bradykinin in the production of postoperative pain in humans.

In addition, antagonists of these mediators is not currently used for the treatment of postoperative pain. The class of medications called 5-HT and norepinephrine, absorbed antagonists, which include amitriptylin was used orally with moderate success for chronic pain. However, the mechanisms Chronicles depending on the state of acute pain differ considerably. In fact, two studies on the establishment of acute pain using amitriptyline during surgery showed no effect amitriptyline in relieving the pain. Levine, J. D./, et al., Desipramine Enhances Opiate Posoperative Analgesia, Pain 27, pp. 45-49 (1986), Kerrick, J. M. , et awali orally. The second study notes that orally injected amitriptylin really produces less overall wellbeing in postoperative patients, which could be due to the affinity of the drug to many of amine receptors in the brain.

Amitriptylin, in addition to blocking the absorption of 5-HT and norepinephrine, is a potent antagonist of 5-HT receptor. Therefore, the lack of efficacy in reducing postoperative pain in the previously mentioned study, it will be obvious to be in contradiction with the proposed role for endogenous 5-HT in acute pain. There are several reasons for the lack of relief of acute pain, found with amitriptilina in these two studies. (1) In the first study used amitriptylin in the preoperative period within one week until the night before the operation, whereas in the second study of amitriptylin used only in the postoperative period. So amitriptylin was not present in the operated tissue during the acute phase of tissue damage, the time during which implies that 5-HT is released. (2) it is Known that amitriptylin intensively metabolised by the liver. When administered orally the e sufficiently long period of time, to inhibit the activity of postoperative release of 5-HT in the second study. (3) since there are many mediators of inflammation, and studies have demonstrated synergism between mediators of inflammation, blocking only one agent (5-HT) may not be sufficient to suppress the inflammatory response in the damaged tissue.

There have been several studies demonstrating the ability of extremely high concentrations (1-3% solutions, i.e., 10-30 mg per milliter) receptor antagonists histamine1(H1to act as a local anesthetic agent for surgical procedures. I believe that this anestesiologi effect is not caused by mediating through H1receptors, but rather due to nonspecific interaction with the neuronal membrane sodium channels (similar to the action of lidocaine). These side effects (e.g. sedation) associated with the specified high "anesthetic" concentrations of antagonists histamine receptor in the conventional local introduction of the antagonists histamine receptor that is not used during surgical operations.

The present invention is particularly the locally mediated pain and inflammation, in the liquid serving as a carrier physiological electrolyte. The invention is also a way to release irrigating solution during operation containing these agents directly to the surgical site where the solution works locally on neuroreceptors level with pre-weakening limit pain and inflammation at the site. Analgesic/anti-inflammatory agents in the solution include agents selected from the following classes of receptor antagonists, receptor agonists and inhibitors of enzymes, each class, acting on different molecular mechanisms of pain and suppress inflammation: (1) antagonists of the serotonin receptor, (2) agonists, serotonin receptor, (3) antagonists histamine receptor, (4) antagonists bradykininase receptor, (5) kallikrein inhibitors, (6) antagonists thickening receptor, including the subtype antagonists of neurokinin1and neurokinin2receptors, (7) antagonists of calcitonin-gene-mediated peptide (CGRP) receptor, (8) antagonists interlacing receptor, (9) inhibitors of lipoxygenase, (10) prostanoid receptor antagonists, including subtypes antag is in leukotriene receptor including the subtype antagonists of leukotriene4and receptor subtype antagonists of leukotriene D4receptor, (12) synthetic narcotic antagonists of the receptor, including the subtype antagonists of mu-opioid, δ-opioid and Kappa-opioid receptors, (13) purinoceptor agonists and antagonists, including antagonists of P2receptor and antagonists of P2receptor, (14) adenosintriphosphate (ATP)-sensitive potassium channels openers, and (15) calcium channel antagonists. Each of the above agents acts as an anti-inflammatory agent, and protivodiareynogo, i.e. analgesic or analgesic agent. The choice of agents from these classes of compounds are adapted for a particular application.

Some preferred variants of the solution of the present invention also include anticonvulsant agents for specific applications. For example, antispasmodic agents may be included in the solutions used for vascular procedures to limit vasospasm and urinary procedures to limit spasm in the urinary tract and the bladder wall. For such applications antispasmodic Agay is legit also as an antispasmodic agent. Suitable analgesic/anti-inflammatory agents that also act as an antispasmodic agent, include antagonists of serotonin receptor antagonists thickening receptor, ATP-sensitive potassium channels openers and calcium channel antagonists. Other agents that may be used in solution specially to make them antispasmodic properties include antagonists indotel and a new receptor and nitroxide donors (activators of the enzyme).

The present invention is also a method for the production of medicinal compounds in the form of irrigating solution for use in continuously irrigated surgical site or wound during the operating procedure. The method comprises dissolving in a liquid serving as a carrier physiological electrolyte, many analgesic/anti-inflammatory agents and for some applications antispasmodic agents, each agent is included with a concentration of preferably not more than 100,000 nanomolar and more preferably not more than 10000 nanomoles.

The method of the present invention provides a release of diluted combestone in the wound, such as articular tissue during arthroscopic procedures. Because the active ingredients in the solution are applied directly to the surgical fabrics in a continuous manner, medications can be used at extremely low doses relative to those of doses required for therapeutic effect, when the same medication is released orally, intramuscularly or vnutrisosudisto. Advantage of agents with low doses is TRACELEVEL. The most important is the lack of systemic side effects that often limit the usefulness of these agents. Low therapeutic doses used in the solution of the present invention, minimizes intravascular absorption enabled agents, thereby minimizing the systemic effects. In addition, the agents selected for specific applications in the solutions of the present invention are highly specific with respect to the mediators, on which they work. This specificity is maintained by the use of low doses. Finally, the cost of these active agents per liter is extremely low.

The local introduction of agents through irrigation guarantees also known conceito, blood flow, etc. due to a direct form of release of therapeutic solution concentration is obtained continuously. Therefore, is an improved dosage control. Local injection of active agents directly into the wound or surgical site, in addition, reduces, essentially, the decomposition agent for extracellular processes, i.e. the first and second pass metabolism, which nevertheless took place, when the agents were administered orally, intravenously or intramuscularly. This is especially true for those active agents that are peptides, which quickly metabolized. For example, some agents in the following classes are peptic: antagonists bradykininase receptor antagonists thickening receptor antagonists synthetic narcotic receptor antagonists of CGRP receptors and antagonists interlacing receptor. Local continuous release into the wound or surgical site to minimise degradation, and at the same time is a continuous replacement of the part of the agent, which may break down, with a guarantee that local therapeutic concentration sufficient to maintain the location of the receptor, podderjivaet procedures in accordance with the present invention produces a "preemptive analysisy" effect. Okkupirovannye receptor targets or inaktivirovanie affected enzymes to initiate extensive surgical trauma locally, the agents of this solution modulate signal transmission for proactive suppression scheduled pathological process. When the mediators of inflammation and ways inhibited before they can affect the tissue damage, the use of which is extracted in this case is more significant than if they are given after the injury.

I believe that the suppression of more than one mediator of inflammation through the use of a multicomponent solution of the present invention significantly reduces the degree of inflammation and pain. Irrigating solutions of the present invention include combinations of drugs, each effective against many anatomical receptors or enzymes. Medicinal agents are, therefore, simultaneously effective against combinations of pathological processes, including pain and inflammation, vasospasm, and a spasm of smooth muscles. It is believed that the action of these mediators is synergistic in that many of receptor antagonists and inhibitory agonists of the present invention is povysheva some agents of the present invention is discussed through an example, below in the detailed description of these agents.

In addition to arthroscopy solution of the present invention can also be locally applied to any cavity of the body of man or channel, surgical wounds, traumatic wounds (e.g., burns) or in any operative procedure or intervention procedure, which can be carried out irrigation. These procedures include, but are not limited to, urological procedures, cardiovascular diagnostic procedures, treatment and/or therapeutic treatments, and oral, dental and periodontal procedures. The term "wound" as it is used here, unless otherwise noted, involves the incorporation of surgical wounds, surgical sites/areas of intervention, traumatic wounds and burns.

Used vnutrikorporativnoj, the solution should give the clinic a significant reduction of pain and inflammation in the operational area than currently used irrigating fluids, thereby reducing postoperative analgesic (i.e., opiate) the needs of the patient and accordingly allows earlier mobilization of the surgical site of the patient. For use nest with regular irrigating fluids.

The present invention will now be described in more detail by means of an example and with reference to the accompanying drawings, in which:

Fig. 1, 2A and 2B are graphs of the percentage of vasoconstriction depending on time in the control arteries in the proximal segment of the examined arteries in the distal segment of the examined arteries, respectively, for the animal study described in Example VII, which demonstrates the effect on the vasoconstriction infusion of histamine and serotonin antagonists used in the solutions of the present invention, in the process of balloon angioplasty, and

Fig. 3 and 4 are diagrams extravasation of plasma, depending on the dose amitriptyline used in the solutions of the present invention, released intravenous and intraarticular, respectively, in the knee joint, in which the radiolabeled induced by injecting 5-hydroxytryptamine animals in the study described in Example VIII.

Irrigating solution of the present invention is a dilute solution containing the set of agents that suppress the pain/inflammation and antispasmodic agents in physiological media. PR or aktirovannye ringer's solution. The carrier is preferably a liquid, but for some applications, such as burns, can be prepared in the form of paste or ointment.

Anti-inflammatory/analgesic agents are selected from the group consisting of (1) antagonists of the serotonin receptor, (2) agonists, serotonin receptor, (3) antagonists histamine receptor, (4) antagonists bradykininase receptor, (5) kallikrein inhibitors, (6) antagonists thickening receptor, including the subtype antagonists neurokinin1and neurokinin2receptor, (7) antagonists of calcitonin-gene-mediated peptide (CGRP) receptor, (8) antagonists interlacing receptor, (9) inhibitors of enzymes active in the synthesis of metabolites of arachidonic acid, comprising (a) phospholipase inhibitors, which include PLA2isoform inhibitors and PLCisoform inhibitors (b) cyclooxygenase inhibitors, and (C) lipooxygenase inhibitors, (10) antagonists prostanoid receptors, including the subtype antagonists eicosanoides ER-1 and ER-2 and receptor subtype antagonists thromboxane receptor, (11) leukotriene antagonists of the receptor, including the subtype antagonists laminations narcotic receptor, including subtypes of agonists of mu-opioid, δ-opioid and Kappa-opioid receptors, (13) agonists and antagonists, purinoceptors receptors, including antagonists of P2and receptor agonists R2receptor, (14) adenosintriphosphate (ATP)-sensitive potassium channels openers, and (15) calcium channel antagonists. Appropriate anti-inflammatory/analgesic agents that also act as spasmolytic agents include antagonists of serotonin receptor antagonists thickening receptor, ATP-sensitive openers potassium channels and calcium channel antagonists. Other agents that may be used in solution to give it an antispasmodic properties include antagonists endothelioma receptor and nitroxide donors (activators of the enzyme).

