MXPA05004985A - Methods of using vitamin d compounds in the treatment of myelodysplastic syndromes. - Google Patents

Abstract

Methods of treating MDS, or ameliorating a symptom thereof, are disclosed. Specific methods encompass the administration of one or more vitamin D compounds, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, alone or in combination with one or more additional active agents. Other methods include intermittent administration of a high dose of one or more vitamin D compounds, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, alone or in combination with one or more additional active agents. Such intermittent administration allows high doses of the vitamin D compounds to be administered while minimizing or eliminating hypercalcemia.

Description

METHODS OF USE OF VITAMIN D COMPOUNDS IN THE TREATMENT OF MYELODISPLASTIC SYNDROMES FIELD OF THE INVENTION This invention relates, in part, to the methods of treating myelodysplastic syndromes, or to the improvement of one or more symptoms thereof, comprising the administration of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate. , stereoisomer, clathrate or prodrug thereof, as monotherapy or in combination with other therapeutic agents. The vitamin D compound can be administered in high doses to treat MDS, or improve a symptom thereof, using intermittent administration to avoid side effects such as hypercalcemia.

BACKGROUND OF THE INVENTION PATHOLOGY OF MDS Myelodysplastic syndrome (MDS) refers to a diverse group of disorders of hematopoietic stem cells. The MDS is characterized by a cellular bone marrow with morphology and maturation Ref. : 163587 impaired (dysmyelopoiesis), peripheral blood cytopenias and a variable risk of progression to acute leukemia, resulting from the ineffective production of blood cells. See The Merck Manual 953 (17th ed. 1999) and List et al., 1990, J. Clin. Oncol. 8: 1424-1441. MDS is mainly a disease of elderly people, with the average onset in the seventh decade of life. The average age of these subjects is 65 years, with ages ranging from the early part of the second decade of life to as old as 80 years or more. However, myelodysplasia can also affect children, who have similar clinical manifestations to adults. See Heany et al., 1999, New Eng. J. Med. 340: 1649-60. Genetic abnormalities such as Dow syndrome are present in approximately 30% of children with MDS, and are thought to predispose such children to myelodysplastic syndrome. See id. MDS can be characterized as primary or secondary, since subjects who survive the treatment of malignancy with certain chemotherapeutic agents or radiotherapy have a high incidence of developing secondary MDS or acute leukemia. See Zeidman et al., 1995, Haematology (Budap) 27: 23-8. Approximately 60 to 70% of the subjects do not have an obvious exposure or cause for MDS and are classified as subjects with primary MDS. However, a non-specific history of exposure to indeterminable chemicals or radiation 10 to 15 years before the onset of the disease may be present in some subjects. Exposure to compounds that include, but are not limited to, benzene, insecticides, herbicides and fungicides is correlated with the increased incidence of MDS. See West et al., 2000, Blood 95: 2093-7 and Goldberg et al., 1990, Cancer Res. 50: 6876-81. Secondary MDS describes the development of MDS or acute leukemia after exposure to genotoxic chemotherapeutic drugs or radiation during treatment for an unrelated malignancy. See Zeidman et al., 1995, Haematology (Budap) 27: 23-8. These drugs are associated with a high incidence of chromosomal abnormalities after exposure and at the time of MDS or the diagnosis of acute 1eukemia. In addition, MDS is associated with severe cytopenias and their expected clinical complications. Possible manifestations of these cytopenias include increased risk of infection due to neutropenia and neutrophil dysfunction, bleeding due to thrombocytopenia and platelet dysfunction, and fatigue due to anemia. Other complications are the development of myelofibrosis, which can accelerate the decline in blood counts and increase transfusion requirements. See Heany et al., 1999, New Eng. J. Med. 340: 1649-60 and Lambertenghi-Deliliers et al., 1992, Leuk. Lymphoma 8: 51-5. Another major clinical problem for patients with MDS is the potential for the disease to progress to acute myeloid leukemia (AML). Any or all of these manifestations can lead to shortened survival of the affected subjects. In MDS, an initial damage to hematopoietic stem cells can be caused by, in other factors, cytotoxic chemotherapy, radiation, virus, exposure to chemicals and genetic predisposition. The early stages of MDS are mainly characterized by cytopenias, including anemia, neutropenia, and thrombocytopenia. The course of the disease varies in each subject, with some cases that behave like an indolent disease and others that behave aggressively with a very short clinical course that quickly turns into acute leukemia. An international group of hematologists, the French-American-British Cooperative Group (FAB), classified MDS disorders into five subgroups, differentiating them from acute myeloid leukemia, see The Merck Manual 954 (17th ed. ); Bennett et al., 1985, Ann. Intern. Med. 103: 620-625; and Besa, 1992 Med. Clin. North Am. 76 (3): 599-617. According to the FAB classification, there are two subgroups of refractory anemia characterized by five percent or less of myeloblasts in the bone marrow: (1) refractory anemia (RA) and; (2) the RA with ring-shaped sideroblasts (RARS), defined morphologically as having 15% erythroid cells with abnormal ring sideroblasts, reflecting an abnormal accumulation of iron in the myochondria. Besa, 1992 ed. Clin. North Am. 76 (3): 599-617. There are also two subgroups of refractory anemias with more than five percent of myeloblasts: (1) RA with excess blasts (RAEB), defined as 6 to 20% of myeloblasts, and (2 RAEB in transformation (RAEB -T), with 21 to 30% of myeloblasts Finally, the fifth type of MDS, and the most difficult to classify, is called chronic myelomonocytic leukemia (CM L.) This subtype can have any percentage of myeloblasts but present with a monocytosis of 1000 / dL or more, see id, Harris et al., 1999, J. Clin. Oncol. 17: 3835-49. 'More recently, the World Health Organization Salud has proposed a classification system for MDS called the International Forecast Rating System (IPSS). This system classifies MDS disorders into four prognostic categories based on the percentage of bone marrow blasts, cytogenetic subgroup, and number of cytopenias. See Greenberg et al., 1998, Blood 89: 2079-88 and Bennett, 2000, Int. J. Hematol. 72: 131-33. While the FAB classification system is still in use, the IPSS best predicts the progression of the disease to acute myelogenous leukemia (AML) and agent survival. According to the IPSS, the values assigned to each classification variable as shown by Table 1 below are aggregated together to determine the MDS forecast category as shown by Table 2 below. See Greenberg et al., 1998, Blood 89: 2079-88. The mean survival time for patients with low risk of MDS is 5.7 years, while the average survival time for patients with high risk of MDS is only 0.4 years. The median survival time for patients with intermediate MDS l 2 is 3.5 and 1.2 years, respectively. See id.

Table 1 Survival Rating Value and Variable Evolution of -0 0.5 1.0 1.5 2.0 Blast Forecast of < 5 5-10 - 11-20 21-30 Marrow (percentage) Karyotype Good Intermediate Poor Cytopenia (total) 0-1 2.3 Table 2 The effective incidence of MDS in the United States is unknown. MDS was first considered as a distinct disease in 1976 and the appearance was then estimated at 1500 new cases each year. At that time, only subjects with less than five percent of myeloblasts were considered to have this disorder. Recent statistics from 1999 estimate 13,000 new cases per year and approximately 1000 cases per year in children, surpassing chronic lymphocytic leukemia as the most common form of leukemia in the Western Hemisphere. The perception of. that the incidence is increasing, may be due to improvements in the recognition and criteria for diagnosis. The disease is found worldwide.

