MX2007014766A - Method and composition for treating osteoarthritis - Google Patents

Abstract

A method and composition for treating osteoarthritis with ion-channel regulators is disclosed. The ion-channel regulators are used alone or in combination with other osteoarthritis treatment agents, including but not limited to injectable agents such as viscosupplements and steroids. A composition comprising one or more ion-channel regulator(s) and one or more osteoarthritis treatment agent(s) is also disclosed.

Description

METHOD AND COMPOSITION FOR TREATING OSTEOARTHRITIS FIELD OF THE INVENTION The present invention relates to the treatment of pain and inflammation in body tissues. In particular, the present invention relates to methods and compositions for treating osteoarthritis using ion channel regulators.

BACKGROUND OF THE INVENTION Osteoarthritis is a degenerative disease of the joints in which the cartilage and bone tissue are mainly affected. Osteoarthritis is especially common among the elderly, and usually affects a joint on one side of the body. In osteoarthritis, the cartilage breaks and wears, causing pain, inflammation, and loss of movement of the joint. Additional details are provided in Osteoarthritis, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, NIH Publication No. 02-4617, July 2002, which is incorporated herein by reference. Rheumatoid arthritis is a disease systemic which, when manifested in the joints, mainly affects the synovial membrane. Rheumatoid arthritis begins at an earlier age than osteoarthritis, is usually present bilaterally in the joints, and sometimes results in the feeling of illness, fatigue, and fever. Additional details are provided in Rheuma toid Arthri tis, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, NIH Publication No. 04-4179, May 2004, which is incorporated in the present invention for reference. Inflammation is a fundamental biological process consisting of a dynamic complex of cytological and chemical reactions that occur in affected blood vessels and adjacent tissues in response to injury or abnormal stimulation caused by a physical, chemical, or biological agent. The inflammation process includes: 1) local tissue reactions and resultant morphological changes; 2) destruction or removal of the material causing the injury; and 3) answers that lead to repair and healing. The so-called "cardinal signs" of inflammation are redness, warmth (or lukewarmness), swelling, pain, and function that is inhibited or lost. All these signs can be observed in some cases, but none of them are necessarily always present. A disease involving inflammation is referred to in the present invention as an "inflammatory disease". The proteins known as cytokines are important factors in the initiation and maintenance of inflammation. Cytokines, which are produced by synovial lining cells, cartilage cells, as well as by other cell types, regulate numerous biological responses, including cell growth, and the nature and degree of proteins that are made by cells. Cytokines include interferons (IFNs), colony stimulating factors (CSFs), interleukins (ILs), and tumor necrosis factors (TNFs). It is known that the presence of inflammatory cytokines (IL-1, IL-8, TNF) initiates a series of complex cellular and molecular events, including expression. of adhesion molecules, the production of secondary inflammatory mediators (prostaglandins, leukotrienes), and the production of growth factors. Arthritis is an inflammatory disease characterized by inflammation of a joint, whose term includes tissue and synovial membranes. There are many forms of arthritis, including without limitation, osteoarthritis (hypertrophic or degenerative arthritis), rheumatoid arthritis, arthritis due to infection (tuberculosis, Lyme disease, rheumatic fever, etc.), suppurating arthritis, juvenile arthritis, and gouty arthritis. In arthritis and other inflammatory conditions, high tissue levels of IL-1, IL-8, and TNF are found. In osteoarthritis, the cartilage that covers the ends of the bones that form the joint is slowly degraded by the action of several enzymes, particularly the matrix metalloproteinases (MMPs), which are secreted in the synovial fluid of the joint by the cells of the synovial lining in response to stimulation by several pro-inflammatory cytokines, particularly IL-1 and TNF. The destruction of cartilage by MMPs perpetuates the inflammatory reaction and leads to joint pain associated with osteoarthritis. Additional details are provided in "Biochemistry and Metabolism of Articular Cartilage in Osteoarthritis," HJ. Mankin and K.D. Brant, in Osteoarthritis: Diagnosis and Medical / Surgical Management, 2nd Ed., R. W. Moskowitz, D. S. Howell, V.M. Goldberg, and HJ. Mankin, .B. Saunders Co., Philadelphia (1992), which is incorporated in the present invention for reference. Ionic channels are glycoprotein structures located in the membrane of cells, including synovial cells and cartilage cells, which allow ions, particularly cations and monovalent and divalent anions, pass through the membrane. Ionic channels include but are not limited to calcium ion channels, sodium ion channels, potassium ion channels, chloride ion channels, cation ion channels, anion ion channels, junction channels and non-selective ion channels. Ionic channel regulators are a known group of agents, usually of a chemical nature, that alter the entry of certain ions into the interior or exterior of cellular cells and organelles, depending on whether the intracellular or extracellular concentration of the particular ion is greater or no, and the difference in electrical potential that exists between the inside and the outside of the cell. The combined effect of the concentration difference and the electric potential difference is called the electrochemical gradient. When the gate of an ion channel is opened, the ions flow to their electrochemical gradient unless they are prevented from flowing, for example, by means of a chemical ion channel regulator. Ion channel regulators that cause a reduction in ion flux that would otherwise occur are known as "ion channel blockers". Ionic channel regulators that cause an increase in ion flux that would otherwise occur are known as "activators of ion channel. "Ionic channel regulators are commonly used to treat a variety of conditions, including cardiac conditions such as atrial fibrillation, supraventricular tachycardia, hypertrophic cardiomyopathy and hypertension, as well as migraine-like headaches, prevention of brain damage, and other disorders Some ion channel regulators and related compounds have been described in the art as being useful in the treatment of inflammatory diseases For example, Thorpe et al (US Patent No. 6,416,758) describe antibody conjugate kits to inhibit selectively binding VEGF to only one (VEGFR2) of the two VEGF receptors Antibodies inhibit angiogenesis and induce tumor regression, and can be used for the treatment of all conditions in which angiogenesis is a factor (including Arthritis.) Thorpe et al. mentions CAI, an angiogenesis inhibitor that it acts as a calcium channel regulator that prevents the reorganization of actin, the migration and dissemination of endothelial cell on collagen IV. Stale, et al. (U.S. Patent No. 6,359,182) describe nitrous C compounds derived from a wide variety of drugs, including known calcium (verapamil, diltiazem, etc.). These derivatives provide relaxation and platelet inhibiting effects, and because of their function as a NO donor, they are said to be useful in treating arthritis. Schonharting, et al. (patent E.U.A. No. 6,337,325), provide a combination preparation that includes a compound that has a phosphodiesterase inhibitory action, and a compound that reduces the biologically effective intracellular Ca 2+ content (such as verapamil). Its preparation can be used to treat rheumatoid arthritis. Medford, et al. (U.S. Patent No. 5,811,449) describe a method for the treatment of atherosclerosis and other cardiovascular and inflammatory diseases that are mediated by VCAM 1 ("vascular cell adhesion molecule 1"). The list of diseases includes rheumatoid arthritis and osteoarthritis. The dithiocarboxylates and other compounds used with the method can be attached to a large number of pharmaceutically active compounds, including calcium channel regulators (verapamil, diltiazem, nifedipine). Some known compositions for the relief of pain associated with inflammatory disease states may contain ion channel regulators and related compounds. For example, Breault (patents E.U.A No. 6,365,603 and No. 6,100,258) describes aromatic / phenyl compounds useful for inhibiting the pain-increasing effects of type E prostaglandins. Compounds can be used to treat pain associated with rheumatoid arthritis, osteoarthritis, and osteoporosis, and may contain additional agents such as calcium channel regulators. Mak (U.S. Patent No. 6,190,691) provides methods for treating various inflammatory conditions that are mediated by TNF production (including rheumatoid arthritis). The treatment is achieved by administering a therapeutically effective amount of any of a number of compounds, including calcium channel regulators such as verapamil, nicardipine or isradipine. Mak shows direct injection of large amounts of (+) - verapamil (20-40 mg in a 10 mg / ml solution) into the joints for the treatment of rheumatoid arthritis. There is no known cure for osteoarthritis and consequently the clinical efforts directed to treat it currently are directed towards the relief of symptomatic pain. Conventional therapies include treatment with analgesics or non-steroidal anti-inflammatory drugs (aspirin, ibuprofen, naproxen, COX-2 inhibitors such as CELEBEX and VIOXX, and the like), inter-articular injection of corticosteroids and hyaluronan not modified or modified (a treatment called visco-complementation), as well as the use of steroids, antibiotics, glucosamine, chondroitin, immuno-modulators, and penicillamine. Traditional remedies such as the application of heat for temporary relief of local pain are useful for some patients, and appropriate exercise and physical therapy programs can help maintain joint mobility. In severe cases, surgery to replace the joint may be advisable. Despite the availability of a wide range of medications and treatment modalities for arthritis and inflammatory diseases in general, as described above, none has been shown to be completely satisfactory for osteoarthritis. In particular, there is still a need for innovative treatments that target the underlying cause of osteoarthritis, for example the production of MMPs, and thus help to reduce, eliminate, or slow down their progress (Symptomatically expressed by bone erosion, cartilage erosion, inflammation, swelling, abnormal neovascularization, etc.).

