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  Treatment of vascular, autoimmune and inflammatory diseases using low dosages of impdh inhibitorsUSPTO Application #: 20060235009Title: Treatment of vascular, autoimmune and inflammatory diseases using low dosages of impdh inhibitors Abstract: The disclosure provides methods and compositions for treating a vascular, autoimmune, and/or inflammatory disease, or a condition associated therewith, with a dose of an inosine monophosphate dehydrogenase (IMPDH) inhibitor effective to treat the vascular, autoimmune and/or inflammatory disease, or associated condition but that does not produce immunosuppression sufficient to reduce the risk of allograft rejection. These lower doses of the immunosuppressant avoid the adverse consequences of severe immunosuppression while providing effective treatment of the vascular, autoimmune and/or inflammatory disease. (end of abstract) Agent: Dechert LLP - Palo Alto, CA, US Inventors: Richard Glickman, Michael R. Hayden, Noel Hall USPTO Applicaton #: 20060235009 - Class: 514231500 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered And Includes At Least Nitrogen And Oxygen As Ring Hetero Atoms (e.g., Monocyclic 1,2- And 1,3-oxazines, Etc.), Morpholines (i.e., Fully Hydrogenated 1,4- Oxazines), Additional Hetero Ring Attached Directly Or Indirectly To The Morpholine Ring By Nonionic Bonding The Patent Description & Claims data below is from USPTO Patent Application 20060235009. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims benefit under 35 U.S.C. .sctn.119(e) to application Ser. No. 60/651,452, filed Feb. 8, 2005, the contents of which are incorporated herein by reference. FIELD [0002] The present disclosure relates generally to compositions and methods for treating vascular, autoimmune and inflammatory diseases, and conditions associated with such diseases, by administering to subjects low dosages of drug compounds that inhibit inosine monophosphate dehydrogenase, and/or prodrugs of such compounds. BACKGROUND [0003] Inosine monophosphate dehydrogenase (IMPDH) is the rate-limiting enzyme in the de novo biosynthesis of guanosine nucleotides in mammals. Both T- and B-lymphocytes rely exclusively on de novo guanosine nucleotide synthesis, as they are deficient in salvage pathways. [0004] Mycophenolic acid ("MPA") is a potent inhibitor of IMPDH that has gained widespread acceptance as an immunosuppressant, particularly in the prophylactic treatment of organ rejection in patients receiving allogenic renal, cardiac or hepatic transplants. MPA treatment in the form of the 2-morpholinoethyl ester prodrug mycophenolate mofetil ("MMF"; structure illustrated below) is marketed in the U.S. for these indications by Hoffman LaRoche under the tradename CellCept.RTM.: [0005] CellCept.RTM. is currently available in capsule (250 mg), tablet (250 mg and 500 mg), oral suspension (200 mg/ml when constituted), and intravenous (6 mg/ml in 5% dextrose when reconstituted) dosage forms. Following oral or intravenous administration, the MMF is rapidly and completely metabolized to the active metabolite MPA (see, e.g., Physicians Desk Reference, 2005 Ed., pp. 2855; "PDR"). [0006] A delayed-release, enterically coated tablet formulation of the sodium salt of mycophenolic acid (mycophenolate sodium) is marketed in the U.S. by Novartis A G under the tradename Myfortic.RTM.. Each tablet contains either 180 mg or 360 mg of mycophenolate sodium. According to the 2005 Edition of the PDR, Myfortic.RTM. is currently approved for the prophylactic treatment of organ rejection in patients receiving allogenic renal transplants. [0007] The recommended dose of CellCept.RTM. is 1 g administered orally or intravenously twice daily for renal transplant (i.e., a daily dose of 2 g; corresponding to a daily dose in the range of about 20-45 mg/kg for a patient body mass in the range of 45-100 kg) and 1.5 g administered orally or intravenously twice daily for hepatic and cardiac transplant (ie., a daily dose of 3 g; corresponding to a daily dose of about 30-67 mg/kg for a patient body mass in the range of 45-100 kg). The recommended dose of Myfortic.RTM. is 720 mg administered orally twice daily (i.e., a daily dose of 1.44 g; corresponding to a daily dose in the range of about 14 mg/kg-32 mg/kg for a patient body mass in the range of 45-100 kg). These relatively large doses are required because clinical evidence does not support their effectiveness to prevent transplant rejection at lower doses. These standard doses require that tablets be of inordinate size so that a patient may consume a minimum number. For MMF, the minimum size tablet approved is 250 mg, with 500 mg being the commonly prescribed tablet. For MPA, the minimum size tablet approved is 180 mg. [0008] Efforts to identify other indications for MMF and MPA have met with limited success to date. Treatment of diabetic nephropathy employing a combination therapy of an ACE inhibitor (Lisinopril; S-1-[N.sup.2-(1-carboxy-3-phenylpropyl)-L-lysyl]-L-proline dehydrate) and MMF at a dose of 1 g/day (10-22 mg/kg/day depending on patient body mass) has been proposed (PCT publication WO 04/98587). Romero et al., 2000, Atherosclerosis 152:127-133, provided evidence that MMF administered to rabbits at 30 mg/kg/day ameliorated the atherogenic potential of a high-cholesterol diet. This work followed Schreiber et al., 1998, Transpl. Proc. 30:901-902, which studied the effect of MMF at 80 mg/kg (subcutaneous injection) in a similar model. Neither of these indications have received approval from regulatory agencies. [0009] A need exists to identify improved therapeutic compositions and methods that can be used for the therapeutic and/or prophylactic treatment of vascular, autoimmune, and/or inflammatory diseases. The instant disclosure provides such compositions and methods, relying on a novel understanding of IMPDH inhibitors and their utility in treating certain vascular, autoimmune and/or inflammatory disease processes. SUMMARY [0010] In one aspect, the present disclosure provides methods for treating vascular, autoimmune and/or inflammatory