EXISTING TREATMENTS FOR MDS Current MDS therapies are based on the mechanisms that predominate in a particular phase of the disease process. For younger subjects, bone marrow transplantation with such a donor is the preferred treatment, but older subjects are often not candidates for such aggressive interventions, since many are symptomatic of anemia and are transfusion dependent. Hematopoietic growth factors or cytokines can be used to stimulate the development of blood cells and are effective in a subset of subjects. Other treatments include supportive care with red cell and platelet transfusions, combined with aggressive treatment of infections. In addition, many other classes of potentially therapeutic agents have also been evaluated for efficacy in the treatment of myelodysplastic syndrome, with limited success. Such classes include xnmunomodulators, cytotoxic agents, agents that affect the transcription of RNA, derivatives of vitamins A, E, and K, agents that specifically bind to biological targets related to MDS, inhibitors of signal transduction, cite-protective agents, and compounds that contain arsenic. Bone marrow transplantation has been used in subjects with poor prognosis or late stage MDS. See Epstein et al., 1985 Surg. Ann. 17: 23-29. Unfortunately, the bone marrow transplant is invasive, painful for the donor and the recipient, and can cause severe to fatal complications in the recipient. Standard allogeneic transplant treatments rely on the maximum tolerated doses of chemotherapy and total body irradiation to eradicate the disease, and immunosuppress the recipient to allow grafting and prevent rejection of the graft. Post-transplant immunosuppression is used to induce tolerance and control graft versus host disease. In this way, allogeneic transplants have been essentially limited to treatments of young people, of healthy subjects and must be administered in specialized units of internal patients. Mortality related to transplantation is approximately 20 to 25% under the best conditions, and can be as high as 30-35%. See Deeg et al., 2000, Leuk. Res. 24: 653-63. For this reason, very few transplants have been performed for subjects over fifty years of age, and have been limited to subjects with otherwise fatal diseases. Repeated transfusions in patients with symptomatic refractory anemia are associated with clinical risks of transmission of infectious diseases, transfusion reactions and cardiovascular overload. In addition, multiple transfusions, such as approximately 20 to 30 transfusions, can cause secondary hemochromatosis, a condition that at least requires close monitoring of serum iron and frequently requires daily chelation therapy. Hematopoietic growth factors or cytokines are an alternative procedure to treat MDS and stimulate the development of blood cells. See Dexter, 1987 Cell. Sci. 88: 1-6; oore, 1991 Annu. Rev. Immunol. 9: 159-91; and Besa, 1992, ed. Clin. North Am. 76 (3): 599-617. Hematopoietic growth factors are hormones involved in the process of blood cell formation. The treatment involves the stimulation of the proliferation of a small number of self-renewing stem cells that give rise to the line-specific progenitor cells, which subsequently proliferate and differentiate to produce mature, circulating blood cells. See Metcalf, 1985, Science 229: 16; Dexter, 1987, J. Cell. Sci. 88: 1-6; Golde et al., 1988, Scientific American: 62-71; Tabbara et al., 1991, Anti-Cancer Res. 11: 81-90; Ogawa, 1989, Environ. Health Persp. 80: 199-207; and Dexter, 1989, Med. Bull. 45: 337-49. Most well-characterized growth factors include erythropoietin (EPO), granulocyte-macrophage colony stimulation factor (GM-CSF) and granulocyte colony stimulation factor (G-CSF). in English) . In addition to inducing proliferation and differentiation of hematopoietic progenitor cells, such cytokines also activate a number of functions of mature blood cells, including the influence of the migration of mature hematopoietic cells. See Stanley et al., 1976, J. Exp. Med. 143. 631-47; Schrader et al., Proc. Nati Acad. Sci. USA, 1981, 78: 323-7; Moore et al., 1980, J. Immunol. 125: 1302-5; Kurland et al., Proc. Nati Acad. Sci. USA, 1979, 76: 2326-30; Handman et al., 1979, J. "Immunol., 122: 1134-7, Vadas et al., 1983, Blood 61: 1232, Vadas et al., 1983, J. Immunol. 130: 795-9, and Weisbart et al. al., 1986, J. Immunol., 137: 3584-87. Recombinantly produced hematopoietic growth factors such as r-HuEPO (recombinant human erythropoietin, alpha epoetin, Epogen®, Amgen, PROC IT®, Ortho Biotech) and r- metHuG-CSF (recombinant human granulocyte colony stimulation factor, filgrastim, Neupogen®, Amgen) have been effective in supporting the production of red blood cells (RBCs) and neutrophils, respectively, in a subset of subjects See Hellstrom-Lindberg, et al., 1998, Blood 92: 68-75 and Hellstrom-Lindber, et al., 1997, Br. J. Haematol., 99: 344-51 Concomitantly, the increased levels of hemoglobin have given as a result, improvements in the quality of life in several tests based on large communities, in subjects with cancer, see, for example, Glaspy et al. al., 1997, J. Clin. Oncol. 15: 1218-34 and Detetri et al., 1998, J. Clin. Oncol. 15: 3412-25. However, MDS anemia is often serious and refractory to hematopoietic growth factors or cytokines. Anemia can aggravate common conditions for older subjects, including but not limited to congestive heart failure, coronary artery disease and chronic lung disease. Only about 20% of the subjects respond to EPO alone, and approximately 40% of the subjects respond to EPO administered with G-CSF. See Hellstrom-Lindberg et al., 1997, Br. J. Haematol. 99: 344-51. A serum erythropoietin level less than 200 mU / ml is often predictive of a response to EPO, but the response capacity depends on the stage of the disease with 21% proportions in refractory anemia and refractory anemia with ringed sideroblasts , but only 8% in refractory anemia with excess blasts. See Hellstrom-Lindberg et al., 1997, Br. J. Haematol. 99: 344-51 and Hellstrom-Lindberg, 1995, Br. J ". Haematol., 89: 67-71 Thus, treatment with EPO, G-CSF or other growth factors is not effective to treat all, or even the majority of subjects with MDS Other growth factors that have been administered in the treatment of MDS include thrombopoietin, interferon, interleukin 1, interleukin 2, interleukin 3, interleukin 6, interleukin 8, interleukin 11 and interleukin 12. that many of these factors show a promising field in in vitro studies and in preclinical studies, clinical trials to date have had little or no success.See Schipperus et al., 1991 Br. «T. Haematol. 77: 515-22; Ganser et al., 2000, Ann. Jiematol. 79: 30-5; Musto et al., 2001, Haematologica 86: 4-51; Gordon, Semin. Hematol. 1999, 36 (4 Suppl 6). 21-4; Zwierzina et al., 1993, Scand. J. Immunol. 37: 322-8; Estey et al., 2002, Blood 99: 4343-9; Pan et al., 2000, Leukemia 14: 1634-41; Hofmann et al., 1999, Eur. J. Haematol. 62: 336-40; Hofmann et al., 1999, Ann. Hematol. 78: 125-30; Haznedaroglu et al., 2002, Clin. Appl. Thromb. He ost. 8: 193-212; and Ogata et al., 2000, Jnt. J. Hematol. 72: 173-7. Attempts have been made to treat MDS with immunomodulators, cytotoxic agents, agents that affect the transcription of RNA, derivatives of vitamins A, E and K, agents that specifically bind to biological targets related to MDS, inhibitors of signal transduction, agents cytoprotectors, and arsenic-containing compounds. For example, immunomodulators that have been tested as potential therapeutic agents for MDS include anti-thymocyte globulin (ATG), anti-lymphocyte globulin (ALG), thalidomide, prednisone, cyclosporin A (CyA for its acronym in English), dexamethasone, and pentoxifylline. See, for example, Molldrem et al., 2002, Ann. Intem. Med. 137: 156; Rong et al., 2002, Eur. J \ Haematol. 68: 210; Tsirigotis et al., 2002, Leuk. Res. 26: 965; Hisconmex et al., 2001, Leuk. Lymphoma 42: 665; Ohga et al., 2002, Br. J. Haematol. 118: 313; Greipp, 2000, Curr. Treat. Options Oncol. 1: 119-26; and Raza et al., 2000, Hematol 5: 274-84. The cytotoxic agents tested include cytarabine, melphalan, topotecan, fludarabine, etoposide, idarubicin, daunorubicin, mitoxantrone, cisplatin, paclitaxel and cyclophosphamide. See, for example, Ga'rcia-Mañero et al., 2002, Haematologica 87: 804; Beran et al., 2001, Cancer 92: 1999; Sackmann-Muriel et al., 1996, Leuk. Res. 20: 973; Oosterveld et al., 2002, Leukemia 16: 1615; Hisconmex et al., 2001, Leuk. Lymphoma 42: 665; Denzlinger et al., 2000, Br. J. Haematol. 108: 93; Oosterveld et al., 2002, Leukemia 16: 1615; and Lee et al., 2002, Am. J. Hematol. 68: 237. In addition, agents that affect the transcription of RNA that have been tested as potential therapies by MDS include decitabine, 5-azacytidine, depsipeptides, and phenylbutyrate. See, for example, Daskalakis et al., 2002, Blood 100: 2957; Grun et al., 2002, Leuk. Res. 26: 893; Ballard et al., 2002, Curr. Med. Chem. 9: 471; Imanishi et al., 2002, J. Clin. Endocrinol Metab. 87: 4821; Silverman et al., 2002, J. Clin. Oncol. 20: 2429; and Gore et al., 2002, Clin. Cancer Res., 8. 963-970. The derivatives of vitamins A, E and K that have been evaluated as therapies for MDS include all-trans-retinoic acid, 12-cis-retinoic acid, tocopherol and menatetrenone. See, for example, Stasi et al., 2002, Blood 99: 1578; Hofmann et al., 2000, Leukemia 14: 1583; Takami et al., 2002, Ann. Hematol. 81: 16; and Besa et al., 1998, Leuk. Res. 22: 741. Agents that specifically bind to biological targets related to MDS that have been tested as potential therapies include anti-VEGF, gemtuzumab ozogamicin, and TNFR: Fe. See, for example, Verstovsek et al., 2002, Br. J. Haematol. 118: 151; List, 2002, Oncologist 7 Suppl 1: 39; and Rosenfeld et al., 2002, Leuk. Res., 26: 721. Inhibitors of signal transduction that have been tested as therapeutic agents for MDS include famesyl transferase inhibitors such as Zarnestram and Sarasar ™ and tyrosine kinase inhibitors such as SU5416, SU6668, and PTK787 / ZK222584. See, for example, Kurzrock, 2002, Semin. Hematol., 39 (3 Suppl 2): 18; Cortes et al., 2002, Semin. Hematol. 39 (3 Suppl 2): 26; List, Oncologist 7 Suppl 1:39 (2002); and Cheson et al., 2000, Semin. Oncol. 27: 560. Finally, the cytoprotective agent and the arsenic-containing compound that have been evaluated as potential therapies for MDS are amifostine and arsenic trioxide, respectively. See, for example, Arboscello et al., 2002, AntiCancer Res. 22: 1819; Invernizzi et al., 2002, Br. J. Hematol. 118: 246; and Miller, 2002, Oncologist 7 Suppl 1: 14. With one exception, none of these treatments has resulted, unambiguously, in significant therapeutic effect in subjects with MDS. The only exception to the results, otherwise uniformly mediocre to poor, observed in the test of the compounds described above as potential therapies for MDS is 5-azacitidine. Silverman reported that approximately 60% of patients who were injected subcutaneously with 75 mg / m2 / day of 5-azacytidine for 7 days out of 28 experienced at least a partial response, with 7% of patients enjoying a complete response. See, Silverman et al., 2002, J. "Clin Oncol 20: 2429. However, this therapeutic regimen suffers from several drawbacks: 5-azacytidine is toxic in excess and can cause severe nausea and emesis in subjects to whom The method of administration of this protocol is also inconvenient for patients who must visit the administration clinic daily for the week of treatment Finally, the administration of 5-azacytidine initially causes the cytopenias of subjects with MDS to worsen before that they improve later, which can be dangerous or lethal for some patients.There is therefore still a need for safe and effective methods of treating and managing MDS, particularly a method that is effective in the treatment of anemia associated with MDS and the reduction of the requirements of reduction of RBC, could be of clinical benefit.

