| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | December 17, 2002 |
| PATENT TITLE |
Method for treating multiple sclerosis |
| PATENT ABSTRACT | Methods and compositions for treating or preventing inflammatory diseases such as psoriasis or multiple sclerosis are provided, comprising the step of delivering to the site of inflammation an anti-microtubule agent, or analogue or derivative thereof. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | June 1, 1998 |
| PATENT REFERENCES CITED |
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Wood et al., "Inhibition of Mitosis and Microtubule Function Through Direct Tubulin Binding by a Novel Antiproliferative Naphthopyran LY290181," Molecular Pharmacology, 52(3), 437-444 (1997).* Chandrasekhar et al., "Identification of a Novel Chemical Series That Block Interleukin-1-Stimulated Metalloprotease Activity in Chrondrocytes," Journal of Pharmacology and Experimental Therapeutics, 273(3), 1519-1528 (1995).* Bollag et al., "Epothilones, a New Class of Microtubule-Stabilizing Agents with a Taxol-Like Mechanisms of Action," Cancer Research, 55(11), 2325-2333 (Jun. 1, 1995).* ter Haar et al., "Discodemolide, A Cytotoxic Marine Agent That Stabilizes Microtubules More Potently Than Taxol," Biochemistry, 35(1), 243-250 (Jan. 9, 1996).* Panda et al., "Suppression of Microtubule Dynamics by LY290181," Journhal of Biological Chemistry, 272(12), 7681-7687 (Mar. 21, 1997).* Wood et al., "Inhibiton of MItosis and Microtubule Function Through DIrect Tubulin Binding by a Novel Antiproliferative Naphthopyran LY290181," Molecular Pharmacology, 52(3), 437-444 (Sep., 1997).* Bartoli et al., "In vitro and in vivo antitumoral activity of free, and encapsulated taxol," Journal of Microencapsulation 7(2): 191-197, 1990. Beranek, "Angiogenesis in Psoriasis," Laboratory Investigation 62(1): 131, 1990. Constable, "Biological And Therapeutic Aspects Of Proliferative Vitreoretinopathy," Jpn. J. Ophthalmol. 31: 513-520, 1987. Coomber and Gotlieb, "In Vitro Endothelial Wound Repair. Interaction of Cell Migration and Proliferation," Arteriosclerosis 10(2): 215-222, 1990. (Mar./Apr., 1990). Cox et al., "Local Delivery of Heparin and Methotrexate Fails to Inhibit In Vivo Smooth Muscle Cell Proliferation," Abstracts From the 64.sup.th Scientific Sessions, American Heart Assoc., Abstract No. 0284, 1991. Detmar et al., "Overexpression of Vascular Permeability Factor/Vascular Endothelial Growth Factor and its Receptors in Psoriasis," J. Exp. Med. 180: 1141-1146, 1994. (9/94). Detmar, "Molecular Regulation of Angiogenesis in the Skin," The Journal of Investigative Dermatology, pp. 207-208, 1996. Further Letter Concerning Notice of Opposition of Grant of European Patent 706376 by Biocompatibles Limited. Produced by Gill Jennings & Every. Dated Mar. 25, 1998. Hermans et al., "Prevention of restenosis after percutaneous transluminal coronary angioplasty: The search for a "magic bullet"," American Heart Journal 122(No. 1, Pt. 1): 171-187, 1991. Hirata et al., "Inhibition Of In Vitro Vascular Endothelial Cell Proliferation And In Vivo Neovascularization By Low-Dose Methotrexate," Arthritis and Rheumatism 32(9): 1065-1073, 1989. (Sep., 1989). Jampel et al., "In Vitro Release of Hydrophobic Drugs From Polyanhydride Disks," Ophthalmic Surgery 22(11): 676-680, 1991. (Nov., 1991). Jeffes and Weinstein, "Methotrexate And Other Chemotherapeutic Agents Used To Treat Psoriasis," Dermatologic Clinics 13(4): 875-890, 1995. (Oct., 1995). Kumar and West, "Psoriasis, Angiogenesis and Hyaluronic Acid" Laboraboty Investigation 62(5): 664-665, 1990. Lebwohl and Abel, "Topical Therapy For Psoriasis," International Journal of Dermatology 34(10): 673-684, 1995. (Oct., 1995). Moses and Langer, "Inhibitors Of Angiogenesis," Bio/Technology 9: 630-634, 1991. (Jul., 1991). Notice of Opposition of Grant of European Patent 706376 by Biocompatibles Limited. Produced by Gill Jennings & Every. Dated Mar. 25, 1998. Notice of Opposition of Grant of European Patent 706376 by Focal, Inc. Produced by Hoffmann Eitle. Dated Mar. 25, 1998. Notice of Opposition of Grant of European Patent 706376 by Inflow Dynamics AG. Produced by Patentanwalt Uwe Czybilka. Dated Mar. 25, 1998 (English translation also provided). Notice of Opposition of Grant of European Patent 706376 by Schering AG. Produced by Frohwitter. Dated Mar. 25, 1998. Notice of Opposition of Grant of European Patent 706376 by STS Biopolymers, Inc. Produced by J.A. Kemp & Co. Dated Mar. 25, 1998. O'Keefe et al., "Ineffectiveness