diseases, and conditions associated with such diseases, in subjects by administering IMPDH inhibitory compounds and/or prodrugs of such IMPDH inhibitory compounds (including the corresponding salts, hydrates and solvates thereof. The amount of compound administered will depend upon the specific identity of the compound, but will generally be less than the amount that would be administered to prophylactically treat allograft transplant rejection (for example, renal, hepatic, or cardiac transplant rejection). In some embodiments, the amount of compound administered is a low dose, an extra-low dose or an ultra-low dose of the compound and/or prodrug, as will be described further hereinbelow. [0011] The compound administered can be any compound that inhibits the activity of IMPDH, or a prodrug of such an IMPDH-inhibitory compound (i.e., a compound that metabolizes under conditions of use to a compound that inhibits the activity of IMPDH). Such IMPDH inhibitory compounds and prodrugs are well-known, and include by way of example and not limitation, inhibitors 3-(1-deoxy-beta-D-ribofuranosyl)benzamide (Jayaramet et al., 1992, Biochem Biophys Res Commun. 186(3): 1600-6); mizoribine, 5-beta-D-ribofuranosylselenophene-3-carboxamide (Franchetti et al., 1997, J Med Chem. 40(11):1731-7); N-[2-[2-[[3-methoxy-4-(5-oxazolyl)phenyl]amino]-5-oxazolyl]phenyl]-N-meth- yl-4-morpholineacetamide (Dhar et al., 2002, J Med Chem. May 45(11):2127-30), and mycophenolic acid (MPA) and their various corresponding salts, hydrates, solvates and esters. Other IMPDH inhibitors include compounds disclosed in U.S. Pat. Nos. 5,807,876; 5,932,600; 6,054,472; 6,344,465; 6,420,403; 6,518,291; 6,541,496; 6,596,747; 6,617,323; and 6,624,184. In some embodiments, the IMPDH inhibitory compound administered is mycophenolic acid and/or a salt, hydrate, solvate and/or ester thereof. In a specific embodiment, the compound administered is selected from a salt of mycophenolic acid, such as, for example, mycophenolate sodium, and an ester of mycophenolic acid, such as, for example, mycophenolate mofetil (MMF). [0012] The methods may be practiced therapeutically in patients suffering from a vascular, autoimmune and/or inflammatory disease, or a condition associated therewith. In some embodiments, the inhibitory compound can be administered prophylactically in patients that do not currently suffer from such a disease or condition. Thus, in some embodiment, the prophylactic therapy is administered to patients who are at risk of developing a vascular, autoimmune and/or inflammatory disease or a condition associated with a vascular, autoimmune and/or inflammatory disease. [0013] In some embodiments, the condition treated is associated with an autoimmune disease, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, and diabetes mellitus, and includes conditions such as atherosclerosis, cardiovascular disease, and other vascular diseases, which occur at higher frequency in such patients. In other embodiments, the condition associated with the autoimmune disease is an inflammatory reaction, which typically accompanies many different autoimmune reactions. In various embodiments, the IMPDH inhibitory compounds may be administered at doses effective to treat or reduce the risk of developing the associated condition regardless of the effectiveness of the drugs on the underlying disease. [0014] In another aspect, the present disclosure provides pharmaceutical compositions comprising an IMPDH inhibitory compound, and/or a prodrug of such a compound (including salts, hydrates and/or solvates of such compounds and prodrugs) and one or more pharmaceutically acceptable carriers, excipients and/or diluents. The amount of compound and/or prodrug included in the composition is specifically suited to provide therapeutic and/or prophylactic benefit in the methods described herein. Accordingly, in some embodiments, the compositions will generally comprise unit dosage amounts or fractional unit dosage amounts of IMPDH inhibitory compounds and/or prodrugs that are tailored to administer low, extra-low or ultra-low daily dosages of the compounds and/or prodrugs. Non-limiting examples of IMPDH inhibitory compounds and prodrugs that can be included in the pharmaceutical compositions are those provided above. [0015] The pharmaceutical compositions can be suited for virtually any mode of administration, including, but not limited to, oral and intravenous administration. In some embodiments, the pharmaceutical compositions are oral tablets or capsules. In one specific embodiment, the tablets or capsules comprise a salt of mycophenolic acid, such as, for example, mycophenolate sodium, and/or an ester of mycophenolic acid, such as, for example, mycophenolate mofetil, and one or more excipients. In a specific embodiment, the total amount of mycophenolate salt and/or mycophenolate ester comprising the tablets or capsules is selected from one, one-half, one-third and one-fourth of the amount necessary to achieve a low, an extra-low or an ultra-low daily dose. BRIEF DESCRIPTION OF THE FIGURES [0016] FIG. 1 illustrates the effect of administering mycophenolate mofetil to Ldlr-/- mice at a dosage of 15 mg/kg/day in reducing atherosclerotic plaques. [0017] FIG. 2 illustrates the effect of mycophenolate mofetil in reducing serum triglycerides (Tgs) in male Ldlr-/- mice when given at a dosage of 15 mg/kg/day. [0018] FIG. 3 illustrates the effect of mycophenolate mofetil in reducing serum phospholipids (PPL) in male Ldlr-/- mice when given at a dosage of 15 mg/kg/day. [0019] FIG. 4 illustrates the effect of mycophenolate mofetil on high-density lipoprotein levels in male Ldlr-/- mice when given at a dosage of 15 mg/kg/day. Continue reading... Full patent description for Treatment of vascular, autoimmune and inflammatory diseases using low dosages of impdh inhibitors Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Treatment of vascular, autoimmune and inflammatory diseases using low dosages of impdh inhibitors patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. 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