COMPOUNDS OF VITAMIN D Vitamin D is a generic term for a family of secoesteroids that have affinity for the vitamin D receptor, and are involved in the physiological regulation of calcium and phosphate metabolism. See Harrison's Principles of Internal Medicine: Part Eleven, "Disorders of Bone and Mineral Metabolism," E. Braunwald et al., 8eds.), 1987, McGraw-Hill, New York in Chapter 335, p. 1860-1865, Stumpf et al., 1979, Science 206: 1188-90, and Holick, 1995, Bone 17: 107S-11S. Vitamin D shows a complex group of actions and synthesis mechanisms. Cholecalciferol (vitamin D3) is synthesized in the skin after exposure to ultraviolet radiation from 7-dehydrocholesterol. Vitamin D2, an analogue of vitamin D3, can be ingested from the diet. Two sequential hydroxylations of vitamin D2 are necessary for full biological activity. The first hydroxylation, which takes place in the liver, results in the formation of 25-hydroxycholecalciferol, while the second hydroxylation takes place in the kidney and results in the formation of the most potent biological metabolite of vitamin D: the? a-25-dihydroxycholecalciferol (also known as calcitriol). Calcitriol maintains calcium homeostasis by modulating intestinal absorption, urinary excretion, and mobilization from skeletal bone. These effects can be exerted through the genomic and non-genomic pathways. Genomic responses are mediated by calcitriol that binds to the nuclear vitamin D receptor (VDR). VDR is a ligand-activated transcription factor that activates the transcription of genes regulated by the vitamin D response element, within its promoter / enhancer regions. See Mangelsdorf et al., 1995, Cell 83: 835-9. The 'non-genomic pathways are mediated by a receptor bound to the membrane, yet characterized. further, VDR has been found in cells of various organs not involved in calcium homeostasis. See Miller et al., 1992, Cancer Res. 52: 515-520. In addition to influencing calcium homeostasis, vitamin D compounds have been implicated in osteogenesis, the modulation of the immune response, the modulation of insulin secretion by pancreatic B cells, and the function of muscle cells, and the differentiation and development of epidermal and hematopoietic tissues. Attempts have been made to use the vitamin D compounds in the treatment of cancer. For example, certain vitamin D compounds and analogs possess potent anti-leukemic activity by virtue of their ability to induce the differentiation of leukemic cells to non-malignant macrophages (monocytes) and are therefore useful in the treatment of leukemia. See suda et al., United States Patent No. 4,391,802; Partridge et al., U.S. Patent No. 4,594,340. The antiproliterative and differentiation actions of calcitriol and other vitamin D3 analogs have also been reported with respect to the treatment of prostate cancer. See Bishop et al., U.S. Patent No. 5,795,882. Vitamin D compounds have also been implicated in the treatment of skin cancer (See Chida et al., 1985, Cancer Res. 45: 5426-5430), colon cancer (See Disman et al., 1987, Cancer Res. 47: 21-25), and lung cancer (See Sato et al., 1982, J. Exp. Med. 138: 445-446). Other reports suggesting the important therapeutic uses of vitamin D compounds are summarized in Rodriguez et al., United States Patent No. 6,034,079. The vitamin D compounds have also been administered in combination with other pharmaceutical agents, in particular cytotoxic agents, for the treatment of hyperproliferative disease. For example, it has been shown that pretreatment of hyperproliferative cells with Vitamin D compounds, followed by treatment with cytotoxic agents, improves the efficacy of cytotoxic agents (U.S. Patent Nos. 6,087,350 and 6,559,139). Although the administration of vitamin D compounds can result in substantial therapeutic benefits, their use as a treatment for cancer or MDS has been severely limited by the effects these compounds have on calcium metabolism. At the levels required for effective in vivo use, vitamin D compounds can induce markedly elevated and potentially dangerous blood calcium levels by virtue of their inherent calcemic activity. That is, the clinical use of calcitriol and another vitamin D compound to treat cancer or MDS has been excluded or severely limited, due to the risk of hypercalcemia.

It has been shown that the problem of systemic hypercalcemia can be overcome by "high dose pulse administration" (HDPA) of a sufficient dose of an active vitamin D compound such that an anti-proliferative effect is observed. while the development of severe hypercalcemia is avoided. According to U.S. Patent No. 6,521,608, the vitamin D active compound can be administered no more than every three days, e.g., once a week at a dose of at least 0.12 μg / kg per day ( 8.4 μg in a 70 kg person). The pharmaceutical compositions used in the HDPA regimen of the 6,521,608 patent comprise 5-100 g of the vitamin D active compound and can be administered in the form of oral, intravenous, intramuscular, topical, transdermal, sublingual, intranasal, intratumoral or other preparations. In a phase I trial of the weekly administration of calcitriol to patients with refractory malignancies, the HDPA of calcitriol showed that it does not produce dose-limiting toxicity and that it produces average maximum levels of calcitriol within the therapeutic range. Beer et al., Cancer 91: 2431 39 (2001).