of Colchicine for the Prevention of Restenosis After Coronary Angioplasty," JACC 19(7): 1597-1600, 1992. (Jun., 1992). Pitt and Schindler, Progress in Contraceptive Delivery Systems, MTP Press, Lancaster, PA, 1980, Chapter 2, "The design of controlled drug delivery systems based on biodegradable polymers," pp. 17-46. Rompps Chemie-Lexicon, pp. 4129-4130, 2577, 1190, (1988). Rote Liste, 85-088--85-092, (1995). Spuls et al., "A Systematic Review of Five Systemic Treatments for Severe Psoriasis," British Journal of Dermatology 137: 943-949, 1997. Supplement to Notice of Opposition of Grant of European Patent 706376 by Schering AG. Produced by Frohwitter. Dated Mar. 25, 1998. Tang et al., "Regression Of Collagen-Induced Arthritis With Taxol, A Microtubule Stabilizer," Arthritis Rheum. 36(9): No. 42, 1993. Verdoorn et al., "Cellular Migration, Proliferation, and Contraction. An In Vitro Approach to a Clinical Problem-Proliferative Vitreoretinopathy," Arch. Ophthalmol 104: 1216-1219, 1986. (Aug., 1986). Wang et al., "Preparation and Characterization of Poly(lactic-co-glycolic acid) Microspheres for Targeted Delivery of a Novel Anticancer Agent, Taxol," Chem. Pharm. Bull. 44(10):1935-1940, 1996. (Oct., 1996). Wolf, "Angiogenesis in Normal and Psoriatic Skin," Laboratory Investigation 61(2): 139-142, 1989. Xi-ran et al., "Clinical Trial And Experimental Study On Treating Psoriasis With Camptothecine," Chinese Medical Journal 101(6): 427-430, 1988. Zonneveld et al., "Ranitidine does not affect psoriasis: A multicenter, double-blind, placebo-controlled study," J. Am. Acad. Dermatol. 36: 932-934, 1997. (Jun., 1997). EP 19931103 A1, Derwent English Abstract, Accession No. 1993-346277/199344, 1993. EP 669916, B1, Derwent English Abstract, Accession No. 1994-193767/199424, 1997. Cao et al.(I), "Inhibition of Experimental Allergic Excephalomyelitis in the Lewis Rat by Paclitaxel," Journal of Neuroimmunology, 108, 103-111 (2000). Moscarello et al., "Paclitaxel Attenuates Demyelination in a Transgenic Spontaneously Demyelinating Model," Annals of Neurology, 46(3), Abstr. No. 92 at p. 469 (Sep., 1999). Cao et al. (II), "Inhibition of Experimental Allergic Encephalomyelitis in Lewis Rats by Paclitaxel,": Annals of Neurology, 46(3), Abstr. No. 94 at p. 470 (Sep., 1999). O'Connor et al.(I), "A Phase I Study of Micellar Paclitaxel in the Treatment of Secondary Progressive Multiple Sclerosis," Annals of Neurology, 46(3), Abstr. No. 95 at p. 470 (Sep., 1999). O'Connor et al. (II), "Micellar Paclitaxel for the Treatment of Secondary Progressive Multiple Sclerosis: Preliminary Results of the Phase I Extension Study," Annals of Neurology, 48(3), Abstr. No. 228 at p. 476 (Sep., 2000). Alberts et al., Molecular Biology of the Cell, 2nd Edition, Garland Publishing, New York, NY, 1989, only p. 653 supplied. The Merck Index, 12th Edition, Merck & Co., Whitehouse Station, New Jersey, 1996, only pp. 1404, 1541 and 1200 supplied. Weinstein and Krueger, "An Overview of Psoriasis," Ch. 1 in Therapy of Moderate to Severe Psoriasis, Weinstein and Gottlieb (eds.), National Psoriasis Foundation, 1993, only pp. 1-22 supplied. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
I claim: 1. A method for treating multiple sclerosis comprising administering to a patient in need thereof a therapeutically effective amount of a paclitaxel-containing, pharmaceutically acceptable composition. 2. The method according to claim 1 wherein said paclitaxel is administered systemically. 3. The method according to claim 1 wherein said paclitaxel is administered orally or intravenously. 4. The method according to claim 1 wherein said paclitaxel is administered at a dosage of 10 to 75 mg/m.sup.2 once every one to four weeks. 5. The method according to claim 1 wherein said paclitaxel-containing-composition comprises paclitaxel and a polymer or a copolymer. 6. The method according to claim 5 wherein said composition is formed into microspheres having an average size of between 0.5 and 200 .mu.m. 7. The method according to claim 5 wherein said composition contains a copolymer of lactic acid and glycolic acid. 8. The method according to claim 5 wherein said polymer is poly(caprolactone). 9. The method according to claim 5 wherein said polymer is a poly(lactic acid). 10. The method according to claim 5 wherein said composition contains a copolymer of lactic acid and poly(caprolactone). 11. The method according to claim 5 wherein said polymer is a polyethylene glycol. 12. The method according to claim 5 wherein said copolymer is ethylene vinyl acetate. 