SUMMARY OF THE INVENTION In accordance with its main aspects and Broadly established, the present invention provides a method and compositions for treating pain, inflammation and loss of function associated with osteoarthritis, by the use of some agents that can regulate the movement of ions into the interior and exterior of cells through structures embedded in the cell membrane called ion channels. As briefly described above, said agents are known in the present invention as "ion channel regulators". One embodiment of the present invention comprises a method for treating osteoarthritis, which comprises administering directly to the affected joint, preferably by direct injection into the closed cavity of the joint ("intra-articular injection"), a therapeutically effective amount of at least one ion channel regulator, alone or in combination with at least one other agent for the treatment of osteoarthritis. The method of the present invention addresses the underlying cellular processes that directly lead to pain and tissue destruction associated with osteoarthritis. In one embodiment, the invention comprises administering to the synovial tissue an effective amount of ion channel regulator; that is, an amount that is sufficient to reduce any or all of the symptoms of osteoarthritis without producing any of the undesirable side effects that result from an ion channel regulator overdose, such as tissue death or injury, swelling of the joints, and so on. The present invention provides means to interfere with cellular signaling by the cytokine IL-1, the major inflammatory cytokine associated with osteoarthritis, thereby leading to lower levels of MMP and correspondingly less destruction of cartilage and pain. resulting. It is believed that this method does not necessarily affect the production of IL-1, but alters its consequences by interfering with the synthesis of MMPs at a point subsequent to the binding of IL-1 to its receptor on the surface of cells, which It is known to those skilled in the art as the first step in the synthesis process. This method is compared to the use of certain ion channel regulators as means to interfere with the production of the cytokine TNF, for example, in the treatment of systemic inflammatory disease rheumatoid arthritis (see Mak, supra). Ion channel regulators contemplated as useful in the present invention include, but are not limited to, calcium channel regulators, sodium channel regulators, potassium channel regulators, chloride channel regulators, channel regulators, cationic ion, anionic ion channel regulators, non-selective ion channel regulators, and conexon channel regulators (ie, chemical agents that regulate the movement of ions and molecules through the connexons in synovial cells, which consist of the protein known as connexin 43). A preferred method for administering the ion channel regulator is to directly inject a pharmaceutically acceptable composition containing at least one ion channel regulator into the closed cavity of an arthritic joint. The ion channel regulator can be administered alone or in combination with other medicaments, preferably other chemical agents used to treat osteoarthritis (referred to herein as "osteoarthritis treatment agents"). Agents for treating osteoarthritis include, but are not limited to, visco-supplements, spheroidal and non-spheroidal anti-inflammatory agents, glucosamines, chondroitins, etc., which are pharmaceutically acceptable. In another embodiment, the present invention comprises a novel composition useful for treating osteoarthritis in accordance with the present invention. The composition of the invention comprises at least one ion channel regulator and at least one other agents for treatment of osteoarthritis. In a preferred embodiment, a composition comprises at least one ion channel regulator and at least one agent for treatment of injectable osteoarthritis, more preferably a visco-complement. The compositions of the invention may also contain other materials such as fillers, stabilizers, coatings, coloring and flavoring agents, preservatives, fragrances, and other additives known in the art. In its various modalities, the present invention provides various methods of treatment to users. The treatment may consist of the administration of an effective amount of at least one ion channel regulator, preferably in a pharmaceutically acceptable composition containing at least one of said compounds. Alternatively, the treatment may include the administration of at least one ion channel regulator in combination with the administration of at least one other agent for treatment of osteoarthritis, preferably in a composition that contains both the ion channel regulator as to the other agent for treatment of osteoarthritis. The treatment can be easily adjusted to the individual needs of the patient, and can be used instead of or in conjunction with other treatment modalities including, but not limited to, physical therapy, treatments that provide localized pain relief (heat, massage, application of salves, etc.), and other medications that help reduce disability, relieve pain , and improve the quality of life of the patient. Other features and advantages of the present invention will be apparent to those skilled in the art from a careful reading of the following detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides methods and compositions in which ion channel regulators are used to treat the inflammation, pain and tissue destruction associated with osteoarthritis. Without pretending to be limited to the theory, it is believed that the presence of inflammatory cytokines in the joint leads to the entry and exit of certain cellular ions, for example, calcium ions, sodium, potassium, chloride, etc., into the interior and exterior of the cells in the joint, particularly synovial lining cells, which results in the initiation of what is known as cell signaling or cellular transduction. The terms are used in the present invention interchangeably. As the signaling process develops, other events occur, including the activation of protein kinase C, changes in intercellular communications, and alteration of protein expression by cells. If these processes are not regulated properly, they eventually lead to osteoarthritis, which is characterized by symptoms that include pain, inflammation, abnormal neovascularization, erosion of bone and cartilage, loss of function, and finally, degeneration of the affected joint. It has been discovered that the entry of certain ions, particularly calcium and sodium ions, is critically important for the ability of cells to secrete MMPs. As previously described, it is believed that MMPs are primarily responsible for the destruction of the cartilage of the joint that leads to joint pain associated with osteoarthritis. It is generally believed that the most important factor responsible for the secretion of MMPs is interleukin-1 (IL-1). See, "Biochemistry and Metabolism of Articular Cartilage in Osteoarthritis," HJ. Mankin and K.D. Brant, supra, which is incorporated in the present invention for reference. The specific MMPs whose levels in the fluid of the joint are regulated by IL-1, and whose deregulation mediates the development of osteoarthritis, include MMP-1, also known as collagenase-1, MMP-2, also known as gelatinase A; MMP-3, also known as stromelysin-1; MMP-8, also known as collagenase-2; and MMP-13 also known as collagenase-3. MMP activity levels produced by synovial tissue from patients who have osteoarthritis are greater than the corresponding level obtained from patients who do not have arthritis (see "Increased Intercellular Communication through Gap Junctions May Contribute to Progression of Osteoarthritis", AA). Marino, DD, Addell, OV Kolomytkin, WD Meek., R. Olf, KK Sadasivan, and JA Albright, Clinical Orthopedics &Related Research 422: 224-232 (2004), which is incorporated in the present invention for reference. It has been discovered that ion channel regulators, particularly calcium channel regulators such as verapamil and nifedipine, are capable of interfering with the effect of IL-1 on synovial cells (see "Interleukin lS Switches Electrophysiological States of Synovial Fibroblasts"; OV Kolomytkin, AA Marino, KK Sadasivan, RE Wolf, and JA Albright, American Journal of Physiology, 273 (Regulatory Integrative Co mp. Physiol. 