ADMINISTRATION OF VITAMIN D COMPOUNDS IN THE TREATMENT OF MDS Although a pre-clinical animal model for MDS is not available, it has been reported that calcitriol alters the development of bone marrow progenitors in vitro and promotes the development of monocytic progenitors in a dose-dependent manner. See, S anson et al., 1986, Blood 67: 1154-1161. In addition, the evidence suggests that there may be a local deficiency of calcitriol in the bone marrow microenvironment in some subjects with MDS. See Blazsek et al., 1996, Cancer Detect. Prevent. 20: 31-42. Calcitriol seems to improve anemia and reduces the need for erythropoietic agents in subjects with hemodialysis. See Goicoechea et al., 1998, Nephron 78: 23-27. While preclinical data that consider the use of calcitriol to treat MDS are consistently positive, results from clinical trials of calcitriol as a therapeutic agent have been limited in scope and mediocre in response. See Morosetti et al., 1996, Semin. Hematol. 33: 236-245. One reason for these results has been the induction of hypercalcemia with the administration of only 2 μg / day of calcitriol. See Koeffler et al., 1985, Cancer Treat. Rep. 69: 1399-1407. A maximum of 0.75 calcitriol has been administered to subjects with MDS without hypercalcemi. See Mellibovsky et al., 1998, Brit. J. Haemotol. 100-516-520. These studies report that the administered doses of vitamin D compounds provide some benefit for some subjects with some forms of MDS, but the doses may not be increased to more effective levels without causing hypercalcemia in the subjects. As demonstrated by the previous review of past and present therapies for MDS, a large number of potential therapeutic agents have been and are being tested for their ability to treat MDS. However, none of these agents has met with unequivocal success in clinical evaluations. Rather, there is still no agent approved by the Food and Drug Administration of the United States with an indication for this disease. See List, 2002, Oncologist 7 (suppl 1): 39-49. In addition, many of the more aggressive therapies, such as bone marrow transplantation and high dose chemotherapy, are inappropriate for a large percentage of subjects with MDS, due to their advanced age and weakened condition. See id. As a result, there remains an unfulfilled need for safe and effective methods of treating MDS, or improving a symptom of it. Particularly, a method that is effective in treating anemia associated with MDS and reducing transfusion requirements could be of clinical benefit. Calcitriol and other vitamin D compounds have been shown to exert such clinical benefit, but their usefulness as a therapeutic agent has been limited by the induction of hypercalcemia. Therefore, methods to treat DS are required, while not causing unwanted and dangerous side effects such as hypercalcemia. The citation or discussion of a reference herein will not be considered as an admission that it is prior art to the present invention.

BRIEF DESCRIPTION OF THE INVENTION The invention encompasses methods and compositions for the treatment of myelodysplastic syndrome (MDS), or the amelioration of a symptom thereof, particularly MDS anemia, which comprises administering to a subject in need thereof a therapeutically effective dose of vitamin D, or the pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof, while avoiding or minimizing hypercalcemia. These methods and compositions can be used for the treatment of MDS, or the improvement of a symptom thereof, with few or no associated symptoms of hypercalcemia.

In some aspects, the methods of the invention comprise intermittently administering a therapeutically effective dose of a vitamin D compound and optionally administering one or more additional active agents. The dose of the vitamin D compound can be a high dose, since the intermittent administration of the vitamin D compounds according to the methods of the invention allows a high dose to be administered to a subject without causing hypercalcemia. The vitamin D compound can be any vitamin D compound without limitation. In preferred embodiments, the vitamin D compound is an active vitamin D compound such as calcitriol. A therapeutically effective dose of a vitamin D compound may be a dose of between about 3 g / day or any dose range therein as described herein. In certain embodiments, vitamin D compounds can be administered no more than once every three days. In preferred embodiments, the vitamin D compound is administered about once a week. A therapeutically effective dose of an active vitamin D compound is preferably between about 3 μg / day to about 300 μg / day, more preferably between about 5 μg / day to about 200 μg / day, more preferably between about 15 μg / day. d up to about 105 ^ g / a, more preferably between about 15 g / day to about 90 μg / day, more preferably between about 20 μg / day to about 80 μg / day, more preferably between about 35 μg / day to about 75 μg / day, more preferably between about 30 μg / day to about 60 μg / day, and even more preferably about 45 μg. In certain embodiments, the therapeutically effective dose of a vitamin D compound safely achieves maximum plasma concentrations of the vitamin D compound of at least about 0.5 M, more preferably 1-7 nM, and even more preferably about 3-5 nM. While any vitamin D compound can be used according to the methods of the invention, the preferred vitamin D compounds reach peak plasma concentrations rapidly and are also rapidly eliminated. In additional embodiments, the invention provides methods for the treatment of MDS, or the improvement of a symptom thereof, which comprises administering a therapeutically effective dose of a vitamin D compound in combination with one or more additional active agents. The therapeutically effective dose of the vitamin D compound can be any dose, in combination with one or more additional active agents, effective to treat MDS or. improve a symptom of it. In certain embodiments, the therapeutically effective dose of the vitamin D compound is a high dose. Additional active agents may be one or more growth factors, for example, hematopoietic growth factors or cytokines; immunomodulators; cytotoxic agents, for example, antimetabolites, anti-microtubule agents, alkylating agents, platinum agents, anthracyclines, antibiotic agents, or topoisomerase inhibitors; agents that affect the transcription of RNA; derivatives of vitamins A, E and K; agents that are specifically linked to biological objectives related to MDS; inhibitors of signal transduction; cytoprotective agents; or compounds that contain arsenic. Examples of haematopoietic growth factors or cytokines include, but are not limited to, erythropoietin (EPO) and granulocyte colony stimulation factor (G-CSF), and more particularly recombinant human erythropoietin (r-HuEPO), and the methionyl-stimulating factor of granulocyte colonies, human, recombinant (r-metHuG-CSF). In further embodiments, the present invention provides pharmaceutical compositions comprising one or more vitamin D compounds and one or more additional active agents.

In the methods of the present invention, a vitamin D compound and optionally one or more additional active agents can be administered in the form of a pharmaceutical composition, a simple unit dosage form, or an article of manufacture suitable for use in the treatment of MDS, or the improvement of a symptom thereof, comprising one or more vitamin D compounds, or the pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, or prodrugs thereof. The vitamin D compound (s) and optionally one or more additional active agents can be formulated in any pharmaceutical composition known to those skilled in the art. In certain embodiments, the vitamin D compounds are administered in oral or intravenous formulations. Preferred oral formulations include emulsion preconcentrates comprising one or more vitamin D compounds, a lipophilic phase component, and a surfactant. In certain embodiments of the invention, pharmaceutical compositions for the treatment of MDS, or the amelioration of a symptom thereof, comprise a therapeutically effective dose of a vitamin D compound, or a salt, solvate, hydrate, stereoisomer, clathrate or prodrug pharmaceutically acceptable thereof, in combination with one or more additional active agents. The methods and compositions of the present invention are useful for the treatment of SD, or the improvement of a symptom thereof, in a subject, preferably a human subject. Significantly, the methods and compositions of the present invention can be used for the treatment of MDS, or the improvement of a symptom thereof, with active vitamin D compounds such as calcitriol, while minimizing or avoiding effects of hypercalcemia.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 provides the plasma concentrations of calcitriol as a function of time. Figures 2A-2C provide the concentration of hemoglobin (in grams per deciliter) and the frequency of transfusion of red blood cells (in transfused units) as a function of time for patient # 1 (Figure 2A), patient # 2 ( Figure 2B) and patient # 3 (Figure 2C).

DETAILED DESCRIPTION OF THE INVENTION The present invention provides methods and compositions for treating myelodysplastic syndrome, or the improvement of a symptom thereof, with one or more vitamin D compounds, preferably an active vitamin D compound such as calcitriol, while minimizing it. or the risks of hypercalcemia are eliminated. In certain aspects of this invention, one or more vitamin D compounds are administered in combination with one or more additional active agents.