Each surgical solution of the present invention, the agents are included in low concentrations and are released locally with relatively low doses of 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 visualaid drugs because the drugs are given systematically exposed to the first and second pass metabolism. Each agent is preferably included with the low concentration of from 0.1 to 10,000 nanomolar, except cyclooxygenase inhibitors that may be required at high concentrations depending on specifically selected inhibitor. Specific agents selected for use in the solution, and the concentration of the agents vary in accordance with the specific application, as described below.

The solution in accordance with the present invention may include exactly one agent or multiple inhibitory agents, pain/inflammation, one agent or multiple antispasmodic agents, or a combination of both inhibiting antispasmodic and inhibiting agents, pain/inflammation of the numbered classes at low concentrations. However, due to the above-mentioned synergistic effect of many agents and desires widely to block pain and inflammation preferably used many agents.

Surgical solutions represent a new therapeutic approach to the release of a number of pharmacological agents acting on the exact receptor and maul tospecifically drugs which are selective for individual receptor subtypes and isoforms of the enzymes that mediate the response to individual neurotransmitters and hormones. As an example, endothelioma peptides represent some of the most well-known potent vasoconstrictors. Selective antagonists that are specific for subtypes endothelioma (ET) receptors, wanted some pharmaceutical companies for use in the treatment of a wide range of disorders, including elevated levels of endothelin in humans. Recognition of the potential role of receptor subtype EMANDwhen hypertension these drug companies specifically target the development of selective antagonists to the subtype EMANDreceptor for preventive treatment of coronary vasospasm. This is a typical pharmacological strategy, although conventional, is not optimal, as many other vasoconstrictor agents (e.g., serotonin, prostaglandin, eicosanoid and so on) can be responsible for the initiation and maintenance of vasospastic episodes. In addition, despite the inactivation of a single receptor subtype or enzyme cascade effect. This explains the considerable difficulty in the application of single receptor-specific drugs to block the pathophysiological process in which multiple transmitters play a role. Therefore, targeting only specific individual receptor subtype, such as NOANDis probably ineffective.

In contrast to the standard approach to pharmacological therapy therapeutic approach surgical solution of the present invention is based on the rationality that the combination of drugs acting at the same time on the exact molecular targets, it is required to suppress the full spectrum of events that underlie the development of pathological conditions. In addition, instead of targeting one specific receptor subtype, surgical solutions consist of drugs that work with the target by conventional molecular mechanisms in different cell physiological processes, including the development of pain, inflammation, vasospasm and spasm of the smooth muscle. Thus, the cascading effect of additional receptors and enzymes in nociceptive, inflammatory and spastic ways, minimizes surgical solutions. the stream".

An example of inhibition "upstream" is cyclooxigenase antagonists in the regulation of pain and inflammation. Cyclooxygenase enzymes (COX1and MOR2) catalyse the conversion of arachidonic acid to prostaglandin H, which is an intermediate in the biosynthesis of inflammatory and nociceptive mediators, including prostaglandins, leukotrienes and thromboxanes. Cyclooxygenase inhibitors block the formation of "upstream" of these inflammatory and nociceptive mediators. This strategy prevents blocking of interactions described seven subtypes prostanoid receptors and their natural ligands. A similar inhibitor "upper stream" that is included in surgical solutions, is Aprotinin, the kallikrein inhibitor. Enzyme kallickrein, serine protease breaks the high kininogen plasma with the formation of bradykinin, important mediators of pain and inflammation. By inhibiting the action of kallikrein Aprotinin inhibits the synthesis of bradykinin, thereby providing effective inhibition "upstream" of these inflammatory mediators.

Surgical solutions are also useful in ispolnitel smooth muscle, which have been subjected to preliminary reduction of various neurotransmitters (such as serotonin, histamine, endothelin and thromboxane), involved in coronary vasospasm ATP-sensitive potassium channels openers (KCOs) produce relaxation of smooth muscle, which is concentration dependent (Quast et al., 1994, Kashiwabada et al., 1994). So KCOs provide a significant advantage in surgical solutions in the regulation of vasospasm and spasm of the smooth muscle by providing antispastic effects "lower flow", which are independent from physiological combinations of agonists that trigger spastic phenomenon. Similarly, NO donors and calcium channel antagonists, dependent on the electric voltage may be limited by vasospasm and spasm of smooth muscle, initiated by a variety of mediators, known previously in action spastic way of metabolism. These antagonists same calcium channels can also provide the blockade of inflammation "lower flow". Moncada, S., Flower, R. and Vane, J. in Goodman's and Gilman's Pharacological Basis of Therapeutics (7th ed.), MacMillan Publ. Inc., pp. 660-5 (1995).

The following is a description of the relevant drugs that fall into the above I in solutions of the present invention. At the same time not wanting to be limited by theory, also sets out the rationale for the selection of different classes of agents that, as expected, do the agents are able to participate in the operation.

A. Antagonists serotonin receptor.

Suggest that serotonin produces pain by stimulating serotonin2(5-HT2) and/or serotonin3(5-HT3) receptors on nociceptive neurons in the periphery. Most researchers agree that the 5-HT3receptors on peripheral nociceptors are communication immediate sensation of pain produced by 5-HT (Richardson et al., 1985). In addition to the inhibition of 5-HT-induced pain antagonists of 5-HT3receptor by inhibiting nociceptive activation can also inhibit neurogenic inflammation. Barnes P. J., et al., Modulation of Neurogenic Inflamation: Novel Approaches to Iflamatory Disease, Trends in Pharmacological Sciences, 11, pp. 185-189 (1990). The study knee joints of rats, however, required 5-HT2receptor, which is responsible for nociceptor activation due to 5-HT. Grubb, B. D. et al., A Study of 5-YN-Receptors Associated with Afferent Nerves Located in Normal and Inflamed Rat Anrle Joints, Agents Actions 25, pp. 216-18 (1988). Therefore, activation of 5-HT2receptors may also play a role which is in blocking pain and a variety of inflammatory processes. Thus, antagonists of 5-HT2and 5-HT3receptor both are suitable for use either individually or together in the solution of the present invention, as will be described later. Amitriptylene (ElavilTM) is a suitable antagonist of 5-HT2receptor for use in the present invention. Amitriptylin has been used clinically for many years as an antidepressant, and found that it had beneficial effects for some patients with chronic pain. Metaclopramide (ReglanTM) is used clinically as an antiemetic drugs, but finds a moderate affinity for 5-HT3receptor and can inhibit the action of 5-HT in the receptor, possibly inhibition of pain caused by the release of 5-HT from platelets. Thus, it is also suitable for use in the present invention.

Other suitable antagonists of 5-HT2receptor include imipramine, trazadon, desipramine and ketanserin. Ketanserin was used clinically due to its anti-hypertensive action. Hender, T., et al., Effects of New Serotonin Anatagonist, Ketaserin, in Experimental and Clinical Hypertension, Am. J. Hypertension, pp. 317s-23s (Jul. 1988). Other suitable antagonists of 5-RA include yohimbin, N-[-methoxy-3-(4-methyl-1-piperazinyl)phenyl] -2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1-biphenyl] -4-carboxamid ("GR127935") and methiothepin.

Therapeutic and preferred concentrations for use of these drugs in the solution of the present invention are presented in table. 1.

Century Agonists serotonin receptor.

5-HT1A, 5-HT1Band 5-HT1Dreceptors are known in the inhibition of adenylate cyclases activity. Thus, the inclusion of these antagonists serotonin1A, serotonin1Band serotonin1Dreceptor with a low dose of the solution must inhibition mediated by neurons in the pain and inflammation. Such actions would expect from agonists serotonin1and serotonin1Freceptor, because these receptors also inhibit adenylate the cyclase.

Buspirone is an agonist of the corresponding 1A receptor for use in the present invention. Sumatriptan is an agonist of the corresponding 1A, 1B, 1D and 1F receptor. Agonist relevant 1A and 1D receptor is digidroergotamin. Agonist appropriate 1E receptor is ergonovine. Therapeutic and preferred concentrations for these and the new buds are usually divided into histamine1(H1) and histamine2(H2) subtypes. Classic inflammatory reaction in the peripheral injection of histamine is mediated by H1receptor, Douglas, 1985. Therefore, the solution of the present invention preferably included antagonist of histamine H1the receptor. Promethazine (PhenerganTM) is the most commonly used antiemetic drug that strongly blocks the H1receptors and is suitable for use in the present invention. Interestingly, it was shown that this drug also has local anesthetic effects, but the concentration required for this effect, several orders of magnitude higher than those needed to block H1receptors, thus, believe that the effects are due to different mechanisms. The concentration of the antagonist of histamine receptor in the solution is sufficient to suppress H1receptors included in nociceptor activation, but does not reach the "local anesthetic" effect, thereby eliminating part of the considered systematic side effects.

Histamine receptors are also known for mediation in vasomotor1receptor mediates the contraction of coronary smooth muscle. Ginsburg, R., et al., Histamin Provacation of Clinical Coronary Artery Spasm: Implications Concerning Pathogenesis of Variant Angina Pectoris, American Heart J., Vol. 102, pp. 819-822 (1980). Some studies show that histamine-induced hypercorrect in the coronary system of the man is most prominent in the proximal arteries in the regulation of atherosclerosis and associated Dendarii arterial endothelium. Keitoku, M. et al., Different Histamin Action in Proximal and Distal Human Coronary Arteries in Vitro, Cardiovascular Reserch 24, pp. 614-622 (1990). Therefore, antagonists histamine receptor can be included in cardiovascular irrigating solution.

Other suitable antagonists H1receptor include terfenadine, diphenylhydramine and amitriptilin. Because of amitriptylin is also effective as an antagonist of the serotonin2receptor, it has a dual function when used in the present invention. Appropriate therapeutic and preferred concentrations for each of these antagonists H1receptor, see table. 3.

D. Antagonists bradykininase receptor.

Bradykininase receptors are generally divided into bradykinin1(B1and bradykinesia by bradykinin, mediated by due to B2subtype, where bradykinin-induced pain in the regulation of chronic inflammation is mediated by subtype B1. Perkins, M. N., et al., Antinociceptive Activity of The Bradykinin B1 and B2 Receptor Antagonists, des-Arg9, [Leu8]-BK and HOE 140, in Two Models of Persistent Hyperalgia in The Rat, Pain 53, pp. 191-97 (1993), Dray, A., et al., Bradykinin and Inflammatory Pain, Trends Neurosci 16, pp. 99-104 (1993), each of these sources is given here by reference.

Currently antagonists bradykininase receptor is clinically used. These drugs are peptides (small proteins), and thus they can be taken orally, because they will not be absorbed. Antagonists to the IN2receptor blocking bradykinin-induced acute pain and inflammation. Dray et al. , 1993. Antagonists IN2receptor inhibit pain in chronic States of inflammation. Perkins et al., 1993, Dray et al., 1993. Therefore, depending on the application of the solution of the present invention preferably includes one or both of the antagonist B1and IN2the receptor. For example, arthroscopy is performed for both acute and chronic conditions, and, thus, the irrigation solution for arthroscopy may include both antagonist B1and B2the receptor.

1receptor: [des-Arg10] derived D-Arg-(Hyp3-Thi5-D-Tic7-Oic8)-BK ("the [des-Arg10] derived NOAH 140", available from Hoechst Pharmaceuticals), and [Leu8] des-Arg9-BK. Appropriate antagonists bradykininase2receptor include: [D-Phe7] -BK, D-Arg(Hyp3-Thi5,8-D-Phe7)-BK ("NPC 349"), D-Arg-(Hyp3-D-Tic7-Oic8)-BK ("HOE 140"). These compounds are more fully described in the above references Perkins et al., 1993, and Dray et al., 1993. Appropriate therapeutic and preferred concentrations are given in table. 4.