13. The method according to claim 1 wherein said paclitaxel-containing-composition comprises paclitaxel and isopropyl myristate. 14. The method according to claim 1 wherein said paclitaxel-containing-composition comprises paclitaxel and a glycol. 15. The method according to claim 14 wherein said glycol is ethoxydiglycol. 16. The method according to claim 5 wherein said copolymer is a diblock or a triblock copolymer. 17. A method for treating multiple sclerosis comprising systemically administering to a patient in need thereof a therapeutically effective amount of a paclitaxel-containing, pharmaceutically acceptable composition. 18. The method according to claim 17 wherein said paclitaxel is delivered at a dose of 25 mg/m.sup.2. 19. The method according to claim 17 wherein said paclitaxel is delivered at a dose of 50 mg/m.sup.2. 20. The method according to claim 17 wherein said paclitaxel is delivered at a dose of 75 mg/m.sup.2. 21. The method according to claim 17 wherein said paclitaxel is infused over 1-2 hours. 22. The method according to claim 17 further comprising premedication of said patient with hydrocortisone. 23. The method according to claim 17 further comprising premedication of said patient with diphenylhydramine and cimetidine or ranitidine. 24. The method of claim 17 wherein said paclitaxel-containing composition comprises paclitaxel and a polymer or a copolymer. 25. The method according to claim 24 wherein said copolymer is a micelle forming copolymer. 26. The method according to claim 25 wherein said micelle forming copolymer is poly(DL-lactide)-block-methoxy polyethylene glycol (PDLLA-MePEG). 27. The method according to claim 25 wherein said micelle forming copolymer is poly(caprolactone)-block-methoxy polyethylene glycol (PCL-MePEG). 28. The method according to claim 25 wherein said micelle forming copolymer is poly(DL-lactide-co-caprolactone)-block-methoxy polyethylene glycol (PDLLACL-MePEC). 29. The method according to claim 17 wherein said paclitaxel is deleivered at a dose of 10 to 175 mg/m.sup.2. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
TECHNICAL FIELD The present invention relates generally to compositions and methods for treating or preventing inflammatory diseases. BACKGROUND OF THE INVENTION Inflammatory diseases, whether of a chronic or acute nature, represent a substantial problem in the healthcare industry. Briefly, chronic inflammation is considered to be inflammation of a prolonged duration (weeks or months) in which active inflammation, tissue destruction and attempts at healing are proceeding simultaneously (Robbins Pathological Basis of Disease by R. S. Cotran, V. Kumar, and S. L. Robbins, W. B. Saunders Co., p. 75, 1989). Although chronic inflammation can follow an acute inflammatory episode, it can also begin as an insidious process that progresses with time, for example, as a result of a persistent infection (e.g., tuberculosis, syphilis, fungal infection) which causes a delayed hypersensitivity reaction, prolonged exposure to endogenous (e.g., elevated plasma lipids) or exogenous (e.g., silica, asbestos, cigarette tar, surgical sutures) toxins, or, autoimmune reactions against the body's own tissues (e.g., rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis). Chronic inflammatory diseases therefore, include many common medical conditions such as rheumatoid arthritis, restenosis, psoriasis, multiple sclerosis, surgical adhesions, tuberculosis, chronic inflammatory lung diseases (e.g., asthma, pneumoconiosis, chronic obstructive pulmonary disease, nasal polyps and pulmonary fibrosis), periodontal disease (i.e., periodontitis) and polycystic kidney disease. Psoriasis Psoriasis is a common, chronic inflammatory skin disease characterized by raised, inflamed, thickened and scaly lesions, which itch, burn, sting and bleed easily. In approximately 10% of patients, psoriasis is accompanied by pronounced arthropathic symptoms that are similar to the changes seen in rheumatoid arthritis. Approximately 2 to 3% of the U.S. population suffers from psoriasis, with 250,000 new cases being diagnosed each year. At present, the cause of psoriasis is unknown, although there is considerable evidence that it is a polygenic autoimmune disorder. In addition, there is currently no cure for psoriasis. Available treatments include topical therapies such as steroid creams and ointments, coal tar and anthralin, and systemic treatment such as steroids, ultra violet B, PUVA, methotrexate and