42): R1822-R1828 (1997), which it is incorporated in the present invention for reference. It is believed, without being limited to the theory, that the mechanism responsible for the beneficial effects of treating osteoarthritis with ion channel regulators in accordance with the present invention involves its ability to antagonize the proinflammatory effect of IL-1, which if not examines, leads to elevated levels of MMPs (which in turn, leads to chronic inflammation, destruction of cartilage, pain and loss of joint mobility associated with osteoarthritis). It is believed that the ability to regulate or block the signaling pathway at the transmembrane ion current level (including, but not limited to, transmembrane calcium ion current) by the administration of ion channel regulators has clinical benefits. For example, by affecting the entry of calcium ions into the affected synovial cells, the calcium signaling pathway is altered, avoiding intracellular events that culminate in inflammation and destruction of cartilage. As previously mentioned, ion channel regulators can sometimes be referred to in the art as ion channel blockers or ion channel activators, depending on their effect on the ion flux. Although these terms may refer to the same chemical agents, it is believed that the terminology "regulators" ion channel "is more accurate in the context of the present invention.The ions that pass through the channels can activate processes (for example, manufacture of MMPs), but these processes are always normal processes in the sense that the reason for the What the ion channels evolved in the first place was to facilitate this process.The pathology refers to the level of regulation, that is, osteoarthritis develops when an inappropriate amount of ions passes through a channel.Therefore, it can be said that The present invention treats osteoarthritis by blocking these channels, which results in allowing less ions to pass through the membrane, so that the situation is very close to normal, however, the coin has another side. It is not always the case that few ions are equal to normal and many ions are equal to abnormal, sometimes many ions are equal to normal, and few ions are equal to abnormal. This invention could not treat osteoarthritis by "blocking" the ion channel, but by "stimulating" it. Therefore, the term "ion channel regulator" is intended to include chemical agents that perform both functions. Ionic channel regulators are commonly used to treat a variety of cardiac conditions, including atrial fibrillation, tachycardia supraventricular, hypertrophic cardiomyopathy, and hypertension, as well as migraine type pains, the prevention of brain damage, and other disorders. These chemical agents are well known to those skilled in the medical arts and it is contemplated that all known calcium channel regulators and those discovered in the future will be useful in the present invention. Specific examples of ion channel regulators include, but are not limited to, calcium channel regulators, sodium channel regulators, potassium channel regulators, chloride channel regulators, cation channel regulators, anion channel regulators, regulators of connecting channel, and non-selective ion channel regulators, as well as specific antibodies against channels. As the name implies, the calcium, sodium, potassium, chloride, cation and anion channel regulators respectively regulate the movement of calcium ions, sodium ions, potassium ions, chloride ions, anions and cations through the ion channels in the membranes of the cells. Non-selective ion channels are ion channels that allow any combination of anions and cations to pass through cell membranes, and non-selective ion channel regulators regulate the movement of said ions. Connection regulators regulate the movement of ions through the connections. Connectionons are a class of ion channels that consist of the connexin protein 43, which is known to be present in synovial tissue and which occurs in increased amounts in arthritic joints. It is believed that all types of ions with a molecular mass less than 300 can pass through the connexons. The amino acid sequence of connexin 43 is listed in the Universal Protein Resources, where it is identified as P17302. A "specific antibody against the channel" means an antibody against an antigenic determinant of the ion channel protein that can block the function of the ion channel when the antibody binds to the antigenic determinant. Representative examples of calcium channel regulators include amlodipine, bepridil, diltiazem hypochloride, felodipine, gallopamil, isradipine, nicardipine, nifedipine, nimodipine, nitrendipine, verapamil, and mixtures thereof, as well as specific antibodies against the channels. Representative examples of sodium channel regulators include quinidine, encainide, mexityl, disopyramide, procainamide, tetrodotoxin, and mixtures thereof, as well as specific antibodies against the channels. Representative examples of potassium channel regulators include tedisamil, glibenclamide, dofetilide, amiodarone, azimilide, tolbutamide, propranolol, and mixtures thereof, as well as specific antibodies against the channels. Representative examples of chloride channel regulators include 5-nitro-2- (3-phenylpropylamino) benzoic acid, chlorotoxin, picrotoxin, and 9-anthracencarboxylic acid and mixtures thereof, as well as channel-specific antibodies. A very complete list of calcium and sodium channel regulators that may be suitable for the present invention is found in the previously cited reference Mak, patent E.U.A. No. 6,190,691, which is incorporated in the present invention for reference. Representative examples of connexin channel regulators include lindane, octanol, 18-glycyrrhetinic acid, calcium ion concentration, pH, peptido-mimetics, some antibodies. It is known that some peptidomimetics can be used to block the connexons and therefore they can be suitable as connexion channel regulators in accordance with the present invention. For example, the tridecapeptide VCYDKSFPISHVR (residue numbers 63-75), and the synthetic undecapeptide SRPTEKTIFII (residue numbers 204-214) can block connexin 43, as described in Leybaert, L., Braet, K., Vandamme, W., Cabooter, L., Martin, P.E.M. and Evans, W.H., "Connexin channels, connexin mimetic peptides and ATP relay". Cell Commun. Accession. 10: 251-257, 2003. Similarly, peptidomimetics consisting of 2 or more amino acids can be formed using any portion of the connexin 43 amino acid sequence, and the peptides can be effective, some more than others, in regulating the movement of ions through the conexón. Peptides consisting of amino acids located in the transmembrane or extracellular domains of connexin 43 can be particularly effective link channel regulators. It is also anticipated that the conexon can be regulated by antibodies directed against the transmembrane or extracellular domains of the conexon. In this case, the synthetic peptides can be injected into the animals for the purpose of inducing an immune response consisting of antibodies against epitopes located on the peptides. Appropriate procedures for obtaining and unifying the antibodies are described in Harlow, E. and Lane, D., "Antibodies: A Laboratory Manual". Woodbury, NY: Cold Spring Harbor Laboratory Press, 1988. In one embodiment of the present invention, a method of treating osteoarthritis comprises administering directly to the joint an effective amount of at least one ion channel regulator. The administration of the ion channel regulator is preferably achieved by direct (intra-articular) injection of a composition comprising at least one ion channel regulator within the arthritic joint. Intra-articular injection differs from other methods of administration of ion channel regulators in that it allows biologically sufficient concentrations of ion channel regulator to be applied to the affected synovial tissue without the risk of producing the undesirable side effects that can occur as result of the higher ion channel regulator concentrations required by other administration techniques. Injection techniques are known to those skilled in the art. For example, a useful description for injecting the knee joint is provided in "Viscosupplementation Under Fluoroscopic Control," D. Waddell, D. Estey, DC Bricker, and A. Marsala, American Journal of Medicine in Sports, 4: 237- 241 and 249, 2001, which is incorporated for reference in the present invention. In one embodiment of the invention, an effective amount of one or more ion channel regulators is administered to an osteoarthritic joint in a pharmaceutically acceptable composition. An "effective amount" is an amount that is sufficient to reduce any or all of the symptoms of osteoarthritis in the treated joint, such as inflammation, pain, stiffness and / or loss of function, without producing any of the undesirable side effects that result from an overdose of ion channel regulator, such as death or tissue damage, swelling of the joints, and so on. Whatever an effective amount may vary depending on the ion channel, the method used for administration and the joint that is being treated. In some embodiments, a combination of ion channel regulators, for example a calcium channel regulator and a sodium channel regulator, may be effective. An effective amount of ion channel regulator for treating osteoarthritis in accordance with the present invention using intra-articular injection may be in the range of 0.00001-2.0 mg, preferably dissolved or suspended in physiological saline or other suitable vehicle for injection into the body. Preferred compositions comprise one or more ion channel regulators at a total concentration of 0.0001-2.0 mg / ml. Typically, 1-4 ml of the composition in the joint can be injected at a time. It has been discovered based on appropriate studies of synovial tissue that the administration of a total dose of more than 2.0 mg of ion channel regulator to a joint by intra-articular injection is likely to produce undesirable side effects that are the result of the toxic effect of the ion channel regulator on the joint tissue at that level. An effective amount of ion channel regulator used in the present invention is an order of magnitude less than the amount of (+) --verapamil considered in the prior art to be effective for the treatment of rheumatoid arthritis by intra-articular injection. See, for example, Mak patent E.U.A. No. 6,190,691, column 83, lines 35-54. As a specific example of the present invention, an effective amount of verapamil can be 0.02-0.5 mg when injected directly into the knee joint of an adult. In another embodiment of the invention, one or more ion channel regulators may be administered in combination with one or more other agents for treatment of osteoarthritis, either in separate compositions or in the same composition. Preferably, the other agent for treatment of osteoarthritis is in the form of an injectable composition, i.e., a composition that is suitable to be injected directly into the affected joint (intra-articular injection). The treatment method of the present invention can be easily adjusted to the individual needs of the patient and can be used in place of or in conjunction with other treatment modalities including but not limited to physical therapy, treatments that provide localized pain relief (heat, massage, application of balms, etc.), and with other medications that help reduce disability, relieve pain, and improve quality of the patient's life. Accordingly, the examples of treatments contemplated by the present invention include an intra-articular injection of a composition that includes one or more ion channel regulators followed by another intra-articular injection of another agent for treatment of osteoarthritis, for example a viscous complement, spheroid or other agent for treatment of injectable osteoarthritis; an intra-articular injection of an ion channel regulator composition followed by the oral or intravenous administration of another agent for treatment of osteoarthritis such as a non-spheroidal anti-inflammatory drug; an intra-articular injection of an individual composition comprising at least one ion channel regulator and at least one visco-complement, spheroid or other agent for treatment of injectable osteoarthritis; etc. A composition for treatment in accordance with one embodiment of the invention comprises one or more ion channel regulators and one or more other agents for treatment of osteoarthritis. The individual concentrations of the ion channel regulator (s) and the other agent or agents for treatment of osteoarthritis are sufficient to provide an effective amount of each ingredient to the affected joint. Preferably, the composition comprises ion channel regulators at a concentration of 0.00001-2.0 mg / ml and another agent or agents for treatment of osteoarthritis at a concentration of 0.01-25 mg / ml. In one embodiment, the composition is suitable for intra-articular injection in accordance with the method of the present invention, and both the ion channel regulator and the other agent for treatment of osteoarthritis are "injectable". As used in the present invention, the term "injectable" means any agent for treatment of osteoarthritis that is in a form suitable for intra-articular injection. In one embodiment, the other injectable osteoarthritis treatment agents may comprise at least one corticosteroid such as a glucocorticoid. As a specific non-limiting example, the composition of the present invention may comprise 1-25 mg / ml of the agent for treatment of spheroidal osteoarthritis injectable methylprednisolone acetate. In another modality, the other agent for Injectable osteoarthritis treatment may comprise at least one visco-complement. As used in the present invention and in the art, the term "visco-complement" refers to any substance that is used to restore and / or increase the cushioning and lubrication of the arthritic synovial fluid by intra-articular injection. Preferred visco-supplements include hilane, hyaluronic acid and other hyaluronan compounds (sodium hyaluronate), which are natural complex sugars of the glycosaminoglycan family. Hyaluronan, in particular, is a long chain polymer containing repeating repeating units of Na-glucuronate-N-acetylglucosamine. By way of example, commercially available hyaluronan visco-supplements include Synvisc®, Hyalgan®, Supartz®, and Orthovisc®. As a specific non-limiting example, the composition of the present invention may comprise 1-15 mg / ml of a hyaluronan compound. Other agents for treating osteoarthritis comprising the composition of the present invention may also include those used in any arthritis treatment modality, such as oral administration, intravenous administration, etc. Examples of other agents for treating osteoarthritis include, without limitation, non-spheroidal anti-inflammatory drugs (NSAIDS) such as ibuprofen, naproxen, and COX-2 inhibitors; analgesics such as aspirin and acetaminophen; glucans, including glucosamines, for example glucosamine sulfate and glucosamine hydrochloride; and proteoglycans, such as chondroitin compounds, as well as some other known narcotics, steroids, antibiotics, immunomodulators, penicillamine, and the like. The compositions of the present invention may also contain other materials such as fillers, stabilizers, coatings, coloring agents, preservatives, fragrances, and other additives known in the art. The compositions may be in liquid or gel form and may be provided in formulations for sustained release.