E. Kallikrein inhibitors.

Peptide bradykinin is the most important mediator of pain and inflammation, as noted earlier. Bradykinin is produced in the form of the product of cleavage by the action of kallikrein on high kininogen in the plasma. So, I think that kallikrein inhibitors are therapeutic in suppressing the production of bradykinin and ultimately pain and inflammation. Appropriate bradykininase inhibitor for use in the present invention is Aprotinin. The appropriate concentration for use in the solutions of the present invention are given in the table. 5.

F peptides which include substance P, neurokinin A (NKA) and neurokinin B (NKB). Neurons are the main source of DCS in the periphery. An important overall effect Tks is neuronal stimulation, but other effects include endothelium-dependent vasodilation, the protein radiolabeled plasma, the degranulation of cells in the breast and recruitment and stimulation of cells with inflammation. Maggi, C. A., Gen Pharmacol., vol. 22, pp. 1-24 (1991). Due to the above physiological effect mediated by the activation of TK receptors, TK receptors aim to accelerate analgesia and treatment of neurogenic inflammation.

1. Subtype antagonists neurokinin1the receptor.

Substance P activates subtype neurokinin receptor, which is referred to as NK-1. It is known that substance P has a set of actions that produce inflammation and pain in the periphery after the activation of C-fibers, including vasodilatation, radiolabeled plasma and degranulation of cells in the breast. Levine, J. D., et al., Peptides and Primary Afferent Nociceptor, J. Neurosci. , 13, p. 2273 (1993). The corresponding antagonist of the substance P is ([D-RHS9[Spiro-gamma-lactam] Lu0, Thr11physalaemin-(1-11)) ("GR82334"). Other antagonists suitable for use in the us-perhydroxanthenes(3R7R) ("RP 67580") and 2s, 3s-CIS-3-(2-methoxybenzylamine)-2-benzhydrylpiperazine ("CP 96345"). The corresponding concentrations of these agents are given in table. 6.

2. Subtype antagonists neurokinin2the receptor.

Neurokinin And is a peptide which is localized in sensory neurons with substance P and which also accelerates inflammation and pain. Neurokinin And activates specific neurokinins receptor, which is referred to as the NK2. Admonds-Alt, S. et al., A Potent and Selective Non-Peptide Antagonist of the Neurokinin A (PC2) Receptor, Life Sci., 50:PL 101 (1992). In the urinary tract, Nks have a powerful spastic effect only via PC2the receptor in the urinary bladder of a person, and in the urethra and ureter person. Maggi, C. A. , Gen. Pharmacol., vol. 22, pp. 1-24 (1991). Thus, the desired medications for inclusion in surgical solution for use in urological procedures will contain the antagonist of the NK-2 receptor to reduce spasm. Examples of suitable NK-2 antagonists include: ((S-)-N-methyl-N-[4-(4-acetylamino-4-phenylpiperidine)-2-(3,4-dichlorophenyl)butyl] benzamide ("(+/-)-SR 48968"), Met-Asp-Trp-Phe-Dap-Leu ("MEN 10627"), and cyc(Gln-Trp-Phe-Gly-Leu-Met) ("L 659877"). The corresponding concentrations of these agents are given in table. 7.

G. Antagonists of the CGRP receptor in the sensory neurons with substance P and which acts as vasodilating agent and enhances the action of substance P. Brain, S. D. , et al., Inflamatory Oedema Induced by Synergism Between Calcitonin Gene-Related Peptide () and Mediators of Increased Vascular Permeability, Br. J. Pharmacolo. 99, p. 202 (1985). An example of a suitable antagonist CGRP receptor is alpha-CGRP-(8-37), a truncated version of CGRP. This peptide inhibits activation of CGRP receptors. Appropriate concentrations of this agent are given in table. 8.

N. Antagonist interlacing receptor.

Interleukins are a family of peptides that are classified as cytokines produced by leukocytes and other cells in response to inflammatory mediators. Interleukins (IL) can be potent perifericheskie hyperlysinemia agents. Ferriera, S. H., et al., Interleukin-Ibeta as a Potent Hyperalgesic Agent Antagonized by a Tripeptide Analogue, Nature 334, p. 698 (1988). An example of a suitable antagonist of IL-1 beta receptor represents Lys-D-Pro-Thr, which is a truncated version of IL-1 beta. This Tripeptide inhibits the activation of IL-1 beta receptors. Appropriate concentrations of this agent are given in table. 9.

I. Inhibitors of the activity of enzymes in the synthetic pathways of metabolism for metabolites of arachidonic acid.

1. Phospholipase inhibitors.

The production of arachidonic acid by phospholipase A2(PLA2) the IDA. There are a number of stages through which this path of metabolism may be inhibited, thereby reducing the production of these inflammatory mediators. Examples of inhibition of these various stages are given below.

Inhibition of enzyme isoforms PLA2inhibits the release of arachidonic acid from cell membranes and therefore inhibits the production of prostaglandins and leukotrienes, resulting in anti-inflammatory and energizerbunny properties of these compounds. Gkaser, K. B., Regulation of Phospholipase A2 Enzymes: Selective Inhibitors and Their Pharamacological Potential, Adv. Pharmacol. 32, p. 3 (1995). An example of a suitable agonist isoforms of PLA2is manoalide. The appropriate concentration for this agent are given in table. 10. Inhibition of PLAisoforms will also result in reduced production of prostanoids and leukotrienes and therefore will result in the reduction of pain and inflammation. An example of an inhibitor PLAisoforms is 1-[6-(17-3-petoksista-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione.

2. Cyclooxygenase inhibitors.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used as heumatology, 3d ed. (Kelley, W. N., et al., eds), p. 258 (1989). The molecular targets for these drugs are cyclooxygenase type I and type II (MOR-1 and MOR-2). These enzymes are well known as Prostaglandin H synthase 1 (constitutive) and 2 (inductive) (PGHS) and catalyse the conversion of arachidonic acid to Prostaglandin H, which is an intermediate in the biosynthesis of prostaglandins and thromboxanes. SOH-2 enzyme has been identified in endothelial cells, macrophages and fibroblasts. This enzyme is induced by IL-1 and endotoxin, and its expression is deregulated in sites of inflammation. Constitutive activity of MOR-1 and induced activity SOH-2 both lead to the synthesis of prostaglandins, which contribute to pain and inflammation.

NSAIDs, currently available on the market (diclofenac, naproxen, and indomethacin, ibuprofen, and so on) are usually non-selective inhibitors of both isoforms of SOKH, but may show greater selectivity for MOR-1 compared with selectivity for COX-2, although this ratio varies for different compounds. The use of inhibitors of MOR-1 and 2 to block the formation of prostaglandins is the best therapeutic approach than trying to block wagonist eicosanoid receptors (ER, ER, ER) are very rare and reported only on a specific, high affinity of the antagonist of the Thromboxane A2 receptor. Wallace, J. and Cirino, G., Trends in Pharm. Sci., Vol., 15, pp. 405-406 (1994).

Use cyclooxygenase inhibitors is contraindicated for patients with peptic ulcer, gastritis or renal impairment. In the United States only available injectable form of this class of drugs is Ketorolac (ToradolTMavailable from Syntex Pharmaceuticals, which is typically used intramuscularly or intravenously for postoperative patients, but again is contraindicated for the above categories of patients. Using ketorolaco or any other cyclooxygenase inhibitor(ROS) in solution in substantially lower concentrations than those used at present in the course of the operation, can afford to use this medicine for other categories of patients with contraindications. Adding cyclooxygenase inhibitor to the solution of the present invention gives the exact mechanism of inhibition of the production of pain and inflammation during arthroscopy or another operating procedure/intervention procedures.

Preferred cyclooxygenase the clients indomethacin is the least preferred, because it requires relatively high doses. Therapeutic and preferred concentrations for use in the solution are given in table. 11.

3. Lipooxygenase inhibitors.

Inhibition of the enzyme lipoxygenase inhibits the production of leukotrienes, such as leukotriene B4which as you know is an important mediator of inflammation and pain. Lewis, R. A., Prostaglandins and Leukotrienes, In: Textbook of Rheumatology, 3d ed. (Kelley, W. N., et al., eds), p. 258 (1989). Example 5-lipooxygenase antagonist is 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadienal)-1,4-benzoquinone ("AA 861"), the corresponding concentration of which is shown in table. 12.

J. Antagonists prostanoid receptor.

Specific prostanoids produced as metabolites of arachidonic acid, mediate their inflammatory effects through activation prostanoid receptors. Examples of specific classes prostanoid antagonists are subtypes antagonists eicosanoid EP-1 and EP-4 receptor subtypes and antagonists thromboxane receptor. The corresponding antagonist of prostaglandin E2receptor is a 2-acetylhydrazide 8-chlorodibenzo[b,f][1,4] oxazepine-10(11N)carboxylic acid ("SC 19220"). Subtype of hydrazino] methyl]-7-oxabicyclo[2,2,1] -hept-2-yl] -5-heptane acid ("SQ 29548"). Appropriate concentrations for these agents are given in table. 13.

As Antagonists of leukotriene receptor.

Leukotrienes (LTB4, LTC4and LTD4represent products 5-lipoxygenase metabolic pathways of arachidonic acid, which is generated by enzymatic and has important biological properties. Leukotrienes are implicated in several pathological conditions, including inflammation. Specific antagonists are currently considered by many pharmaceutical companies for potential therapeutic intervention in these diseases. Halushka, P. V. , et al., Annu. Rev. Pharmacol. Toxicol. 29:213-239 (1989), Ford-Hutchison, A. Crit. Rev. Immunol. 10:1-12 (1990). LTB4is in certain immune cells, including eosinophils and neutrophils. LTB4attaches to these receptors as a result of chemotaxis and lysosomal enzyme release, thus contributing to the process of inflammation. The process of signal transduction associated with activation of LTB4receptor, includes G-protein-mediated stimulation Gospodinova (P1) metabolism and increases the concentration of intracellular calcium.

An example of a suitable antagonist of leucotrienos)-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid ("SC-53228"). Concentrations of this agent, which is applicable for the practice of the present invention are given in the table. 14. Other suitable antagonists of leukotriene B4receptor include[3-[2(7-[7-chloro-2-chinoline)ethyl)phenyl] [[3-(dimethylamino-3-oxopropyl)thio] methyl] thio propanoic acid (MK 0571), and drugs LY 66071, a ICI 203219. MK 0571 also acts as a subtype antagonist LTB4the receptor.