DEFINITIONS "Active vitamin D compound" refers to a vitamin D compound that is biologically active when administered to a subject or brought into contact with cells. The biological activity of a vitamin D compound can be evaluated by assays described herein or well known to a person skilled in the art such as, for example, immunoassays (e.g., enzyme-linked immunoassays ("ELISAs")) that measure the expression of a gene. Vitamin D compounds exist in several forms with different levels of activity in the body. For example, a vitamin D compound can be partially activated by first undergoing hydroxylation in the liver to 25-hydroxycholecalciferol and then can be fully activated in the kidney to the 25-dihydroxycholecalciferol, which is also known, among others, as " calcitriol. " Calcitriol, however, is the main biologically active form of vitamin D in humans, and does not require further modification in the body for immediate use. "Calcemic index" refers to a measure of the relative ability of a drug to generate a calcemic response.Examples of such measurements are demonstrated in Bouillon et al., 1995, Endocrine Reviews 16: 200-7. A calcaemic index of 1 corresponds to the relative calcemic activity of calcitriol. An index calcemic of approximately 0.01 corresponds to the calcemic activity of calcipotriol. A calcaemic index of 0.5 could correspond to a drug that has approximately half the calcemic activity of calcitriol. The calcaemic index of a drug can vary depending on the test used, for example, if the calcium absorption stimulation (ICA) is measured, or the bone calcium mobilization activity (BCM for short). English), as reported in Hurwitz et al., 1967, J. "Nutr. 91: 319-323 and Yamada et al., 1988, Mol. Cell. Endocrinol." 59: 57-66. Relative calcemic activity is expressed major in relation to the calcemic activity of calcitriol, which is one of the best characterized vitamin D compounds. "Clinical hypercalcemia" refers to one or more of the signs or symptoms of hypercalcemia.

Early manifestations of hypercalcemia include weakness, headache, drowsiness, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain or metallic taste. Late manifestations include polydipsia, polyuria, weight loss, pancreatitis, photophobia, pruritus, renal dysfunction, elevation of aminotransferase, hypertension, cardiac arrhythmias, psychosis, stupor, coma and ectopic calcification. Hypercalcemia can be life-threatening and is thus typically avoided in the administration of the vitamin D compound. "Pre-concentrated in emulsion" refers to a formulation capable of providing an emulsion after contact with a polar medium such as water. The term "emulsion" refers to a colloidal dispersion comprising a polar medium such as water and organic components including, but. they are not limited to hydrophobic, for example, lipophilic, organic components and encompass conventional emulsions and submicron droplet emulsions. The term "submicron droplet emulsion" refers to an emulsion wherein the droplets or particles that form the colloidal dispersion of the organic components have a maximum average dimension of less than about 1000 nm. "Hypercalcemia" refers to a condition in which the blood calcium concentration is higher than normal (although the normal value may vary slightly depending on the measurement technique used). Although the concentration that is considered "normal" will vary slightly with the variation in measurement techniques, a value above 10.5 mg / dl in humans is considered hypercalcemia. Hypercalcemia can be divided into grades 0-4. Grade 0 corresponds to a blood calcium concentration value that is less than 10.6 mg / dl; Grade 1 corresponds to a blood calcium concentration value of 10.6-11.5 mg / dl; Grade 2 corresponds to a blood calcium concentration of 11.6-12.5 mg / dL; Grade 3 corresponds to a blood calcium concentration of 12.6-13.5 mg / dL; and Grade 4 corresponds to a blood calcium concentration value that is greater than 13.5 mg / dL. See, for example, United States Patent No. 6,521,608. "In combination" refers to the use of more than one therapeutic agent. The use of the term "in combination" does not restrict the order in which the therapeutic agents are administered to a subject with MDS. A first therapeutic agent can be administered before, concurrently with, after, or within any cyclic regimen involving the administration of a second therapeutic agent to a subject with MDS. For example, the first therapeutic agent can be administered 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before a second therapeutic agent; or the first therapeutic agent can be administered 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks after a second therapeutic agent. "Isomer" refers to a chemical compound that has the same chemical formula as another but different structure. An example of a "constitutional isomer" of propanol is isopropanol, where the compounds have the same molecular formula but differ in the placement of the bonds between the atoms. An example of a "stereoisomer" is an "enantiomer", which is any compound that is the mirror image of another compound. Another example of a stereoisomer is a diastereomer, which is any stereoisomer that contains more than one chiral center but is not an enantiomer. "Intermittent" administration refers to a method to achieve periodically high blood concentrations of vitamin D compounds without the onset of hypercalcemia. The method of intermittent administration comprises periodically dosing a subject with a high level of one or more vitamin D compounds. Intermittent administration may comprise, for example, but not by way of limitation, the administration of one or more vitamin D compounds no more than every three days, approximately once every four days, approximately once every five days, approximately once every six days, approximately once a week, approximately once every nine days, approximately once every two weeks, approximately once every three weeks, or approximately once every four weeks. The period of intermittent administration may continue for one, two, three or four weeks, or one, two, three, four, five or six months or more. Schemes intermittent dosing may comprise the administration of vitamin D compounds, which is more or less frequently than those mentioned so far, or that continues for periods longer or shorter treatment, depending on the pharmacokinetics or pharmacodynamics of Pharmaceutical agent employed. One skilled in the art will readily understand the potential need for adjustments regimes periodic dosing, and any scheme periodic dosage includes the administration of high doses of vitamin D compounds without the onset of hypercalcemia is within the scope of the invention. An example of a dosage scheme that can be used by the methods of the present invention is provided in U.S. Patent No. 6,521,608, which is incorporated by reference herein. "Metabolite" refers to a substance that results after the body has processed, for example, metabolized, another substance. An example of a series of metabolites can start with 1,25-dihydroxiergocalciferol, the most active form of vitamin D2, which is a metabolite of 25-hydroxiergocalciferol, which is a metabolite of ergocalciferol (vitamin D2), which is a ergosterol metabolite. Another example of a series of metabolites can begin with 1,25-dihydroxycholecalciferol (calcitriol), which is a metabolite of 25-hydroxycholecalciferol, which is a metabolite of cholecalciferol (vitamin D3), which is a metabolite of 7-dehydrocholesterol. Another example of a series of metabolites may begin with tachisterol, which is a metabolite of dihydrotachysterol, which is a metabolite of 25-hydroxydihydrotachisterol. "Non-hypercalcemic Compound D" refers to a vitamin D compound that has less of a tendency to produce the onset of hypercalcemia than a comparable dose of calcitriol, as evaluated by well-known assays for a person skilled in the art. . Examples of such non-hypercalcemic vitamin D compounds include calcitriol analogues, such as o23-7553 and Ro24-5531 (la, 25-dihydroxy-16-en-23-in-26, 27-hexafluorocolecalciferol) available from Hoffmann -LaRoche. Other examples of non-hypercalcemic vitamin D compounds can be found in U.S. Patent No. 4,717,721, which is incorporated herein by reference, in its entirety. "Pharmaceutical formulation" refers to a formulation comprising ingredients that are pharmaceutically acceptable for their intended use. "Pharmaceutical agent" refers to one or more vitamin D compounds or one or more vitamin D compounds in combination with one or more active ingredients that are not vitamin D compounds, including but not limited to bisphosphonates. . The pharmaceutical agent may be administered in combination with other active ingredients as well, such as, for example, the administration of vitamin D compounds in combination with hematopoietic growth factors or cytokines in the treatment of MDS. "Precursor" refers to a compound that can be transformed to another compound that is biologically active. An example of a series of precursors can start with ergosterol, which is the precursor of ergocalciferol (vitamin D2), which is the precursor of 25-hydroxiergocalciferol, which is the precursor of 1,25-dihydroxiergocalciferol, the most active form of vitamin D2. Another example of a series of precursors may begin with 7-dehydrocholesterol, which is the precursor of cholecalciferol (vitamin D3), which is the precursor of 25-hydroxycholecalciferol, which is the precursor of 1,25-dihydroxycholecalciferol (calcitriol ). Another example of a series of precursors may begin with tachysterol, which is the precursor of dihydrotachysterol, which is the precursor for 25-hydroxydihydrotachysterol. "Refractory" and "unresponsive" refers to subjects treated with a therapeutic agent currently available for MDS, which is not clinically adequate to alleviate one or more symptoms associated with MDS. Typically, such subjects suffer from severe, persistently active disease and require additional therapy to ameliorate the symptoms associated with their MDS. "Synergistic" refers to a combination of therapeutic agents that is more effective than the additive effects of any two or more simple agents. A synergistic effect of a combination of therapeutic agents allows the use of lower doses of one or more of the agents and / or less frequent administration of said agents to a subject with MDS. The ability to use lower doses of the therapeutic agents and / or administer said agents less frequently, reduces the toxicity associated with the administration of the agents without reducing the efficacy of the agents in the treatment of MDS, or the improvement of a symptom of the same. In addition, a synergistic effect can result in improved efficacy of the agents in the treatment of MDS, or improvement of a symptom thereof. Finally, the synergistic effect of a combination of therapeutic agents can prevent or reduce adverse or unwanted side effects, associated with the use of any simple therapy. "Subject" and "patient" are used interchangeably. As used herein, the term "subject" and "subjects" refers to an animal, preferably a mammal that includes a non-primate (for example, a cow, pig, horse, cat, dog, rat and mouse) and a primate (e.g., a monkey, such as a cynomolgus monkey, and a human), and more preferably a human. "Therapeutic agents" refers to any agents that can be used in the prevention or treatment of MDS, or the improvement of a symptom thereof. In certain embodiments, the term "therapeutic agents" refers to one or more vitamin D compounds. In other embodiments, the term "therapeutic agents" does not refer to a vitamin D compound. Preferably, a therapeutic agent is known to be useful , or has been or is currently being used to prevent or prevent the development, onset or progression of MDS, or to improve the symptoms of MDS. A "therapeutically effective dose" refers to a dose of an ingredient that can achieve the desired therapeutic or prophylactic effects, such as, for example, a dose that can reach the blood level of a vitamin D compound that is above the normal for a period of time sufficient to have the therapeutic benefit, without clinically relevant toxicity. According to the methods of the invention, a therapeutically effective dose of the vitamin D compounds may be in the range of about 3 μg to about 300 g, or any range of amounts therein. Higher peak blood levels of vitamin D compounds are associated with increased efficacy, but at some point the benefit may be limited by toxicity. Specific administration regimens allow higher doses to be administered safely, ie without the onset of symptoms associated with hypercalcemia. In a specific embodiment, a therapeutically effective amount of a vitamin D compound (preferably an active vitamin D compound or a non-hypercalcemic vitamin D compound) is, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130 , 135, 140, 145, 150, 55, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255 , 260, 265, 270, 275, 280, 285, 290, 295 or 300 μg or more. In certain embodiments, a therapeutically effective dose of an active vitamin D compound is preferably between about 3 μ9 ^? 3 to about 300 μg / day, more preferably between about 5 to about 200 μg / day, more preferably between about 15 μg / day to about 105 μg / day, more preferably between about 15 μg / day to about 90 μg / day. day, more preferably between about 20 μg / day to about 80 μg / day, more preferably between about 35 μg / day to about 75 μg day, more preferably between about 30 μg day to about 60 μg / day, and even more preferably about 45 μg. In certain embodiments, the therapeutically effective dose of the vitamin D compound safely reaches maximum plasma concentrations of the vitamin D compound and at least about 0.5 nM, more preferably about 1-7 nM, and even more preferably about 3-5 nM. 4"Treat" and "treatment" refers to the administration of one or more prophylactic or therapeutic agents, either before or after the onset of MDS symptoms. "Treat" or "treatment" also includes the "management" of MDS, which includes lengthening the time a subject remains in remission and / or preventing the reappearance of MDS in subjects at risk of MDS. "Treat" or "treatment" further includes prevention of the recurrence or onset of one or more symptoms of MDS in a subject. Symptoms associated with MDS include, but are not limited to, anemia, thrombocytopenia, neutropenia, bicytopenia (two deficient cell lines), and pancytopenia (three deficient cell lines). A "vitamin D compound" refers to any form of chemical compound with an affinity for the vitamin D receptor (VDR). The vitamin D compounds of the present invention can be concentrated in the blood at a therapeutically effective level. VDR is a transcription factor activated by the ligand, or an intracellular receptor, which initiates transcription by binding to elements of vitamin D response, within the promoter / enhancer region of the target or target genes. Examples of vitamin D compounds within the scope of the invention include, but are not limited to calcitriol, 1,25-dihydroxiergocalciferol, calcifediol, 25-hydroxiergocalciferol, ergocalciferol, cholecalciferol, doxercalciferol, dihydrotaquisterol, paracalcitol, as well as derivatives, analogs , homologues, precursors and metabolites thereof. Preferred vitamin D compounds are active vitamin D compounds and include, but are not limited to, calcitriol and all its derivatives, analogs, homologs, precursors and metabolites. The most preferred vitamin D compound is calcitriol.