EXAMPLES The present invention can be illustrated by the following non-limiting examples: EXAMPLE 1 The patient M.L. is a 57-year-old female individual with osteoarthritis of the knee joint (grade IV on the Kellgren-Lawrence scale). An assessment of joint pain and function is performed immediately before treatment, and at various times after treatment, using the visual analogue scale (VAS) for pain, and the Osteoarthritis Index of Western Ontario universities and McMaster (WOMAC for its acronym in English), which assesses pain, function and stiffness in arthritic joints. A more detailed description of the nature and use of these clinical endpoints is provided in "Clinical Development Programs for Drugs, Devices, and Biological Products, Intended for the Treatment of Osteoarthritis, North American Department of Health and Human Services, Agency for Food and Drug Administration. , July 1999", which is incorporated for reference in the present invention. Immediately after the VAS and WOMAC measurements are made, the patient's right knee is injected with 1 ml of saline solution containing 0.2 mg of the calcium channel regulator verapamil using the following basic injection procedure: The patient sits in a standard dental chair, with the knee flexed between 30-40 degrees. The knee is prepared with a sterile betadine preparation. Ethyl chloride aerosol provides skin anesthesia for injection of undiluted 1% xylocaine, which is injected into the skin and subcutaneous tissue. Precautions are taken not to inject any fluid inside the knee. The patient is warned that although most of the pain will be removed, there will still be some pain as soon as the needle passes through the synovial lining. After sufficient time has elapsed to achieve effective local anesthesia, it is often useful to activate a fluoroscopy unit in the lateral position to obtain a view of the patella and contact area of the femoral condyle with the tibia plateau. The insertion point for the 21-gauge injection needle is then chosen using the lateral view of the knee and taking as reference the point of an anterolateral standard arthroscopy portal. The injection site is close to the normal portal site in approximately 1 to 1.5 centimeters. Using this as a guide, the needle is advanced inward toward the intra-articular space to the anterior point of contact of the femoral condyle and the tibia plateau. At this point, verapamil-free injection is performed without injecting the soft tissues. The above procedure is described in greater detail in the aforementioned periodical publication entitled "Viscosupplementation Under Fluoroscopic Control," cited supra.