L. synthetic narcotic Agonists of the receptor.

Synthetic narcotic receptors are antinociceptive and therefore agonists to these receptors are desirable. Synthetic narcotic receptors include subtypes of mu-, Delta - and Kappa-opioid receptors. Mu receptors are located on the terminal sensory neurons in the periphery and activation of these receptors inhibits sensory activity of a neuron. Basbaum, A. I. et al., Opiate analgesia: How Central is a Peripheral Target? , N. Engl. J. Med., 325:1168 (1991). Delta - and Kappa-receptors are located at sympathetic terminal aferente and inhibit the release of prostaglandins, thereby suppressing pain and inflammation. By Taiwo on, Y. O. et al., Kappa - and Delta-Opoids Block Sympathetically Dependent Hyperalgesia, J. Neurosci, Vol. 11, page 928 (1991). Examples of agonists of mu-opioid receptors are fentanyl and Try-D-Ala-Gly-[N-MePhe]P>D-Pen5] enkephalin ("DPDPE"). An example of the corresponding agonist and a Kappa-opiate receptor is (TRANS)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] -benzene ndimethylacetamide ("U50488"). Appropriate concentrations of each of these agents are given in table. 15.

M Purinoceptor antagonists and agonists.

Extracellular ATP acts as a signaling molecule through interaction with P2purinoceptors. One of a large class of purinoceptors are purinoceptor P2which are ligand-bound ion channels with a characteristic permeability of ion channels to the ions of Na+TO+and CA+. P2the receptors described in sensory neurons are important for primary afferent neurotransmission and nociceptive. ATP is known in the depolarization of sensory neurons and plays a role in nociceptor activation, as ATP released from damaged cells, stimulates P2xreceptors, leading to depolarization of nociceptive terminal nerve fibers. P2the receptor has a very limited distribution (Chen, C. C., et al., Nature, vol. 377, pp. 428-431 (1995), as it is selectively expressed in nervii to pain stimulus. Thus, much restrictiona localization of expression for abedini P2xreceptor makes these subtypes are excellent targets for analysing impact.

Appropriate antagonists P2x/ATP of purinoceptors for use in the present invention include, as an example, suramin and pyridoxalphosphate-6-zofenil-2,4-disulfonate acid (PPADS"). Appropriate concentrations for these agents are given in table. 16.

It is known that agonists P2receptor, G-protein-coupled receptor, have an effect on the relaxation of smooth muscles through lifting IP3 levels with a subsequent increase of intracellular calcium. An example of agonist P2receptor is 2-me-S-ATP.

N. Adenosine triphosphate (ATP)-sensitive potassium channels openers.

ATP-sensitive potassium channels have been found in a large number of tissues, including the brain, and studies linking the use of radioactive labeled ligands confirmed their existence. Opening of these channels causes the flow of potassium (K+and to hyperpolarizing the cell membrane. This hyperpolarization induces a decrease in intracellular free calcium is of analy, operated by the receptor. These combined actions have an impact on the cell in relaksirano state, i.e. a state that is more resistant to activation. It was shown that the potassium channels openers (KCOs) prevent the stimulus paired secretion and are considered to influence pre-United neuronal receptors and, thus, will suppress effects due to nervous stimulation and release of inflammatory mediators. Quast. U., et al., Cellular Pharmacology of Potassiun Channel Openers in Vascular Smooth Muscle Cardiovasc. Res., Vol. 28, pp. 805-810 (1994).

ATP-sensitive potassium channels have been found in vascular and non-vascular smooth muscle, and studies on the binding of radioactive labeled ligands confirmed their existence. Opening of these channels, hyperpolarizing the cell membrane and thus leads to the fact that acts on the smooth muscle cell in relaksirano state or condition, which is more resistant activation, reaching from here vasorelaxation. Openers TO+channels (CSR) were characterized as possessing potent antihypertensive activity in vivo and vasorelaxation activity in vitro. Medical is especiallyh, antinociceptive and antispasmodic agents of the urinary bladder.

Expected synergistic interaction between antagonists endothelium (NOAand openers of ATP-sensitive potassium channels (KCOs) in achieving vasorelaxation or relaxation of smooth muscle. The feasibility of dual-use of these drugs is based on the fact that these drugs have different molecular mechanisms of action to accelerate the relaxation of smooth muscles and the prevention of vasospasm. The initial raising intracellular calcium in smooth muscle cells induced EMAreceptor, sequentially transmits the activation-dependent electrical voltage channels and the entry of extracellular calcium, which is required for reduction. Antagonists EMAreceptor specifically block this indirect effect of the receptor, but will not block the increase in calcium released through the activation of other G-protein-coupled receptors in the muscle cell.

Drugs acting in the role of potassium channels openers, such as pinacidil will open these channels, causing leakage and To hyperpolarization of the cell membrane. This Hyper is mechanisms: (1) induce a reduction of intracellular free calcium through inhibition-dependent electrical voltage of CA channels by reducing the likelihood of opening both types of L-type and T-type calcium channels, (2) limitations induced by the agonist (channels managed by the receptor) release of CA from intracellular sources by inhibiting the formation of IP3 and (3) reducing the effectiveness of calcium as an activator redundant proteins. Therefore, the combined action of these two classes of drugs will bind to target cells in relaksirano state or condition, which is more resistant to activation.

Appropriate Triatel ATP-sensitive K+channels for the practice of the present invention include: (-)pinacidil, cromakalim, nicorandil, Minoxidil, N-cyano-N'-[1,1-dimethyl-[2,2,3,3-3H]propyl]-N ' -(3-pyridinyl)guanidine ("P 1075) and N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboxamide nanomeasurement ("KRN 2391"). Concentrations for these agents are given in table. 17.

Acting Antagonists calcium channel.

Antagonists calcium channel represent a distinct group of drugs that interfere with the transmembrane flux of calcium ions required for the activation of cellular responses mediating neuroforamina. The calcium included in the platelets and white blood cells, is a key mediating activation of response in these cells. Except that the real way transduction increases the amount of intracellular calcium, thus leads to the activation of antagonists of calcium channels in the plasma membrane. In many tissues, calcium channel antagonists such as nifedipine may reduce the release of arachidonic acid, prostaglandins and leukotrienes, which are awakened by various stimuli. Moncada, S., Flower, R. and Vane, J., in Goodman's and Gilman's Pharmacological Basis of Theurapeutics (7th ed.), MacMillan Publ. Inc., pp. 660-5 (1995).

Calcium channel antagonists also prevent the transmembrane flow of calcium ions required for vascular smooth muscle for contraction. This effect represents the feasibility of the use of calcium antagonists in the intended application of the procedures during the operation, the purpose of which is to mitigate vasospasm and relaxation of smooth muscle. The dihydropyridines including nisoldipine, act as specific inhibitors (antagonists) - dependent voltage reference subtype of L-type calcium channels. Systematic introduction of the calcium channel antagonist nifedipine during cardiac surgery was previously used to prevent or reduce vasospasm of the coronary artery. Seitelberg, R. et al. , Circulation, vol. 83, pp. 460-468 (1991). Again, in the medical literature there is a divided Jerusalem.-nociceptive and antispasmodic agents of the urinary bladder.

Calcium channel antagonists, which are among the analgesic/anti-inflammatory/antispasmodic agents useful in the present invention, showing a synergistic effect when combined with other agents of the present invention. Calcium channel antagonists (CA2+and nitroxide (NO) donors interact to achieve vasorelaxation or relaxation of smooth muscle, i.e. the inhibition of spasmodic activity. Tselesoobraznee dual-use, based on the fact that these drugs have different molecular mechanisms of action, may not be fully effective in achieving one of relaxation, and may be different periods of effectiveness. There are actually a large number of studies showing that some calcium channel antagonists may not achieve complete relaxation of vascular muscle, which was reduced pre-receptor agonist.

Influence nisoldipine used without additives and in combination with nitroglycerin, spasm of the internal artery mammary (IMA) shows that the combination of these two drugs produces a significant positive synergistic effect in Pradollano channel and nitroxide (NO) donor for more effective prevention of vasospasm and relaxation of smooth muscle. Reported examples of systematic administration of nitroglycerin and nifedipine in the process of cardiac surgery for the prevention and treatment myocardinal ischemia or vasospasm of the coronary artery (Cohen et al., 1983, Seitelberger et al., 1991).

Calcium channel antagonists also exhibit a synergistic effect with subtype A (OA)antagonists, indotel and a new receptor. Yanagisawa and co-authors observed that dihydropyridine antagonists and calcium channel antagonists blocked the effects of ET-11endogenous agonist in NOAthe receptor in the smooth muscle of the coronary artery and, therefore, suggested that ET-1 is an endogenous agonist of calcium channels that are sensitive to electric voltage. It was found that the continuous phase of increased intracellular calcium in smooth muscle cells induced EMAreceptor activation requires extracellular calcium and at least partially blocked by nicardipine. Thus, the transfer of the calcium channel antagonist is expected synergies to enhance the action of the antagonist ETAwhen combined surgical solution.

Calcium channel antagonists and openers E are ATP-sensitive (KATP), a pair of membrane potential of cells with cell metabolic state due to the sensitivity of agonizing nucleotides. TOATPthe channels are suppressed intracellular ATP, but stimulated intracellular nucleotide diphosphate. The activity of these channels is controlled by the electrochemical driving force for potassium and intracellular signals (e.g., ATP or G-protein), but not passed membrane potential per se. TOATPchannels hyperpolarizes membrane and thus allow her to control the residual potential of the cell. ATP-sensitive potassium fluxes were detected in skeletal muscle, brain, and vascular and non-vascular smooth muscle, and studies on the binding of radioactive labeled ligand confirmed the existence of these channels, which are receptors-targets for drugs of potassium channel openers, such as pinacidil. Opening of these channels causes the release of potassium and hyperpolarization of the cell membrane. This hyperpolarization (1) induces a decrease in intracellular free calcium through inhibition-dependent electrical voltage of CA2+channels by reducing the probability of opening of calcium Kahn is (channels, managed receptor from intracellular source, through the suppression of the formation of Inositol triphosphate (R), and (3) decrease the effectiveness of calcium as an activator redundant proteins. These combined actions of these two classes of drugs will bind to target cells in relaksirano state or condition, which is more resistant to activation.

Finally, calcium channel antagonists and tachykinin and bradykininase antagonists exhibit synergistic effects in indirect neuronopathy. Role has been installed neurokinin receptors in mediating neurospine. The path of metabolism signal transduction neuroligin1(NK1) and neurolysin2(NK2) receptor (members of the superfamily, the coupled G-proteins) includes increases in intracellular calcium, thus leading to activation of calcium channels in the plasma membrane. Similarly, connects activation bradykininase (BK2) receptors to increase intracellular calcium. Thus, calcium channel antagonists interfere with the normal mechanism of inclusion of higher levels of intracellular calcium, some of which enters through the channels of L-type. This is the basis for the Directors.

Appropriate antagonists calcium channel for the practice of the present invention include nisoldipine, nifedipine, nimodipine, lacidipine, isradipine. Appropriate concentrations for these agents are given in table. 18.

R. Antispasmodic agents.

1. Multifunctional agents

Some analgesic/anti-inflammatory agents, described above, will also be used for inhibiting wasextremely or spasm of the smooth muscle. As such, these agents also function as antispasmodic agent and, thus, are used with advantage in vascular and urinary applications. Analgesic/anti-inflammatory agents that also serve as spasmolytic agents include antagonists of serotonin receptor-specific antagonists serotonin2antagonists thickening receptor, ATP-sensitive potassium channels openers and calcium channel antagonists.

Nitroxide donors.