COMPOUNDS OF VITAMIN D In the methods of the present invention, the vitamin D compound can be any compound that binds to a vitamin D receptor, and thus can be any vitamin D compound known to a person skilled in the art. For example, the term "vitamin D" traditionally refers to ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3), but the present invention encompasses the use of any vitamin D compound or its derivatives, analogs, homologs, precursors and metabolites . As such, the term "vitamin D compound" includes not only, for example, ergocalciferol and cholecalciferol of natural origin, but also includes its respective precursors ergosterol and 7-dehydrocholesterol. In addition, the term vitamin D compound also includes the activated forms or the metabolites of ergocalciferol and colecalciferol, which include 25-hydroxiergocalciferol and 25-hydroxycholecalciferol (calcifediol) in addition to the most active forms, which are 1,25- dihydroxiergocalciferol and 1, 25-dihydroxicclecalciferol (calcitriol). The chemical structure of calcitriol is as follows: The vitamin D compound can be isolated from natural sources or synthesized by methods known to those skilled in the art. An example of a synthetic analogue of vitamin D is dihydrotachysterol. Dihydrotaquisterol is a synthetic reduction product of tachisterol. Tachysterol is a by-product formed during the irradiation of 7-dehydrocholesterol, the precursor for vitamin D3. Dihydrotaquisterol is ten times more active than its precursor tachisterol, and is activated in the liver to 25-hydroxydihydrotachisterol even more active. Other examples of synthetic analogs of vitamin D are paricalcitol and doxercalciferol, which can be used to decrease levels of parathyroid hormone. Yet another example of a synthetic vitamin D analogue is alfacalcidol, which is currently in clinical use in Canada for the treatment and prevention of renal bone disease, rickets, hyparathyroidism and osteoporosis.