The following Table 1 shows in summary form the VAS and WOMAC scores obtained before and at various time points after the injection.

TABLE 1 Time Arthritis scores of patient M.L. VAS of the VAS doctor of the patient WOMAC Before the injection 72 67 57 1 week after injection 44 43 47 2 weeks after injection '20 25 38.5 3 weeks after the injection 20 33 46 8 weeks after injection 20 33 34 12 weeks after injection 20 28 41 16 weeks after the injection 28 34 33 weeks after injection 15 27 37 As shown in Table 1, immediately before treatment, the patient has a doctor's VAS score of 72, a patient VAS score of 67, and a WOMAC score of 57. One week after the injection, the patient's pain is markedly reduced, as indicated by the reduced VAS scores of 44 and 43, and the general function of the patient is improved, as it is demonstrated by the decrease in the WOMAC score to 47. The patient is monitored periodically for up to 20 weeks after the injection, and it is found that the reduction in pain and improvement in functioning continue to be observed.

EXAMPLE 2 Patient O.B. is a 73-year-old male who suffers from osteoarthritis of the left knee (grade IV on the scale of Kellgren-Lawrence). As can be seen in the following Table 2, before the treatment, the patient has a doctor VAS score of 50, a patient VAS score of 46 and a WOMAC score of 30.

After the patient's left knee is injected with 1 ml of saline containing 0.2 mg of verapamil using the same basic procedure described in Example 1, both VAS scores and the patient's WOMAC score improve significantly. The following Table 2 summarizes these results: TABLE 2 Time Arthritis scores of patient O.B. VAS of the VAS doctor of the patient WOMAC Before the injection 50 46 30 1 week after the injection 12 28 12 2 weeks after the injection 11 25 10 3 weeks after injection 10 10 8 weeks after injection 12 17 EXAMPLE 3 The patient R.R. is a 41-year-old male who suffers from osteoarthritis of the left knee joint (grade II on the Kellgren-Lawrence scale). Before treatment, the patient's main complaint is pain, as demonstrated by a patient's VAS of 55. After treatment with 0.5 mg of verapamil in 1 ml of solution Using the same basic injection procedure indicated in Example 1, the patient's pain decreases and remains low throughout the period during which the data is collected. The following table 3 presents in summary form these results: TABLE 3 Time Arthritis scores of the patient R.R. VAS of the VAS doctor of the WOMAC doctor Before the injection 35 55 17 1 week after the injection 10 12 2 weeks after injection 26 3 weeks after injection 10 16 8 weeks after injection 11 20 12 weeks after injection 12 20 16 weeks after the injection 10 10 EXAMPLE 4 The patient A.W. is a 56-year-old female individual who initially has physician and patient VAS scores of 50 and 59, respectively, and also has limited joint function as indicated by a WOMAC of 43. After treatment with 0.2 mg of verapamil in 1 ml of saline solution using the same basic procedure as injection as indicated in example 1, the condition The patient's clinic improves markedly, as shown in table 4.