Nitroxide donors can be included in the solutions of the present invention is particularly due to their anticonvulsant activity. Nitroxide (NO) plays a critical role as a mediator molecules many physiologically cells the enzyme, known as NO synthase (NOS), catalyzes the conversion of L-arginine to NO, which acts as a messenger and mediates the response in adjacent smooth muscle cells. NO is continuously formed and is released through vascular endothelium under basal conditions, which inhibit the reduction and control of basal coronary tone and are produced in the endothelium in response to various antagonists (such as acetylcholine) and endothelium-dependent vasodilators. Thus, the regulation of NO synthase activity and final levels of NO are key molecular targets, controlling vascular tone. Muramatsu, K., et al., Coron. Artery Dis., vol. 5, pp. 815-820 (1994).

Expect a synergistic interaction between the NO donors and openers of ATP-sensitive potassium channels (KCOs) in achieving vasorelaxation or relaxation of smooth muscle. The feasibility of dual-use is based on the fact that these drugs have different molecular mechanisms of action to accelerate the relaxation of smooth muscles and the prevention of vasospasm. Grown coronary arterial smooth muscle cells, it is obvious that vasoconstrictors: vasopressin, angiotensin II and endothelin, all inhibit KATP, proteca bladder, inhibited mukharinova agonists. Steps in NO-mediated relaxation of smooth muscle runs through independent molecular pathway of metabolism (described above), including protein kinase G. This confirms that the combination of the two drugs is more effective in relaxation of smooth muscles than using one drug.

Appropriate nitroxide donors for the practice of the present invention include nitroglycerin, sodium nitroprusside, medicine FK 409, 3-morpholinosydnonimine or linsidomine hydrochloride (SIN-1), and S-nitroso-N-acetylpenicillamine ("SNAP"). Concentrations for these agents are given in table. 19.

3. Antagonists indotel and a new receptor.

Endothelin is a 21 amino acid peptide, which is one of the most potent vasoconstrictors. Were described three different human endothelial peptide, designated as E, ET and ET that oposredovany their physiological effects through at least two subtypes of receptors, referred to as the NOAand NOBthe receptors. Cardiac and vascular smooth muscles contain predominantly EMAreceptors, and this subtype is responsible for counter what the information in the selected drugs smooth muscle. It was found that antagonists of ETAreceptors are potent antagonists of the contraction of the human coronary artery. Thus, antagonists to NOAthe receptor must be therapeutically useful in the inhibition during the operation, coronary vasospasm and can additionally be used in the inhibition of the contraction of smooth muscles in urological applications. Miller, R. C. et al., Trends in Pharmacol. Sci., vol. 14, pp. 54-60 (1993).

Appropriate antagonists endothelioma receptor include cyclo(D-Asp-D-Val-Leu-D-Trp) ("BQ 123"), (N,N-hexamethylene)-carbamoyl-Lu-D-Trp(CHO)-D-Trp-OH ("BQ 610"), (R)2-[R-[(s)-2-([1-hexahydro-1H-azepine]carbonyl]amino-4-methyl-pentanoyl)amino-3-(3-[1-methyl-1H-indolyl)]propionamido-3-(2-pyridyl)propionic acid ("FR 139317"), cyclo(D-Asp-Pro-D-Ile-Leu-D-Trp) ("JKC 301"), cyclo(D-Ser-Pro-D-Val-Leu-D-Trp) ("JK 302"), and 5(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonate ("BMS 182874"). Concentrations for the two agents, acting as representatives of the relevant compounds are given in table. 20.

VI. Applications.

The solution of the present invention used for different operating procedures/intervention procedures, including surgical, diagnostic, and therapeutic techniques. Oh surgery anatomical joints, urological procedures and intravascular diagnostic and therapeutic procedures. The term "operation" as it is used here, refers to the application of the solution during surgery or medical intervention procedures, and for many procedures will preferably also be the solution to initiate the procedure. Such procedures typically use physiological irrigating fluid such as normal saline or aktirovannye the ringer's solution used for surgical site using techniques that are well known to specialists in this field. The method of the present invention is analgesic/anti-inflammatory/ anticonvulsant irrigating solution of the present invention, instead of the commonly used irrigating fluids. Irrigating solution is applied to the wound or surgical site prior to the procedure, it is preferable to tissue injury, and continues uninterruptedly during the whole procedure, with proactive blocking of pain and inflammation and/or spasm. The term "irrigation" as it is used here, refers to the washing of wounds or anatomical structures of the fluid flow. The term "continuously", as he used sdstate, sufficient to maintain a predefined therapeutic concentrations used agents, and applications, which can be intermittent cessation of irrigation fluid flow, caused by the necessity of operative technique.

Arthroscopic technique that can be applied to this solution, includes, as an example, but not limited to the example, a partial meniscectomy and reconstruction of the ligaments in the knee, acromioplasty shoulder, sanitation cuff rotation of the shoulder, synovectomy joint replacement and arthroscopy of the wrist and knee. Irrigating solution is fed continuously during the operation to the joint with a flow rate sufficient to blow the joint capsule, removal of operational debris and to enable seamless intra-articular visualization.

Appropriate irrigating solution to control pain and swelling during arthroscopic procedures presented in Example I, below. For arthroscopy preferably, the solution included a combination of, and preferably all or any of the following agents: serotonin antagonist2receptor antagonist serotonin3prescriptions and/or 1E receptors, antagonist bradykininase1receptor antagonist bradykininase2receptor and ziklooksigenazny inhibitor, and preferably all of the above agents.

This solution uses very low doses of these inhibitors pain and inflammation due to local agents are applied directly to the surgical site during the procedure. For example, less than 0.05 mg amitriptyline (corresponding antagonist serotonin2and glutaminovaja1dual receptor) required per liter of irrigating solution to ensure significant local concentration in the tissue, which will inhibit 5-HT2and H1the receptors. This dose is extremely low relative to the dose of 10-25 mg oral amitriptyline, which is the usual initial dose for this medication.

In each of the surgical solutions of the present invention, the agents included in low concentrations and are released locally with relatively low doses of concentrations and doses required in conventional methods of drug administration to achieve the desired therapeutic effect. It is impossible to obtain an equivalent therapeutic effect due to vysvobozhdenijah, because the drugs are given systematically exposed to the first and second pass metabolism.

For example, using a rat model of arthroscopy, applicants investigated the ability amitriptilina antagonist of 5-HT2to inhibit 5-HT-induced radiolabeled plasma in the knee rats in accordance with the present invention. This study, described more fully in Example VIII, compares therapeutic dosage of amitriptyline released locally (i.e., intra-articular) in the knee and vnutrisosudisto. The results demonstrate that intra-articular injection of amitriptyline require a full level of dosing is approximately 200 times lower than that required through the intravenous route, to achieve the same therapeutic effect. Evidence suggests that only a small fraction of drug released intra-articular, is absorbed local synovial tissue, and the difference of levels of the drug in the plasma between the two ways of introducing much more than the difference in the full dosing levels of amitriptyline.

The practice of the present invention must be different from the usual intra-articular injection of opiates and/or analgesics after the procedure, arthroscopy or open the Ziya throughout the surgical procedure to ensure the preferential inhibition of pain and inflammation. Compared to the high concentrations required to achieve therapeutic efficacy, continuous infusion of local analgesics, such as lidocaine (0.5-2% solutions), will lead to a deep systematic toxicity.

The completion procedure of the present invention may be desirable injection or in other respects, the use of higher concentrations of the same inhibitors pain and inflammation in irregular solution in the operational area, as an alternative or Supplement to opiates.

The solution of the present invention also finds application in intramuscular diagnostic and therapeutic procedures with potentially reduced spasm of the vessel wall, platelet aggregation and nociceptive activation produced vascular manipulation. The appropriate solution for such a procedure disclosed in Example II, below. Intravascular solution preferably includes any combination of and preferably all of the following agents: antagonist of 5-HT2receptor (Saxena, P. R. et al., Cardiovascular Effacts of Serotonin Inhibitory Agonists and Antagonists, J. Cardiovasc. Pharmacol. 15, (Suppl. 7), pp. S17-S34 (1990), Douglas, 1985), antagonist of 5-HT3receptor to block the activation of these p is provided, produce Brady - and tachycardia (Saxena, P. R. et al., 1990), the antagonist bradykininase1receptor and ziklooksigenazny inhibitor to prevent the production of prostaglandins in the areas of damaged tissue, which reduce pain and inflammation. In addition, intravascular solution will also preferably contain an antagonist of the serotonin1B(also known as serotonin1dbecause it was known that serotonin produces significant vascular spasm through activation of serotonin1Breceptors in humans. Kaumann, A. J., et al., Variable Participation of 5-YN1-Like Receptors and 5-YN2 Receptors in Serotonin-Induced Contraction of Human Isolated Coronary Arteries, Circulation 90, pp. 1141-53 (1994). This stimulating effect of serotonin 1B receptors on the vascular wall, leads to vasoconstriction, which is in contradiction with the previously discussed inhibitory action of serotonin1Breceptors in neurons. For the purpose of preparation of intravascular fluid, the term "inhibiting agents pain/inflammation" is referring to the inclusion of inhibitory agents spasm of the vascular walls and inhibiting agents platelet aggregation.

The solution of the present invention is also used to reduce pain and inflammation,environmental procedures, using the laser. Studies have shown that serotonin, histamine and bradykinin produce inflammation in the tissues of the lower urinary tract. Schwarz, M. M. et al. , Vascular Leakage in the Kidney and Lower Urinary Tract: Effect of Histamine, Serotonin and Bradykinin, Proc. Soc. Exp. Biol. Med. 140, pp. 535-539 (1972). Appropriate irrigating solution for urological procedures disclosed in Example III, below. The solution preferably includes a combination of and preferably all of the following agents: histamine antagonist1receptor for inhibition of histamine-induced pain and inflammation, antagonist of 5-HT3receptor to block the activation of these receptors on peripherally C-fiber nociceptive neurons, antagonist Bredikhina1and Bredikhina2and cyclooxigenase inhibitor to reduce pain/inflammation produced by prostaglandins in the areas of damaged tissue. Preferably there is also an antispasmodic agent to prevent spasm in the urethral canal and spasm of the bladder wall.

The solution of the present invention can also be applied during the operation for inhibition of pain and inflammation in surgical wounds, and to reduce pain and inflammation associated the biogenic amines, which not only produce pain and inflammation, but also lead to deep extravasation of plasma (fluid loss), often releasing component severe life-threatening burns. Holliman, C. J., et al., The Effect of Ketanserin, a Specific Serotonin Antagonist, on Burn Shock Hemodynamic Parameters in a Porcine Burn Model, J. Trauma 23, pp. 867-871 (1983). The solution disclosed in Example I for arthroscopy can also be applied to wounds or burns to control pain and inflammation. Agents of the solution of Example I can be an alternative made with the same concentrations in the paste or ointment to apply to the burn or wound.

VII. Examples

The following example presents several compositions in accordance with the present invention suitable for certain operating procedures followed by the summation of two clinical trials using agents of the present invention.

A. Example I

Irrigation solution for arthroscopy.

The following composition is suitable for use in the irrigation of the anatomical joint during arthroscopic procedures. Each medication was solubilizers in the liquid acting as the media containing physiological electrolytes, such as normal saline or Lactina the

C. Example II

Irrigating solution for intravascular therapeutic procedures.