cyclosporin. However, unsatisfactory remission rates and/or potentially serious side effects characterize most anti-psoriatic therapies. The overall cost of treating psoriasis in the United States is estimated at between $3 to $5 billion per year, making psoriasis a major health care problem. Multiple Sclerosis Multiple sclerosis (MS), affecting 350,000 people (women:men=2:1) in the United States, with 8,000 new cases reported each year, is the most common chronic inflammatory disease involving the nervous system. Typically, MS presents clinically as recurring episodes of adverse neurological deficits occurring over a period of several years. Roughly half of MS cases progress to a more chronic phase. Although the disease does not result in early death or impairment of cognitive functions, it cripples the patient by disturbing visual acuity; stimulating double vision; disturbing motor functions affecting walking and use of the hands; producing bowel and bladder incontinence; spasticity; and sensory deficits (touch, pain and temperature sensitivity). The cause of MS is unknown, although there is considerable evidence that it is an autoimmune disease. Currently, there is no cure available for multiple sclerosis, and present therapeutic regimens have been only partially successful. For example, although chemotherapeutic agents such as methotrexate, cyclosporin and azathioprine, have been examined for the management of patients with treatment unresponsive progressive disease, minimal long-term beneficial effects have been demonstrated to date. Other therapeutics which have been recently approved include interferon-.beta. for use in ambulatory patients with relapsing-remitting MS (Paty et al., Neurology 43:662-667, 1993), specifically, Betaseron (recombinant interferon .beta.-1.beta.; human interferon beta substituted at position 17, Cys.RTM. Ser; Berlex/Chiron) or Avonex (recombinant interferon .beta.1.alpha.; glycosylated human interferon beta produced in mammalian cells; Biogen). Unfortunately, while Betaseron provides for an enhanced quality of life for MS patients, disease progression does not appear to be significantly improved. Adverse experiences associated with Betaseron therapy include: injection site reactions (inflammation, pain, hypersensitivity and necrosis), and a flu-like symptom complex (fever, chills, anxiety and confusion). Rheumatoid Arthritis Rheumatoid arthritis (RA) is a debilitating, chronic inflammatory disease affecting 1 to 2% of the world's population. This condition causes pain, swelling and destruction of multiple joints in the body and can also result in damage to other organs such as the lungs and kidneys. People with advanced disease have a mortality rate greater than some forms of cancer and because of this, treatment regimes have shifted towards aggressive early drug therapy designed to reduce the probability of irreversible joint damage. Recent recommendations of the American College of Rheumatology (Arthritis and Rheumatism 39(5):713-722, 1996) include early initiation of disease-modifying anti-rheumatic drug (DMARD) therapy for any patient with an established diagnosis and ongoing symptoms. Anticancer drugs have become the first line therapy for the vast majority of patients, with the chemotherapeutic drug, methotrexate, being the drug of choice for 60 to 70% of rheumatologists. The severity of the disease often warrants indefinite weekly treatment with this drug and, in those patients whose disease progresses despite methotrexate therapy (over 50% of patients), second line chemotherapeutic drugs such as cyclosporin and azathioprine (alone or in combination) are frequently employed. Restenosis Restenosis is a form of chronic vascular injury leading to vessel wall thickening and loss of blood flow to the tissue supplied by the blood vessel. It occurs in response to vascular reconstructive procedures, including virtually any manipulation which attempts to relieve vessel obstructions, and is the major factor limiting the effectiveness of invasive treatments for vascular diseases. Restenosis has been a major challenge to cardiovascular research for the past 15 years. According to 1994 estimates (U.S. Heart and Stroke Foundation), over 60 million Americans have one or more forms of cardiovascular disease. These diseases claimed approximately 1 million lives in the same year (41% of all deaths in the United States) and are considered the leading cause of death and disability in the developed world. Currently, no existing, technically