Active vitamin D compounds The vitamin D compounds used in the present invention comprise the active vitamin D compounds. While not intended to be compromised by any particular theory or particular mechanisms of action, vitamin D compounds may become activated, for example, through (1) ultraviolet conversion of 7-dehydrocholesterol in the skin to vitamin D3 ( cholecalciferol) and (2) dietary intake of either vitamin D2 (ergocalciferol) or vitamin D3. The compounds of vitamin D2 and vitamin D3, for example, become fully active on target tissues when they are metabolically activated in the liver and kidney. Regardless of whether the vitamin D compound was a product of ultraviolet conversion to the skin or dietary intake, the next step in activation may be the introduction of a hydroxyl group in the side chain at the C-position. 25 for a liver enzyme known as CYP 27 (a vitamin D-25-hydroxylase). At this point, the partially activated compounds of vitamin D2I and D3 are known as, among others, 25-hydroxycergocalciferol and 25-hydroxycholecalciferol, respectively. These partially activated compounds become fully activated in the mitochondria of renal tissue by the renal 25-hydroxyvitamin D-hydroxylase to produce the 25- (OH) 2D2, the primary biologically active form of vitamin D2, and the 25- ( OH) 2D3 (calcitriol), the biologically most active form of vitamin D3. The active vitamin D compounds of the present invention include, but are not limited to analogs, homologs and derivatives of the vitamin D compounds described in the following patents, each of which is incorporated by reference herein, in its whole: U.S. Patent Nos. 4,391,802 (α-hydroxy-vitamin D derivatives); 4,717,721 (α-hydroxy derivatives with a side chain 17 greater in length than the side chains of cholesterol or ergosterol); 4,851,401 (cyclopentane-vitamin D analogs); 5,145,846 (vitamin D3 analogues with alkynyl, alkenyl and alkanyl side chains); 5,120,722 (trihydroxicalciferol) 5,547,947 (fluorocolecalciferol compounds); 5,446,035 (vitamin D substituted with methyl); 5,411,949 (23-oxa-derivatives); 5,237,110 (19-or-vitamin D compounds); 4,857,518 (hydroxylated derivatives of 2-homo-vitamin D). Additional examples of active vitamin D compounds are listed in the following patents, each of which is incorporated by reference herein, in its entirety: 6,503,893, 6,482,812, 6,441,207, 6,410,523, 6, 399, 797, 6,392, 071, 6, 376,480, 6,372, 926, 6,372,731, 6,359,152, 6,329,357, 6,326,503, 6,310,226, 6,288,249, 6,281,249, 6,277, 837, 6,218,430, 6,207, 656, 6,197,982, 6, 127,559, 6,103,709, 6, 080, 878, 6, 075, 015, 6, 072,062, 6, 043,385, 6, 017, 908, 6, 017, 907, 6,013,814, 5, 994,332, 5,976,784, 5, 972, 917, 5, 945,410, 5,939,406, 5, 936,105, 5, 932,565, 5, 929, 056, 5, 919, 986, 5, 905, 074, 5, 883, 271, 5, 880, 113, 5,877, 168, 5, 872, 140, 5, 847, 173, 5, 843, 927, 5, 840, 938, 5, 830, 885, 5, 824, 811, 5, 811, 562, 5, 786, 347 5, 767, 111, 5, 756, 733, 5, 716, 945, 5,710,142, 5, 700, 791 5,665,716, 5,663,157, 5,637,742, 5,612,325, 5,589,471 5,585,368, 5,583,125, 5,565,589, 5,565,442, 5,554,599 5,545,633, 5,532,228, 5,508,392, 5,508,274, 5,478,955 5,457,217, 5,447, 924, 5,446,034, 5,414, 098, 5,403, 940 5,397,775; 5, 395, 830; 5,393,749; 5,384,313; 5,374,629 5,373, 004; 5,371,249; 5, 321, 018; 5,281,731; 5,260,290 5,254,538; 5,250,523; 5,247,104; 5,246, 925; 5,232,836 5, 194,431; 5,185,150; 5,086,191; 5, 036, 061; 5, 030,772 4, 973, 584; 5,354,744; 4, 940, 700; 4, 927, 815; 4,866,048 4, 851,400; 4, 847, 012; 4, 804, 502; 4,769,181; 4,755,329 4, 719,205; 4, 719, 204; 4,619,920; 4,594,192 4,588,716; 4,588,528; 4, 564, 474; 4,552,698; 4,689,180 4,505.906; 4,502, 991; 4,481,198; 4,448,726; 4,448,721 4,428,946; 4,411, 833; 4,367,177; 4,360,472; 4,360,471 4,358,406; 4,336,193; 4,307,231; 4,307,025; 4,305,880; 4,279,826; Y, 4,248,791. • A more complete list of active vitamin D compounds can be found in published PCT Application No. O99 / 49870, which is incorporated by reference herein in its entirety. Other vitamin D compounds active in clinical use include, but are not limited to, Leo Pharmaceutical research drugs such as EB 1089 (24a, 26a, 27a-trihomo-22,24-dien-laa, 25- (OH) 2-D3), KH 1060 (20-epi-22-oxa-24a, 26a, 27a-trihomo-la-25- (OH) 2-D3), MG 1288 and MC 903 (calcitriol); Roche Pharmaceutical drugs such as 1, 25- (OH) 2-16-en-D3, 1, 25- (OH) 2-16-en-23-in-D3 and 25- (OH) 2-16-en -23-in-D3; from Chugai Pharmaceuticals such as 22-oxacalcitriol (22-oxa-l < x, 25- (OH) 2 ~ D3); University of Illinois such as la- (0H) D5; and from the Institute of Medical Chemistry-Schering AG such as ZK 161422 (20-methyl-l, 25- (0H) 2-D3) and ZK 157202 (20-methyl-23-en-l, 25- (OH) 2- D3). Vitamin D analogs also include topical preparations of vitamin D compounds, such as calcipotriene (Dovonex®) and Tacalcitol (Curatoderm®). Examples of commercially available active vitamin D compound formulations, particular, are Rocaltrol®, which is available from Roche; and Calcijex®, which is available from Abbott. Additional examples of vitamin compounds D actives and their derivatives, analogs, homologues, precursors and metabolites include, but are not limited to: la, 25- (OH) 2-26,27Td6-D3; la, 25- (OH) 2-22-en-D3; la- (OH) 2-D3; la, 25- (OH) 2-D2; la, 25- (OH) 2-D4; la, 24.25- (OH) 3-D3; la, 24, 25- (OH) 3-D2; la, 24, 25- (OH) 3-D4; 'la- (OH) -25-FD3; la- (OH) -25-FD4; (OH) -25-FD2; la, 24- (OH) 2-D4; la, 24- (OH) 2-D3; la, 24- (OH) 2-D2; la, 24- (OH) 2-25-FD4; la, 24- (OH) 2-25-FD3 la, 24- (OH) 2-25-FD2; la, 25- (OH) 2-26, 27-F6-22-en-D3; la, 25- (OH) 2-26, 27-F6-D3; la, 25S- (0H) 2-26-F3-D3; la, 25- (OH) 2-24-F2-D3; la, 25S, 26- (OH) 2-22-en-D3; la, 25R, 26- (OH) 2-22-en-D3; la, 25- (OH) 2-D2; la, 25- (OH) 2-24-epi-D3; la, 25- (0H) 2-23-in-D3; la, 25- (OH) 2-24R-F-D3; la, 25S, 26- (OH) 2-D3; la, 24R- (OH) 2-25F-D3; la, 25- (OH) 2-26, 27-F6-23-in-D3; la, 25- (OH) 2-26-F3-D3; la, 25, 28- (OH) 3-D2; la, 25- (OH) 2-16-en-23-in-D3; la, 24R, 25- (OH) 3-D3; la, 25- (OH) 2-26, 27-F6-23-en-D3; la, 25R- (OH) 2-22-en-26-F3-D3; la, la, 25- (OH) 2-22-en-26-F3-D3; la, 25R- (OH) 2-D3-26, 26, 26-D3; la, 25S- (OH) 2-D3-26, 26.26-D3; and the, 25R- (OH) 2-22-en-D3-26, 26, 26-D3. In addition, while any vitamin D compound can be used according to the methods of the invention, the preferred vitamin D compounds have pharmacokinetic properties that make them more suitable for the methods described below, than other vitamin D compounds. Generally, preferred vitamin D compounds reach peak plasma concentrations rapidly, for example, within about four hours, and are rapidly eliminated, for example, with a half-life of about 12 hours or less. The elimination half-life describes the time for the plasma concentration of the agent to be reduced by 50%, while eliminated in this context, it is understood that it refers to plasma concentrations below about 0.5 nM. While the endogenous vitamin D plasma concentrations vary from subject to subject, they are typically approximately 0.16 nM. Calcitriol is an example of such a preferred vitamin D compound with desirable pharmacokinetic properties as described above. While it is not intended to be compromised by any particular theory or mechanism of action, it is believed that vitamin D compounds with these pharmacokinetic properties can initiate therapeutic biological response during the brief period of high concentration, then rapidly fall below the concentration threshold that facilitates the release of calcium, which minimizes hypercalcemia. In preferred embodiments of the invention, the active vitamin D compound is calcitriol.

Non-Hypercalcemic Vitamin D Compounds The vitamin D compounds used in the present invention also comprise the non-hypercalcemic vitamin D compounds. However, in certain embodiments of the invention, the vitamin D compound is not a non-hypercalcemic vitamin D compound. The non-hypercalcemic vitamin D compounds have less of a tendency to produce the onset of hypercalcemia than a comparable dose of calcitriol, as evaluated by assays well known to a person skilled in the art. Examples of such non-hypercalcemic vitamin D compounds include calcitriol analogs such as Ro23-7553 and Ro24-5531 (la, 25-hydroxy-16-en-23-in-26, 27-hexafluorocolecalciferol) available from Hoffmann-LaRoche . Other examples of non-hypercalcemic vitamin D compounds can be found in U.S. Patent No. 4,717,721, which is incorporated herein by reference in its entirety. The above description of vitamin D compounds is not exhaustive and is merely exemplary of all compounds capable of binding to VDRs. A person skilled in the art will appreciate that this invention encompasses all vitamin D compounds, for example, all compounds capable of binding to VDRs, and derivatives, analogs, homologs, precursors, metabolites and salts, solvates, hydrates. , stereoisomers, clathrates and pharmaceutically acceptable prodrugs thereof.