The following drugs and concentrations in solution in the liquid serving as physiological media are suitable for use in irrigation operating sites during intravascular procedures (see tab. B).

C. Example III

Irrigating solution for urological procedures.

The following drugs and concentrations in solution in the liquid serving as physiological media are suitable for use in irrigation operating areas during urological procedures (see tab. C).

D. Example IV

Irrigation solution for arthroscopy, burns, General surgical wounds and oral/dental applications.

The following composition is preferred for use in anatomical irrigation during arthroscopy and oral/dental procedures and have the ability to deal with burns and General surgical wounds. While the solution described in Example I, is suitable for use in the present invention, the following solution is even more preferable, because eidetic therapeutic procedures.

The following drugs and concentrations in solution in the liquid serving as physiological media are preferred for use in irrigation operating areas during intravascular procedures. Again, this solution is preferred relative to the solution shown in Example II, due to the higher efficiency (see tab. E).

F. Example VI

Irrigating solution for urological procedures.

The following drugs and concentrations in solution in the liquid serving as physiological media are preferred for use in irrigation operating areas during urological procedures. Suppose that the solution has an even more efficient than the solution given in the previous Example III (see tab. F).

G. Example VII

Balloon dilatation normal iliac artery at the new Zealand white rabbit and the impact of the blockade histamine/serotonin receptor on the response.

The purpose of this study was focused on two aspects. First, using a new in vivo model for the study of arterial tone. The period of time during which the change occurs and the Mina and serotonin, used together, in the control of arterial tone in this environment, and then the study due to selective infusion blocking agents histamine and serotonin receptors before and after angioplasties damage.

1. Structural consideration.

This study was designed to describe the period of time during which had been a change in the arterial lumen size in one group of arteries, and to assess the impact of the blockade of the serotonin/Getmanova receptor on these changes in the second group of the same arteries. To facilitate comparison of the two different groups, both groups were treated identically except for the contents of the infusion, made in the course of the experiment. Control animals (arteries) infusion was performed with normal saline solution (the solvent for the test solution). Histamine/serotonin receptor blockade-treated arteries treated with saline solution containing blocking agents with the same speed and in the same part of the Protocol as control animals. Specifically, the test solution consisted of: (a) an antagonist of the serotonin3metoclopramide at a concentration of 1 is n at a concentration of 1.0 μm, all in normal saline. This study was performed for intelligence purposes, statistically and blind. Assignment to specific groups was statistical and researchers worked blindly with the contents of the infusion solution (one saline or saline containing antagonists histamine/serotonin receptor) before the end of the angiographic analysis.

2. The Protocol of the animal.

This Protocol was approved by the Medical center Seattle Veteran Affiars on the use of animals and research laboratory was fully accredited by the American Association for Accreditation of Laboratory Animak Care. Were studied iliac artery 3-4 kg male new Zealand white rabbit, nursed a regular rabbit food. Animals were relieved with the use of intravenous injection of xylazine (5 mg/kg of body weight) and Ketamine (35 mg/kg of body weight) was cut in the middle part of the ventral neck to highlight the carotid artery. The artery was Legerova distal made arteriotomy and the shell 5 French was introduced omitted in the aorta. Were registered zero baseline blood pressure and the frequency of heart contractions and then angiogram of the distal aorta using injections manually iopamidol 76% (Squibb Diagnostics, Princeton, NJ) omitted in the aorta. For each angiogram kalibrovany the sample was placed in the radiographic field of view to adjust the values, when conducting a measurement of the diameter. 2,5 French infusion catheter (Advanced Cardiavascular Systems, Santa Clara, CA) was introduced through the carotid sheath and set at 1-2 cm above the bifurcation of the aorta. The infusion of the test solution, either saline or saline containing antagonists histamine/serotonin receptor, was launched with a speed of 5 cm3per minute and continued for 15 minutes. After 5 minutes of infusion was held the second angiogram, using the previously described procedure, then a 2.5 mm balloon angioplasty catheter (the Ligthning, Cordis Corp., Miami, FGL) was quickly promoted through fluoroscopically guiding device to the left and then the right iliac artery. In each iliac artery balloon-catheter was carefully installed between the proximal and distal femoral branches using bony landmarks (bony landmarks), and the balloon was inflated for 30 seconds to a pressure of 12 ATM. A balloon catheter was filled using a diluted solution of radiographic contrast agent so the l quickly removed and another angiogram was recorded on film in 8 minutes after how was initiated infusion. The infusion was continued until the point corresponding to 15 minutes, and was registered with another angiogram (fourth). Then the infusion was stopped (it was introduced, the total amount of solution 75 cm3and infusion catheter was removed. The point corresponding to 30 minutes (15 minutes after cessation of infusion) was registered final angiogram as before. Blood pressure and heart rate were recorded at locations corresponding to 15 minutes and 30 minutes immediately before the start of the angiograms. After the final angiogram animal was painlessly killed by an overdose of anesthetic agents administered intravenously, and the iliac arteries were repaired and fixed by immersion in formation for histological analysis.

3. Angiographic analysis.

Angiograms were recorded on 35 mm film at a speed of frame 15 passes per second. For the analysis of angiograms were projected from the projector Vanguard at a distance of about 15 cm (5.5 ft). The diameters of the iliac artery in predefined locations relative to the cylinder angioplasties plot were recorded mostly by hand, holding the tools which were carried out on the zero line (before it was launched infusion of the test solution), 5 minute infusion, immediately after the cylinder angioplastie (after 8 minutes after the start of injection of the test solution), 15 minute (just before it was discontinued infusion) and 30 minutes (15 minutes after stopping the infusion). Diameter measurement were conducted in three sites in each iliac artery: closer to the site of balloon dilatation, in the area of balloon dilatation and distal section of the balloon dilatation.

Diameter measurement were then transferred to area measurement using the formula:

Area=(PI)(Diameter2)/4.

To calculate the vasoconstriction was used the value of the zero line to represent the maximum area of the artery and the percentage of vasoconstriction was calculated as:

% Vasoconstriction = {Area zero line Area at the point in the last time / Area zero line] 100.

4. Statistical methods.

All values are expressed as a value of +/-1 standard error values. The time course vasomotor response in the control arteries was determined using one way analysis of changes adjusted for repeated measurements with Post hoc comparison of data between specific time points was conducted with use the information in the control arteries, control arteries and arteries treated with an antagonist of the serotonin/histamine receptor were compared in those time points where there were significant vasoconstriction in control arteries, using multiple analysis of variations, with the treated group, identified as the independent variable. To compensate for the absence of previously established hypotheses p - value less than 0.01 was considered significant. Statistical calculations were performed using the statistical program for Wibdows, version 4.5 (Statsoft, Tulsa, OK).

5. Results.

The time course of changes in the size of the artery before and after the cylinder angioplasty in normal arteries treated with infusion of saline, was estimated at 16 arteries from 8 animals (PL. 21). Were studied in three segments each artery: proximal segment immediately upstream of the cylinder dilational segment, the balloon dilutionary segment and the distal segment directly downward flow from the cylinder dilational segment. The proximal and distal segments showed similar options changes in arterial dimensions: each of them had a significant change in the capacity segment, R is less than about 0.001, ANOVA). Post hoc tests showed that the diameters at the point immediately after angioplasty were significantly less than the diameters of the zero line or at a point of 30 minutes in each of these segments. On the other hand, arterial diameters in each segment at points on 5 minute, 15 minute and 30 minute were similar with diameters in the zero line. Balloon dilatrane segments showed smaller changes in arterial size than the proximal and distal segments. The diameter of the zero line of this segment was 1,81+/-0,05 mm, normal stretched diameter of the cylinder was 2,20+/-0,03 mm (p less than 0,0001 against the diameter of the zero line of the cylinder of the treated segment). Thus, the inflated balloon made perifericheskie to stretch the balloon dilutionary segment, but observed only a small increase in the diameter of the lumen from the zero line to a point on the 30 minute (1,82+/-0,05 mm to 1,94+/-0,07 mm, p=NS due to the post hoc tests).

Arterial diameters of the lumen were used to calculate the area of the lumen, then measure the area were used to calculate the percentage of vasoconstriction by comparing the 5-minute data, immediately after angioplasty, 15 and 30 minute data from the measurements is konstrukcii, it is shown in Fig. 1, changes in the amount of vasoconstriction over time are significant (in the proximal segment p=0,0008 in the distal segment p=0.0001 ANOVA). Post hoc tests identified the vasoconstriction immediately after angioplasty as significantly different from that which takes place in the 30th minute (p less than 0.001 in both segments). In the distal segment, immediately after angioplasty, vasoconstriction was significantly less than it was at the point corresponding to 5 minutes (p less than 0.01), other differences within this period were insignificant according to post hoc tests.

The change of the lumen in the control arteries can be summarized as follows: 1) Vasoconstriction with the loss of approximately 30% of the area of the lumen of the zero line in the segments proximal and distal artery to balloon dilational segment immediately after balloon dilatation. There are trends to less content vasoconstriction in the proximal and distal segments to dilation, but also in the point corresponding to 15 minutes (approximately 7 minutes after dilation), the point corresponding to 30 minutes (approximately 22 minutes after dilation), ten the ones observed only small changes in the dimensions of the lumen, and, despite the use of a cylinder with substantially more stretched diameter than was present in this segment in the zero line, a significant increase in lumen diameter dilational segment was not observed. These findings lead to the conclusion that any impact of the proposed histamine/serotonin treatment will be found only in the proximal and distal segments at points corresponding to the time when there was vasoconstriction.

A blocking solution of histamine/serotonin receptor was introduced in the 16th arteries (8 animals), angiographic findings were assessed at all time points in 12 arteries. Measurement of heart rate and cisterniga blood pressure were evaluated in a subset (subset) animals (table. 22). Differences in heart rate or cisterniga blood pressure was not observed when comparing the two groups of animals within a specific time points. Histamine/serotonin treatment of animals showed a tendency to a relative decrease in santolina blood pressure from the zero line to the 30-minute (-14+/-5 mm Od, p=0.04) and decreased heart rate (-26+/-10, p=0.05). Within the group of control animals was not Izmeni">

A comparison was made between proximal and distal segments histamine/serotoninreuptake arteries with control arteries, using the percentage measurement of vasoconstriction. Fig. 2A shows the impact of the introduction of the histamine/serotonin in the proximal segment of vasoconstriction, relative to the vasoconstriction that occurs in the control arteries. When a comparison was made between results in the two treated groups in the zero line immediately after angioplasty and the point corresponding to 15 minutes, histamine/serotonin introduction resulted in less vasoconstriction compared with the control by the introduction of saline (p=0.003, 2 way ANOVA). The comparison in the distal segment of the two treated groups is illustrated in Fig. 2B. Despite the observed difference in the measured values of the diameter in the distal segment, vessels, solution treated, showed less vasoconstriction than the vessels treated with salt solution in the zero line immediately after angioplasty and in the 15th minute, this sample did not reach statistical significance (p= 0.32, 2 way ANOVA). The absence of statistical significance may be attributed to lower than expected, vasoconstriction in control of the second plasma extravasation in the knee joint - comparison of intra-articular and intravenous routes of administration.