approved, treatments for the prevention of restenosis have been effective in humans. Systemic therapies which have been investigated include agents directed at treatment of endothelial loss, anti-platelet agents (e.g., aspirin), vasodilators (e.g., calcium channel blockers), antithrombotics (e.g., heparin), anti-inflammatory agents (e.g., steroids), agents which prevent vascular smooth muscle cell (VSMC) proliferation (e.g., colchicine) and promoters of re-endothelialization (e.g., vascular endothelial growth factor). Local treatments which have been investigated include local drug delivery (e.g., heparin) and beta and gamma radiation. All have been disappointing in human use, primarily because they appear to act on a limited portion of the restenotic process. Systemic treatments have also encountered the additional problem of achieving adequate absorption and retention of the drug at the site of the disease to provide a lasting biological effect, without causing unfavorable systemic complications and toxicities. Inflammatory Bowel Disease Inflammatory bowel disease (IBD) refers to chronic disorders (primarily Crohn's disease and ulcerative colitis) that cause inflammation or ulceration in the small and large intestines. Briefly, approximately 2 million people in the United States suffer from IBD with males and females affected equally. The peak incidence primarily occurs between the ages of 15 and 30 with a second peak often reported between 55 and 60 years of age. Although there are many documented patterns of prevalence, it is a disease of unknown cause. IBD is often characterized with alternating periods of remission followed by periods of unpredictable relapse or flare of varying severity. About 50% of patients are in remission at any given time and the majority suffer at least one relapse in a 10 year period. In addition, there are many systemic complications that accompany this disease with the most common being arthritis. Symptoms of arthritis occur in one fourth of all people with IBD. Joint inflammation occurs most often when the colon is involved in the disease process and flares when the bowel disease is most active. This form of inflammatory arthritis does not cause permanent deformity and is often short lived. Other complications of this disease include eye inflammation (iritis, conjunctivitis and episcleritis), mouth inflammation (mucositis), skin inflammation (erythema nodosum and pyoderma gangrenosum), musculoskeletal abnormalities (ankylosing spondylitis), renal complications (kidney stones and fistulas to urinary tract), gallstones and other diseases of the liver (e.g., hepatitis) and biliary system (sclerosing cholangitis). Unfortunately, in many cases, long-term disease (>10 years) can lead to more severe complications such as colonic cancer and extraintestinal carcinomas. At present, there is no cure for IBD. Many of the current therapeutic agents focus on controlling the disease symptoms by suppressing the inflammation associated with the disease. The principle drugs used to treat IBD are aminosalicylates and corticosteroids and for those individuals that do not respond well to these agents, antibiotics and immunosuppressive medications can also be used. Although drug treatment is effective for 70 to 80% of patients, surgery is often required for individuals having more active disease. Chronic symptoms and complications associated with active disease such as intestinal blockage, perforation, abscess, or bleeding can be relieved and corrected with invasive surgery. Although surgery does not cure the disease permanently and recurrence rate is high, it does relieve active symptoms. Surgical Adhesions Surgical adhesion formation, a complex process in which bodily tissues that are normally separate grow together, is most commonly seen to occur as a result of surgical trauma. These post-operative adhesions occur in 60 to 90% of patients undergoing major gynaecologic surgery and represent one of the most common causes of intestinal obstruction in the industrialized world. These adhesions are a major cause of failed surgical therapy and are the leading cause of bowel obstruction and infertility. Other adhesion-treated complications include chronic pelvic pain, urethral obstruction and voiding dysfunction. Currently, preventative therapies, administered 4 to 5 days following surgery, are used to inhibit adhesion formation. Various modes of adhesion prevention have been examined, including (1) prevention of fibrin deposition, (2) reduction of local