TABLE 4 Time Arthritis scores of patient A.W. VAS of the VAS doctor of the WOMAC doctor Before the injection 50 59 43 1 week after injection 12 2 weeks after injection 3 weeks after injection 13 8 weeks after injection 15 The destructive action of MMPs and the role of potentially useful agents in blocking this destructive activity can be studied in a model system involving synovial tissue obtained from knee joints, a pro-inflammatory agent that causes tissue to secrete. MMPs, and an agent whose effectiveness to reduce MMP production will be evaluated. An appropriate procedure for performing this test is described in Kolomytkin, O. V., Marino, A.A., Waddell, D.D., Mathis, J.M., Wolf, R.E., Sadasivan, K.K. & Albright, J.A., "IL-lß-induced production of metalloproteinases by synovial cells depends on gap-junction conductance during the early stage of signal transduction. "Am. J. Physiol: Cell Physiol. 282: C1254- C1260, 2002, which is incorporated for reference in the present invention and should be consulted for further details. The following test results using the procedure described above confirm that the administration of an ion channel regulator to synovial tissue in accordance with the present invention significantly reduces the production and secretion of MMPs by the treated synovial tissue. As previously indicated, it is believed that this reduction in MMPs leads to the reduction of pain and improvement in function achieved by the method of the present invention, for example as demonstrated in examples 1-4 above.

EXAMPLE 5 When about 20 mg of synovial tissue is obtained from a 78-year-old female subject with osteoarthritis (grade IV, Kellgren-Lawrence scale), it is discovered, using the procedure described above, that the amount of MMPs produced under standard incubation conditions it is reduced by 60% when the calcium channel regulator verapamil is applied at a concentration of 0.005 mg / ml, total volume, 1 ml; and MMPs are reduced by 63% when the Verapamil concentration is increased to 0.05 mg / ml in the same volume. In another patient, an individual of female gender 61 years of age, the activity of MMP is reduced 63% in the presence of a verapamil concentration of 0.005 mg / ml and in 77% in the presence of verapamil at a concentration of 0.05 mg / ml; both with a total volume of 1 ml. Similar results are found using synovial tissue from an individual of the male gender of 69 years old and a 70-year-old female gender individual, both of whom have osteoarthritis (grade IV, Kellgren-Lawrence scale).

EXAMPLE 6 The experiments are carried out using the procedure described above, but using the calcium channel regulator nifedipine instead of verapamil. It was found that the amount of MMPs produced under standard conditions by approximately 20 mg of synovial tissue obtained from a 73-year-old female subject with osteoarthritis (Grade IV, Kellgren-Lawrence) is reduced by 69% in the presence of 0.015 mg / ml nifedipine, total volume, 1 mL; and the activity of MMP is reduced by 76% at a nifedipine concentration of 0.03 mg / ml, total volume, 1 mL. When the test is repeated using synovial tissue from a 59-year-old female individual with osteoarthritis (grade IV, Kellgren-Lawrence scale), the MMP activity produced by the tissue under standard conditions is reduced by 64% and 71% when the tissue it is exposed to 0.015 mg / ml of nifedipine and 0.03 mg / ml of nifedipine, respectively. Similar results are obtained using the synovial tissue of a 50-year-old male and a 68-year-old female individual, both of whom have osteoarthritis (grade IV, Kellgren-Lawrence scale).

EXAMPLE 7 The experiments are carried out using the procedure described above, but using the sodium channel regulator procainamide instead of a calcium channel regulator. It was found that the amount of MMP produced under standard conditions by approximately 20 mg of synovial tissue obtained from a 77-year-old male individual with osteoarthritis (Grade IV, Kellgren-Lawrence) is reduced by 67% when the tissue it is treated with 0.01 mg / ml; total volume, 1 ml.

EXAMPLE 8 The experiments are carried out using the procedures described above, but using the sodium channel regulator tetrodotoxin. It was found that the amount of MMP produced under standard conditions by approximately 20 mg of synovial tissue obtained from a 64-year-old male individual with osteoarthritis (Grade IV, Kellgren-Lawrence) is reduced by 100% when the tissue it is treated with 0.00002 mg / ml; total volume, 1 ml. The trypan blue exclusion test is commonly used to assess whether the cells are alive or dead. The test consists of adding an appropriate amount of trypan blue dye to the cell environment. The cells can exclude the dye if they are healthy, but if they are damaged or dead, the dye enters the cells and dyes them blue. By means of the trypan blue exclusion test, as described in the following example 9, it is found that ion channel regulators produce harmful and lethal effects on cells when used to treat osteoarthritis at the concentrations taught by the technique antecedent to treat rheumatoid arthritis.