The following study was conducted to compare the two routes of administration of the antagonist of 5-HT2receptor, amitriptilina: 1) continuous intra-articular introduction, compared with 2) intravenous injection of synovial model of inflammation in the rat knee. Was determined the ability of amitriptyline to inhibit 5-HT-induced radiolabeled plasma joint by comparing the effectiveness and full dose of amitriptyline delivered through each path.

1. Animals.

Received the approval of the Institutional Animal Care Committee at the University of California, San Francisco for these studies. Male rats Sprague-Dawley (Bantin and Kingman, Fremont, CA) weighing 300-450 g were used in these studies. Rats were housed under controlled lighting conditions (light included from 6 am to 6 PM) with food and water ab libitum.

2. Radiolabeled plasma.

Rats were subjected to anesthesia by barbitala sodium (65 mg/kg), and then they were injected into the tail vein of blue dye Evans (50 mg/kg in a volume of 2.5 ml/kg), which acted as a marker for plasma extravasation. The capsule of the knee sutau and used for introduction of fluid. The rate of infusion (250 µl/min) was controlled using a siphon Sage instruments Syringe pump (Model 341 D, Orion Research Inc. , Boston, MA). In sustavnoi space was introduced 25-kalibrovany needle and perform the extraction perfusate liquid at 250 ál/min by controlling the process by Sage instruments Syringe pump (Model 351).

Rats were statistically distributed into three groups: 1) those who received only intra-articular (IA) 5-HT (1 μm), 2) those who received amitriptylin intravenous (IV) (with doses in the range from 0.01 to 1.0 mg/kg) followed IA 5-HT (1 mm), and 3) those who received amitriptylin intra-articular (IA) (concentrations in the range from 1 to 100 nm) with subsequent IA 5-HT (1 mm) plus IA of amitriptylin. In all groups the levels of plasma extravasation zero line were obtained first, each experiment by perfusion with 0.9% saline intra-articular and collect three samples of the perfusion solution during 15-minute period (once every 5 minutes). The first group was then introduced 5-HT IA for a full 25 minutes. Samples of the perfusion solution was collected every 5 minutes for a full 25 minutes. Then the samples were analyzed for the content of blue dye Evans by spectrophotometric measurement of absorbance at 620 nm, which is linearly related to its concentration (Carr and Wilhtlm, 196 is fixed joints were then subjected to perfusion for 15 minutes saline (zero line) with the subsequent 25-minute perfusion with 5-HT (1 μm). Samples of the perfusion solution was collected every 5 minutes and analyzed as above.

The knees of some of the rats were excluded from the study due to physical damage to the knee joint or errors during infusion or extraction (detected by the presence of blood in the perfusion solution and high levels of plasma extravasation zero line or swelling of the knee joint, due to incorrect insertion of the needle).

A. 5-HT-induced radiolabeled plasma.

The zero line extravasation of plasma was measured in all three of the tested knee joints (full number n=22). Levels zero line extravasation of plasma were below the average of 0.022+/-0,003 units absorption at 620 nm (mean +/- standard error values). This level zero line extravasation shown in Fig. 1 and 2 as dashed lines.

5-HT (1 μm) perfuziruemye in the knee joint was produced time-dependent increase in extravasation of plasma at a rate above the zero line. Within 25 minutes of perfusion with 5-HT intra-articular, maximum levels extravasation of plasma were reached within 15 minutes and lasted until until perfusion was not terminated after 25 minutes (data not p 15, 20 and 25 minutes during each experiment. The average 5-HT-induced radiolabeled plasma 0,192+/-0,011 led to approximately 8-fold stimulation above the zero line. This value is represented graphically in Fig. 3 and 4 corresponding to "0" dose IV amitriptyline and "0" concentration, IA amitriptilina respectively.

b. The influence of amitriptyline, administered intravenously, on 5-HT-induced radiolabeled plasma.

Amitriptylin introduced by injection into the tail vein, has produced a dose-dependent decrease in 5-HT-induced plasma extravasation, as shown in Fig. 3. The value of the IC50for IV amitriptylinemga inhibition of 5-HT-induced plasma extravasation completely inhibited dose IV amitriptyline 1 mg/kg, averaged radiolabeled plasma equal 0,034+/-0,010.

C. the Effect of intraarticular injection of amitriptyline on 5-HT-induced radiolabeled plasma.

Amitriptylin, put one in increasing concentrations of intra-articular, had no effect on the levels of plasma extravasation respect to the zero line, with the average radiolabeled plasma 0,018+/-0,002 (data not shown). Amitriptylin, superfusion in povyshayuschimisya, as shown in Fig. 4. 5-HT-induced radiolabeled in the presence of 3 nm IA amitriptilina not significantly different from that which was produced by one 5-HT, however, 30 nm amitriptyline, superfusion with 5-HT, has produced more than 50% inhibition, whereas 100 nm amitriptyline has produced a complete inhibition of 5-HT-induced plasma extravasation. The value of the IC50for IA amitriptylinemga inhibition of 5-HT-induced plasma extravasation was approximately 20 nm.

Most are found in the present study is that 5-HT (1 μm), perfuziruemye intra-articular knee joint was produced promoting extravasation of plasma, which was approximately the size of an 8-fold higher levels of the zero line and that either intravenously or intra-articular injection of antagonist 5-HT2receptor, amitriptyline, can inhibit induced 5-HT the radiolabeled plasma. Full dose entered amitriptyline, however, differs significantly between the two methods of drug release. The value of the IC50for inhibition IV amitriptilina 5-HT-induced plasma extravasation was 0.025 mg/kg, or 7,510-3mg to 300 is Azmi was approximately 20 nm. Since 1 ml of this solution was freed every 5 minutes for a full 35 minutes during the experiment, the total dose perfoirmance in the knee of the solution was 7 ml, with a total dose of 4,410-5mg, perfesional in the knee. This IA amitriptilina dose was approximately the size of 200 times less than the dose of IV amitriptyline. In addition, it is likely that only a small fraction IA perfoirmance drugs systematically absorbed, resulting in even greater difference to the full dose of released drugs.

Because 5-HT may play an important role in the occurrence of surgical pain and inflammation, as discussed earlier, the 5-HT antagonists such as amitriptylin can be useful if used during the operation. In recent studies, attempts were made to determine the effect of oral administration of amitriptyline on postoperative orthopedic pain (Kerrick et al., 1993). Oral dose, such low as 50 mg, was produced undesirable CNS side effects, such as poor sense of well-being". Their study also showed that orally injected amitriptylin have produced higher rates of pain scale than placebo (RO.05) polomercantil, is unknown. In contrast, intra-articular administration allows you to enter an extremely low concentration of the drug that is released locally to the site of inflammation, leading, perhaps, to the maximum benefit with minimal side effects.

While a preferred variant of the invention has been illustrated and described, it should be clear that various changes in the discussed solutions and methods may be made without deviating from the essence and scope of the invention. For example, can be considered an alternative inhibitors of pain and inflammation and antispasmodic agents that can enhance or replace disclosed agents in accordance with the description contained in them. Therefore, this description is intended to be protected by a patent, which is limited only by the definitions of the appended claims.

1. The method of inhibition of pain, inflammation and/or spasm in the wound by use of the relevant part in the process arthroscopic, urological procedures, procedures surface of the opening or cavity of the body by intraprocedure of application of the composition to the wound, wherein the composition is used for NY least two inhibiting agent selected from the inhibiting agents of pain/inflammation inhibitory agents spasm in physiological fluid, serving as a carrier, the said agents selected from several classes of agents acting through different molecular mechanisms in specific molecular target cells, which mediate pain and inflammation or spasm, agents, collectively which is effective for inhibition of pain and inflammation and/or spasm in the wound, and each agent in the composition is at a concentration of not more than 100,000 Nola.

2. The method according to p. 1, characterized in that each agent in the composition is at a concentration of not more than 10,000 Nola.

3. The method according to p. 1 or 2, characterized in that the classes of inhibitory agents pain/inflammation in the composition is selected from the group consisting of antagonists of serotonin receptor agonists serotonin receptor antagonists histamine receptor antagonists bradykininase receptor, kallikrein inhibitors, antagonists neurokinin receptor, including the subtype antagonists neurokinin1and receptor subtype antagonists neurokinin2receptor, antagonist pisnogo inhibitor, including inhibitors PLA2isoforms and PLCthe isoforms cyclooxygenase inhibitors, lipoxygenase inhibitors, antagonists prostanoid receptors, including the subtype antagonists eicosanoid EP-1 and EP-2 receptor subtype antagonists thromboxane receptor antagonists leukotriene receptor subtype antagonists of leukotriene4and D4receptor antagonists synthetic narcotic receptors, including the subtype antagonists of mu-opioid receptor subtype antagonists Delta-opioid receptor subtypes and antagonists of the Kappa-opiate receptor, purinoceptor agonists and antagonists, including agonists2and receptor agonists R2receptor, and the openers of ATP-sensitive potassium channel.

4. The method according to p. 3, characterized in that the selected inhibitory agent of pain/inflammation in the composition is in a concentration of from 0.1 to 10,000 Nola for antagonists of the serotonin receptor, 0,1-2000 nmoles for agonists serotonin receptor, 0,1-1000 nmole for antagonists histamine receptor, 1-10000 of Nola for antagonists bradykininase receptor, 0,1-1000 nmole for kallikrein inhibitors, 0.1 to 10000 Nola for subtypes of aptina, 1-1000 of Nola for antagonists of interleukin, 100-100000 of Nola for inhibitors PLA2isoforms, 100-100000 of Nola for cyclooxygenase inhibitors, 100-10000 of Nola for lipooxygenase inhibitors, 100-10000 of Nola for subtype antagonists eicosanoid EP-1 receptor, 100-10000 of Nola for subtypes of leukotriene antagonists IN4receptor, 0.1 to 100 nmole for subtype agonists mu-opiate receptor, 0.1 to 500 nmoles for subtype agonist Delta-opiate receptor, 0.1 to 500 nmoles for subtype agonists of the Kappa-opiate receptor, 100-100000 of Nola for purinoceptor antagonists and 0.1-10000 nmole the openers of ATP-sensitive potassium channel.

5. The method according to any of paragraphs. 1-4, characterized in that at least one of the selected classes of agents in the composition includes the class antispasmodic agents for the inhibition of spasm of smooth muscle, where, preferably, antispasmodic agent or agents are selected from the group consisting of subtype antagonists serotonin2receptor antagonists thickening receptor, nitroxide donors, the openers of ATP-sensitive potassium channel and antagonists endothelioma receptor.

6. The method according to p. 5, characterized by the t is serotoninovogo2receptor, from 0.1 to 10000 Nola for antagonists thickening receptor, from 1 to 10000 Nola for nitroxide donors, from 0.1 to 10000 Nola for the openers of ATP-sensitive potassium channel and from 0.01 to 100,000 Nola for antagonists endothelioma receptor.

7. The method according to p. 1 or 2, characterized in that the classes of agents in the composition include receptor agonists, receptor antagonists, enzyme inhibitors, enzyme activators, openers potassium channels and antagonists of ion channels.