tissue inflammation and (3) removal of fibrin deposits. Fibrin deposition is prevented through the use of physical barriers that are either mechanical or comprised of viscous solutions. Although many investigators are utilizing adhesion prevention barriers, a number of technical difficulties exist. Inflammation is reduced by the administration of drugs such as corticosteroids and nonsteroidal anti-inflammatories. However, the results from the use of these drugs in animal models have not been encouraging due to the extent of the inflammatory response and dose restriction due to systemic side effects. Finally, the removal of fibrin deposits has been investigated using proteolytic and fibrinolytic enzymes. A potential complication to the clinical use of these enzymes is the possibility for excessive bleeding. Inflammatory Lung Diseases Chronic inflammatory lung diseases, including for example, asthma, pneumoconiosis, chronic obstructive pulmonary disease, nasal polyps and pulmonary fibrosis, affect many people worldwide. Typically such diseases are characterized by an invasive inflammatory process, and thickening of the affected tissues. For example, nasal polyps are characterized by thickened tissue of the nasal lining. Polyps may occur in respiratory diseases such as asthma, cystic fibrosis, primary ciliary diskinesia and immune deficiencies. Nasal polyps are thought to develop as a manifestation of chronic inflammatory processes involving the upper airways. They are found in 36% of patients with aspirin intolerance, 7% of those with asthma, 0.1% in children and about 20% in those with cystic fibrosis. Other conditions associated with nasal polyps are Churg-Strauss syndrome, allergic fungal sinusitis and cilia dyskinetic syndrome and Young's syndrome. About 40% of patients with surgical polypectomies have recurrences (Settipane, Allergy Asthma Proc. 17(5):231-236, 1996). The main symptoms of nasal polyposis are nasal obstruction and disturbance of sense of smell. The objectives of medical treatment of nasal polyposis are (1) to eliminate nasal polyps and rhinitis symptoms, (2) to re-establish nasal breathing and olfaction and (3) to prevent recurrence. Occlusion of the nasal passage by a few large polyps can be treated by simple polypectomy to help the patient breathe through the nose. The aim of surgery is to restore the physiological properties of the nose by making the airway as free from polyps as possible and to allow drainage of infected sinuses. However, recurrent nasal polyposis is one of the most common unsolved problems of clinical rhinology. Complementary medical treatment of polyposis is always necessary, as surgery cannot treat the inflammatory component of the mucosal disease. Topical corticosteroids are the most widely utilized treatment to reduce the size of polyps and to prevent recurrence after surgery. Steroids reduce rhinitis, improve nasal breathing, reduce the size of the polyps and decrease recurrence rate but they have negligible effect on the sense of smell and on any sinus pathology. The use of steroids in polyposis, however, is associated with infectious complications that require antibiotics. Other drugs for the management of nasal polyposis include H1-receptor antagonists (e.g., azelastine HCL) and anti-diuretics (e.g., furosemide). These treatments are not always effective and recurrence rates are still very high. Current medical treatment of nasal polyposis utilizes corticosteroids to alleviate the symptoms of the disease but has no action against the underlying pathology of the disease. In addition, recurrence of the disease or resistance to steroid therapy has been observed in patients with nasal polyps. Graft Rejection Graft rejection is a complex process whereby the grafted tissue is recognized as foreign by the host's immune system. On the basis of morphology and the underlying mechanism, rejection reactions fit into three categories: hyperacute, acute and chronic. With the risks of infection eliminated and early (acute) rejection being managed by immunosuppressive therapy, chronic rejection has become an increasingly important cause of graft dysfunction and ultimate failure. Currently, chronic vascular rejection is the leading cause of death or graft failure in cardiac transplant recipients after the first year. The present invention provides compositions and methods suitable for treating or preventing inflammatory diseases. These compositions and methods address the problems associated with the existing procedures, offer