EXAMPLE 9 Approximately 20 mg of synovial tissue from a human knee joint at 10 mg / ml of the ion channel regulator verapamil (total volume 1 ml) is exposed and evaluated using the trypan blue dye exclusion test. It is found that the synovial lining cells in the tissue are annihilated. A certain amount of cell death occurs after exposure for several hours, and all cells in the tissue are killed after exposure for 12 to 16 hours. Similar tests are performed on additional samples of human synovial tissue using various concentrations of different ion channel regulators. By the tests described above, it is discovered that the concentration of verapamil, nifedipine, procainamide, and other ion channel regulators used in the compositions of the present invention should not be higher than 2.0 mg / ml, and that the total dose of the blocker of Ionic channel should not be greater than 2.0 mg. The markedly lower concentration and dose used in the practice of the present invention have the additional significant advantage of completely avoiding the systemic side effects that can be expected to occur at the concentrations and doses described in the prior art, for example intra-articular injection of 20-40 mg of verapamil in an aqueous solution of 10 mg / ml as described in Mak, patent E.U.A. No. 6,190,691 for treatment of rheumatoid arthritis. The above description is considered only as illustrative of the principles of the invention. In addition, because numerous modifications and changes would be apparent to those skilled in the art, it is not desired to limit the invention to the exact details shown and described herein, and accordingly, all appropriate modifications and equivalents are considered as within of the field of the invention. Therefore, it will be apparent to those skilled in the art that many changes and substitutions can be made to the preferred embodiments described in the present application without departing from the scope and scope of the present invention as defined by the appended claims.

Claims (22)

NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and therefore the content of the following is claimed as property: CLAIMS

1. A method for treating osteoarthritis comprising injecting an effective amount of one or more ion channel regulators into the closed amount of a joint that has osteoarthritis.

2. A method according to claim 1 characterized in that the effective amount is 0.00001-2.0 mg of the ion channel regulator (s) supplied in 1-4 ml of a pharmaceutically acceptable composition.

3. A method according to claim 1 characterized in that the ion channel regulator (s) are selected from the group consisting of calcium channel regulators, sodium channel regulators, potassium channel regulators, channel regulators of chloride, anion channel regulators, cation channel regulators, non-selective ion channel regulators, channel regulators connection, combinations of the above and antibodies against the respective channels.

4. - A method according to claim 1, which also comprises administering an effective amount of one or more other agents for treatment of osteoarthritis in combination with the ion channel regulator (s).

5. A method according to claim 4, characterized in that the other agent for treatment of osteoarthritis is administered separately from the ion channel regulator (s).

6. A method according to claim 4, characterized in that the ion channel regulator (s) and the injectable osteoarthritis treatment agent (s) are injected together as a single composition.

7. - A method according to claim 6, characterized in that the composition comprises 0.00001-2.0 mg of the ion channel regulator (s) and 0.01-25 mg / ml of the injectable osteoarthritis treatment agent (s).

8. A method according to claim 4, characterized in that the one or more other agents for treatment of osteoarthritis are selected from the group consisting of visco-complements, corticosteroids, non-spheroidal and spheroidal anti-inflammatory drugs, analgesics, glucosamines and other glucans, chondroitin and other proteoglycans, narcotics, steroids, antibiotics, immunomodulators, and penicillamine.

9. A method according to claim 1, characterized in that a composition comprising 0.00001-2.0 mg / ml of a calcium ion channel regulator and / or sodium ion channel regulator is injected into the joint of a knee. .

10. A method according to claim 9, characterized in that the ion channel regulator or regulators are selected from the group consisting of verapamil, nifedipine, procainamide, tetrodotoxin and combinations thereof.

11. A composition for treating osteoarthritis comprising: an effective amount of one or more ion channel regulators; and an effective amount of one or more other agents for treatment of osteoarthritis.

12. A composition according to claim 11, characterized in that the ion channel regulator (s) are selected from the group consisting of calcium channel regulators, sodium channel regulators, potassium channel regulators, chloride channel blockers, anion channel regulators, cation channel regulators, connecton channel regulators, combinations of the above and antibodies against the respective channels.

13. A composition according to claim 11, characterized in that the other agent for treatment of osteoarthritis is selected from the group consisting of visco-supplements, corticosteroids, non-spheroidal and spheroidal anti-inflammatory drugs, analgesics, glucosamines and others. Glucans, chondroitin and other proteoglycans, narcotics, steroids, antibiotics, immunomodulators, and penicillamine.

14. A composition according to claim 13, characterized in that the other agent for treatment of osteoarthritis is injectable.

15. A composition according to claim 14, characterized in that the other agent for treatment of injectable osteoarthritis is a visco-complement that is selected from the group consisting of hilane and other compounds containing the hyaluronan molecule (sodium hyaluronate). ).

16. A composition according to claim 14, characterized in that the other agent for treatment of injectable osteoarthritis is a spheroid.

17. - A composition according to claim 11, characterized in that the concentration of the ion channel regulator (s) is 0.00001-2.0 mg / ml.

18. A composition according to claim 17, characterized in that the concentration of the other agent for treatment of osteoarthritis is 0.01-25 mg / ml.

19. A composition according to claim 18, characterized in that the other agent for treatment of osteoarthritis is a hyaluronan compound at a concentration of 1-15 mg / ml.

20. A composition according to claim 18, characterized in that the other agent for treatment of osteoarthritis is methylprednisolone acetate at a concentration of 1-25 mg / mL.

21. A composition according to claim 11, which also comprises a filling material, a stabilizer, coating, coloring agent, preservative, fragrance, and / or other additive.

22. A composition according to claim 11, characterized in that the ion channel regulator or regulators are selected from the group consisting of verapamil, nifedipine, procainamide, tetrodotoxin and combinations thereof.