8. The method according to p. 1, characterized in that the solution comprises inhibiting agents pain/inflammation selected from the group comprising a serotonin antagonist2receptor at a concentration of 50-500 Nola, serotonin antagonist3receptor at concentrations of 200-1000 Nola, the antagonist of histamine receptor in a concentration of 50-500 Nola, the agonist serotonin receptor at a concentration of 10-200 Nola, ziklooksigenazny inhibitor at a concentration of 800-5000 nmole subtype antagonist neurokinin1receptor at a concentration of 10-500 nmole subtype antagonist neurokinin2receptor at a concentration of 10-500 Nola, purinoceptor antagonist at a concentration of 10000-100000 Nola, Otkrytie 50-500 of Nola.

9. The method according to p. 1, characterized in that the composition is used for irrigation, at least part of the urinary tract during urological procedures and irrigating solution includes at least one selected antispasmodic agent and at least one selected inhibitory agent of pain/inflammation, however, the selected agents include subtype antagonist serotonin2receptor at a concentration of 1-100 nmole subtype antagonist histamine1receptor at a concentration of 50-500 Nola, ziklooksigenazny inhibitor at a concentration of 800-5000 nmole subtype antagonist neurokinin2receptor at a concentration of 10-500 Nola, purinoceptor antagonist at a concentration of 10000-100000 Nola, the opener of ATP-sensitive potassium channel in a concentration of 100-1000 Nola and kallikrein inhibitor at a concentration of 50-500 Nola, and nitroxides donor at a concentration of 100-1000 Nola.

10. The method according to p. 1, characterized in that the solution comprises an antagonist of a serotonin receptor agonist ATP-sensitive potassium channel or calcium channel antagonist in a concentration of not more than 100,000 Nola.

11. The solution for the inhibition of pain, inflammation and/or spasm eskay procedures an open surgical procedure or procedures in the body cavity, characterized in that it is a solution of at least two inhibitory agents selected from the inhibiting agents of pain/inflammation inhibitory agents spasm in physiological fluid, serving as a carrier, the said agents selected from several classes of agents acting through different molecular mechanisms in specific molecular target cells, which mediate pain and inflammation or spasm, agents, collectively which is effective for inhibition of pain and inflammation and/or spasm in the wound, moreover, each agent is in a concentration of not more than 100,000 Nola.

12. The solution on p. 11, characterized in that the classes of inhibitory agents pain/inflammation selected from the group consisting of antagonists of serotonin receptor agonists serotonin receptor antagonists histamine receptor antagonists bradykininase receptor, kallikrein inhibitors, antagonists neurokinin receptor, including the subtype antagonists of neurokinin1and receptor subtype antagonists of neurokinin2receptor antagonists of calcitonin gene on inhibitory PLA2isoforms and PLCthe isoforms cyclooxygenase inhibitors, lipoxygenase inhibitors, antagonists prostanoid receptors, including the subtype antagonists eicosanoid EP-1 and EP-2 receptor subtype antagonists thromboxane receptors, leukotriene receptor antagonists, including subtype antagonists of leukotriene4and D4receptor agonists synthetic narcotic receptors, including subtypes of agonists of mu-opioid receptor subtype agonists Delta-opioid receptor subtypes and agonists of the Kappa-opiate receptor, purinoceptor agonists and antagonists, including agonists2receptor and antagonists of P2receptor, and the openers of ATP-sensitive potassium channel.

13. The solution on p. 12, characterized in that the inhibiting agents of pain/inflammation in solution are in a concentration of from 0.1 to 100,000 Nola for antagonists of the serotonin receptor, 0,1-2000 nmoles for agonists serotonin receptor, 0,1-1000 nmole for antagonists histamine receptor, 1-10000 of Nola for antagonists bradykininase receptor, 0,1-1000 nmole for kallikrein inhibitors, 0.1 to 10000 Nola for subtype antagonists neurokininTipov antagonists of calcitonin-gene dependent peptide, 1-1000 of Nola for antagonists interlacing receptor, 100-100000 of Nola for phospholipase inhibitors, 100-100000 of Nola for cyclooxygenase inhibitors, 100-10000 of Nola for lipooxygenase inhibitors, 100-10000 of Nola for antagonists eicosanoid EP-1 receptor, 100-10000 of Nola for leukotriene antagonists IN4receptor, 0.1 to 100 nmole for subtype agonists mu-opiate receptor, 0.1 to 500 nmoles for subtype agonist Delta-opiate receptor, 0.1 to 500 nmoles for subtype agonists of the Kappa-opiate receptor, 100-100000 of Nola for purinoceptor antagonists and 0.1-10000 Nola for the openers of ATP-sensitive potassium channel.

14. The solution according to any one of paragraphs. 11-13, characterized in that at least one of the selected classes of agents in the solution includes the class antispasmodic agents for the inhibition of spasm of smooth muscle, where, preferably, antispasmodic agents are selected from the group consisting of subtypes of serotonin antagonists2receptor antagonists thickening receptor, nitroxide donors, the openers of ATP-sensitive potassium channel, calcium channel antagonists and antagonists endothelioma receptor.

15. Radle subtype antagonists serotonin2receptor, from 0.1 to 10000 Nola for antagonists thickening receptor, from 1.0 to 10,000 Nola for nitroxide donors, from 0.1 to 10000 Nola for the openers of ATP-sensitive potassium channel and from 0.01 to 100,000 Nola for antagonists endothelioma receptor.

16. The solution according to any one of paragraphs. 11-15, characterized in that each agent is in a concentration of not more than 10,000 Nola.

17. The solution according to any one of paragraphs. 11-16, characterized in that the classes of agents in the solution include receptor agonists, receptor antagonists, enzyme inhibitors, enzyme activators, openers ion channels and antagonists of ion channels.

18. The solution according to any one of paragraphs. 11-17, characterized in that the solution comprises a calcium channel antagonist in a concentration of not more than 100,000 Nola.

19. The method of inhibition of pain, inflammation and/or spasm through the use of relevant staff in the course of the operation in the vascular structure during intravascular procedures, due to the intraprocedure of application of the composition into the vascular structure, wherein the composition is used for continuous irrigation of the wound with a solution in the course of a medical procedure and it includes in supereditor specific molecular mechanism, where each class of agent is selected from the classes of receptor antagonists, receptor agonists, inhibitors of enzymes, activators of enzymes, discoverers of ion channels and receptor antagonists, operating with ion channels, agents, collectively which is effective for inhibition of pain and inflammation and/or spasm in the vascular structure, where each agent is in a concentration of not more than 100,000 Nola.

20. The method according to p. 19, characterized in that it is defined according to any of paragraphs. 2-4.

21. The method according to p. 19 or 20, characterized in that at least one of the selected classes of agents in the composition includes the class antispasmodic agents, focused on the enzyme, receptor ATP-sensitive potassium channel or receptor, operating ion channel, for inhibition of vascular spasm or spasm of smooth muscle, where, preferably, antispasmodic agent or agents are selected from the group consisting of subtypes of serotonin antagonists2receptor antagonists thickening receptor, nitroxide donors, the openers of ATP-sensitive potassium channel and antagonists endothelioma receptor.

22. The method according to p. 21, characterized the revisionists serotonin2receptor, from 0.1 to 10000 nmole antagonists thickening receptor, from 1.0 to 100,000 nmole nitroxide donors, from 0.1 to 10000 nmole the openers of ATP-sensitive potassium channel and from 0.01 to 100,000 nmole antagonists endothelioma receptor.

23. The method according to p. 19 or 20, wherein the irrigating solution includes at least one of the selected antispasmodic agents, and at least one of the selected inhibiting agents, pain/inflammation, however, the selected agents include subtype antagonist serotonin2receptor at a concentration of 50-500 Nola, ziklooksigenazny inhibitor at a concentration of 800-5000 Nola, antagonist endothelioma receptor at a concentration of 10-1000 Nola, the opener of ATP-sensitive potassium channel in a concentration of 100-1000 Nola, and nitroxides donor at a concentration of 100-1000 Nola.

24. The method according to p. 19, wherein the solution comprises an antagonist of a serotonin receptor or agonist of ATP-sensitive potassium channel.

25. The solution for the inhibition of pain, inflammation and/or spasm in the course of the operation in the vascular structure during intravascular procedures due to the intraprocedure primeneniya agents, selected from the inhibiting agents of pain/inflammation inhibitory agents spasm in physiological fluid, serving as a carrier, the said agents selected from several classes of agents acting through specific molecular mechanisms, where each class of agent is selected from the classes of receptor antagonists, receptor agonists, inhibitors of enzyme activators of the enzyme, discoverers of ion channels and receptor antagonists, operating with ion channels, agents, collectively which is effective for inhibition of pain and inflammation and/or spasm in the vascular structure, where each agent is in a concentration of not more than 100,000 Nola.

26. The solution on p. 25, characterized in that the classes of inhibitory agents pain/inflammation selected from the group consisting of antagonists of serotonin receptor agonists serotonin receptor antagonists histamine receptor antagonists bradykininase receptor, kallikrein inhibitors, antagonists neurokinin receptor, including the subtype antagonists of neurokinin1and receptor subtype antagonists of neurokinin2receptor antagonists of calcitonin gene operado the s PLA2isoforms and PLCthe isoforms cycloxygenase inhibitors, lipoxygenase inhibitors, antagonists prostanoid receptors, including the subtype antagonists eicosanoid EP-1 and EP-2 receptor subtype antagonists thromboxane receptors, leukotriene receptor antagonists, including subtype antagonists of leukotriene4and D4receptor agonists synthetic narcotic receptors, including subtypes of agonists of mu-opioid receptor subtype agonists Delta-opioid receptor subtypes and agonists of the Kappa-opiate receptor, purinoceptor agonists and antagonists, including agonists2receptor and antagonists of P2receptor, and the openers of ATP-sensitive potassium channel.

27. The solution on p. 26, characterized in that the inhibiting agents of pain/inflammation in solution are in a concentration of from 0.1 to 100,000 Nola for antagonists of the serotonin receptor, 0,1-2000 nmoles for agonists serotonin receptor, 0,1-1000 nmole for antagonists histamine receptor, 1-10000 of Nola for antagonists bradykininase receptor, 0,1-1000 nmole for kallikrein inhibitors, 0.1 to 10000 Nola for subtype antagonists neurokinin14receptor, 0.1 to 100 nmole for subtype agonists mu-opiate receptor, 0.1 to 500 nmoles for subtype agonist Delta-opiate receptor, 0.1 to 500 nmoles for subtype agonists of the Kappa-opiate receptor, 100-100000 of Nola for purinoceptor antagonists and 0.1-10000 Nola for the openers of ATP-sensitive potassium channel.

28. The solution according to any one of paragraphs. 25 to 27, characterized in that at least one of the selected classes of agents in the solution includes the class antispasmodic agents for inhibiting vascular spasm or spasm of smooth muscle, where, preferably, antispasmodic agents are selected from the group consisting of subtypes of serotonin antagonists2receptor antagonists thickening receptor, nitroxide donors, the openers of ATP-sensitive potassium channel and antagonists endothelioma receptor.

29. The solution on p. the antagonists serotonin2receptor, from 0.1 to 10000 Nola for antagonists thickening receptor, from 1.0 to 10,000 Nola for nitroxide donors, from 0.1 to 10000 Nola for the openers of ATP-sensitive potassium channel and from 0.01 to 100,000 Nola for antagonists endothelioma receptor.

30. The solution according to any one of paragraphs. 25 to 29, characterized in that each agent is in a concentration of not more than 10,000 Nola.

 

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