significant advantages when compared to existing procedures, and further provide other, related advantages. SUMMARY OF THE INVENTION Briefly stated, the present invention provides methods for treating or preventing inflammatory diseases, comprising delivering to a site of inflammation an anti-microtubule agent. Representative examples of such agents include taxanes (e.g., paclitaxel and docetaxel), campothecin, eleutherobin, sarcodictyins, epothilones A and B, discodermolide, deuterium oxide (D.sub.2 O), hexylene glycol (2-methyl-2,4-pentanediol), tubercidin (7-deazaadenosine), LY290181 (2-amino-4-(3-pyridyl)-4H-naphtho(1,2-b)pyran-3-cardonitrile), aluminum fluoride, ethylene glycol bis-(succinimidylsuccinate), glycine ethyl ester, nocodazole, cytochalasin B, colchicine, colcemid, podophyllotoxin, benomyl, oryzalin, majusculamide C, demecolcine, methyl-2-benzimidazolecarbamate (MBC), LY195448, subtilisin, 1069C85, steganacin, combretastatin, curacin, estradiol, 2-methoxyestradiol, flavanol, rotenone, griseofulvin, vinca alkaloids, including vinblastine and vincristine, maytansinoids and ansamitocins, rhizoxin, phomopsin A, ustiloxins, dolastatin 10, dolastatin 15, halichondrins and halistatins, spongistatins, cryptophycins, rhazinilam, betaine, taurine, isethionate, HO-221, adociasulfate-2, estramustine, monoclonal anti-idiotypic antibodies, microtubule assembly promoting protein (taxol-like protein, TALP), cell swelling induced by hypotonic (190 mosmol/L) conditions, insulin (100 nmol/L) or glutamine (10 mmol/L), dynein binding, gibberelin, XCHO1 (kinesin-like protein), lysophosphatidic acid, lithium ion, plant cell wall components (e.g., poly-L-lysine and extensin), glycerol buffers, Triton X-100 microtubule stabilizing buffer, microtubule associated proteins (e.g., MAP2, MAP4, tau, big tau, ensconsin, elongation factor-1-alpha (EF-1.alpha.) and E-MAP-115), cellular entities (e.g., histone H1, myelin basic protein and kinetochores), endogenous microtubular structures (e.g., axonemal structures, plugs and GTP caps), stable tubule only polypeptide (e.g., STOP145 and STOP220) and tension from mitotic forces, as well as any analogues and derivatives of any of the above. Within other embodiments, the anti-microtubule agent is formulated to further comprise a polymer. Representative examples of inflammatory diseases which may be treated include multiple sclerosis, psoriasis, arthritis, stenosis, graft rejection, surgical adhesions, inflammatory bowel disease and inflammatory lung disease. Within certain embodiments of the invention, the anti-microtubule agents may be formulated along with other compounds or compositions, such as, for example, an ointment, cream, lotion, gel, spray, foam, mousse, coating, wrap, paste, barrier, implant, microsphere, microparticle, film or the like. Within certain embodiments, the compound or composition may function as a carrier, which may be either polymeric, or non-polymeric. Representative examples of polymeric carriers include poly(ethylene-vinyl acetate), copolymers of lactic acid and glycolic acid, poly (caprolactone), poly (lactic acid), copolymers of poly (lactic acid) and poly (caprolactone), gelatin, hyaluronic acid, collagen matrices, celluloses and albumen. Representative examples of other suitable carriers include, but are not limited to ethanol; mixtures of ethanol and glycols (e.g., ethylene glycol or propylene glycol); mixtures of ethanol and isopropyl myristate or ethanol, isopropyl myristate and water (e.g., 55:5:40); mixtures of ethanol and eineol or D-limonene (with or without water); glycols (e.g., ethylene glycol or propylene glycol) and mixtures of glycols such as propylene glycol and water, phosphatidyl glycerol, dioleoylphosphatidyl glycerol, Transcutol.RTM., or terpinolene; mixtures of isopropyl myristate and 1-hexyl-2-pyrrolidone, N-dodecyl-2-piperidinone or 1-hexyl-2-pyrrolidone. Within yet other aspects, the anti-microtubule agent may be formulated to be contained within, or, adapted to release by a surgical or medical device or implant, such as, for example, stents, sutures, indwelling catheters, prosthesis, and the like. These and other aspects of the present invention will become evident upon reference to the following detailed description and attached drawings. In addition, various references are set forth below which describe in more detail certain procedures, devices or compositions, and are therefore incorporated by reference in their entirety. |
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