OTHER THERAPEUTIC AGENTS In certain aspects, the present invention provides the compositions for the treatment of MDS, or the improvement of one or more symptoms thereof, by administration of a vitamin D compound in combination with one or more additional active agents. The additional active agent can be any active agent that has a therapeutic effect to treat MDS, or ameliorate a symptom thereof, which is known to a person skilled in the art, without limitation. Active agents include, but are not limited to, small molecules, synthetic drugs, peptides, polypeptides, proteins, nucleic acids (e.g., DNA and RNA nucleotides) including, but not limited to, antisense nucleotide sequences, triple helices and nucleotide sequences encoding biologically active proteins, polypeptides or peptides), antibodies, synthetic or natural inorganic molecules, mimetics, and synthetic or natural organic molecules. Any agent that is known to be useful, or which has been used or is currently being used for the treatment of MDS, or the improvement of one or more symptoms associated with MDS, may be used in combination with a vitamin D compound in accordance with the invention described here. In certain embodiments, the compositions of the invention encompass the administration of a vitamin D compound of the invention in conjunction with one or more additional active agents that have combinatorial, synergistic, additive or other therapeutic effects. In one embodiment, a vitamin D compound of the invention can be administered with a growth factor such as a cytosine or a hematopoietic growth factor. In another embodiment, a vitamin D compound of the invention can be administered with an immunomodulator. In yet another embodiment, a vitamin D compound of the invention can be administered with a cytotoxic agent. In yet another embodiment, a vitamin D compound of the invention can be administered with an agent that affects the transcription of RNA. In yet another embodiment, a vitamin D compound of the invention can be administered with a vitamin A, E or K derivative. In yet another embodiment, a vitamin D compound of the invention can be administered with a specifically binding agent. to the biological objectives related to MDS. In yet another embodiment, a vitamin D compound of the invention can be administered with an inhibitor of signal transduction. In another modality more, a vitamin D compound of the invention can be administered with an aminothiol. In yet another embodiment, a vitamin D compound of the invention can be administered with an arsenic-containing compound. Additional embodiments of the invention encompass administration of the vitamin D compound of the invention in conjunction with more than one of the active agents described herein.

Growth factors or cytokines In one embodiment of the invention, a vitamin D compound of the invention can be administered with a growth factor. Any growth factor known to a person skilled in the art, which is effective in treating MDS, or improving a symptom thereof, can be administered with a vitamin D compound to a subject in need of such administration. In a further embodiment of the invention, one or more growth factors known to a person skilled in the art, which is effective to treat MDS, or ameliorate a symptom thereof, can be administered with a vitamin D compound and one or more additional active agents as described herein. Examples of growth factors that can be used in the various embodiments of the invention, including pharmaceutical compositions, dosage forms, and kits of the invention, include, without limitation, cytokines or hematopoietic growth factors such as, for example, EPO, TPO, GM-CSF, G-CSF, IFN-alpha, IL-1, IL-2, IL-3, IL-6, IL-8, IL-11 and IL-12. In addition, the recombinant, modified, mimetic, fragmentary or analogous forms of the cytokines or hematopoietic growth factors described above can also be used in the various embodiments of the invention. See, for example, United States Patents Nos. 6,358,505, 6,346.51, 6,340,742, 6,262,253, 6,261,550, 6,166,183, 6,100,070, 5,986,047, 5,981,551, 5,916,773, 5,902,584, 5,835,382, 5,824,778, 5,773,581, 5,773,569 and 5,756,349, all of which describe the recombinant, modified, mimetic, fragmentary or analogous forms of EPO and G-CSF and each of which is incorporated by reference herein, in its entirety. Preferred cytokines or hematopoietic growth factors include r-HuEPO and r-metHuG-CSF. An example of a commercial form of r-HuEPO is Epogen®, which is produced by recombinant DNA technology and has the same biological effects and the same amino acid sequence as endogenous erythropoietin. One dosage form of 1 ml of Epogen® can contain 2000, 3000, 4000 or 10,000 Units of epoetin alfa, 2.5 mg of albumin (human), 1.2 mg of monobasic sodium phosphate, monohydrate, 1.8 mg of anhydrous dibasic sodium phosphate , 0.7 mg of sodium citrate, 5.8 mg of sodium chloride, and 6.8 mg of citric acid, in water for injection, USP (pH 6.9 ± 0.3). The multiple dose forms of Epogen® are available, and all dosage forms are in bottles for parenteral administration. See Physicians' Desk Reference 582 (56th ed., 2002). An example of a commercial form of r-metHuG-CSF, also known as filgrastim, is Neupogen®, which is produced by recombinant RNA technology in E. coli, and differs from G-CSF isolated from human cells in that it is not glycosylated A dosage form of 1 ml of Neupogen® can contain 300 μg of filgrastim, 0.59 mg of acetate, 50.0 mg of sorbitol, 0.004% of Tween® 80, 0.035 mg of sodium and 1.0 ml of water for injection, USP. Larger dosage forms of Neupogen® are available, and all dosage forms are in bottles for parenteral administration. See Id. In 588.

Immunomodulators In yet another embodiment of the invention, a vitamin D compound of the invention can be administered with an immunomodulator. The immunomodulator can be any immunomodulator known to one of skill in the art that is effective in treating MDS, or improving a symptom thereof. In a further embodiment of the invention, one or more immunomodulators known to a person skilled in the art, which are effective in treating MDS or ameliorating a symptom thereof, can be administered to a subject with a vitamin D compound and one or more additional active agents described herein. Examples of immunomodulators that can be used in the various embodiments of the invention, including pharmaceutical compositions, dosage forms, and kits of the invention include, without limitation, anti-thymocyte globulin (ATG). , anti-lymphocyte globulin (ALG), thalidomide, predinosone, cyclosporin A (CyA for its acronym in English), dexamethasone and pentoxifylline.

Cytotoxic Agents In yet another embodiment of the invention, a vitamin D compound of the invention can be administered with a cytotoxic agent. The cytotoxic agent can be any cytotoxic agent known to a person skilled in the art, which is effective to treat MDS, or ameliorate a symptom thereof. In a further embodiment of the invention, one or more cytotoxic agents known to a person skilled in the art, which is effective to treat MDS, or ameliorate a symptom thereof, can be administered to a subject with a vitamin D compound and one or more additional active agents, as described herein. Any cytotoxic agent can be used according to the methods of the invention; many suitable cytotoxic agents for MDS chemotherapy or cancer in general are known in the art. For example, the cytotoxic agent can be an anti-metabolite (e.g., 5-fluorouracil (5-FU)), methotrexate (MTX), fludarabine, etc.), an anti-microtubule agent (e.g., vincristine; vinblastine; taxanes such as paclitaxel and docetaxel, etc.), an alkylating agent) (eg, cyclophosphamide, melphalan, bischloroethylnitrosourea, etc.), platinum agents (eg, cisplatin, carboplatin, oxaliplatin, JM-216, CI- 973, etc.), anthracyclines (eg, doxorubicin, daunorubicin, etc.), antibiotic agents (eg, mitomycin C, actinomycin D, etc.), topoisomerase inhibitors (e.g., etoposide, camptothecins, etc.), or other cytotoxic agents. Particular examples of cytotoxic agents that can be used in the various embodiments of the invention, including the pharmaceutical compositions, dosage forms, and kits of the invention, include, without limitation, cytarabine, melphalan, topotecan, fludarabine, etoposide, idarubicin, daunorubicin, mitoxantrone, cisplatin, paclitaxel and cyclophosphamide.

Other Therapeutic Agents for MDS In yet another embodiment of the invention, a vitamin D compound of the invention can be administered with an agent that affects RNA transcription. The agent that affects RNA transcription can be any agent that affects the transcription of RNA, known to a person skilled in the art as effective in treating MDS, or improving a symptom thereof. In a further embodiment of the invention, one or more agents that affect RNA transcription known to a person skilled in the art as effective in treating MDS, or ameliorating a symptom thereof, can be administered to a subject with a compound of vitamin D and one or more additional active agents as described herein. Non-limiting examples of an agent that affects the transcription of RA that can be used in the various embodiments of the invention, including the pharmaceutical compositions, dosage forms and kits of the invention, include decitabine, 5-azacytidine, depsipeptides and phenylbutyrate. In yet another embodiment of the invention, a vitamin D compound of the invention can be administered with a vitamin A, E or K derivative. The vitamin A, E or K derivative can be any vitamin A, E or K derivative. known to a person skilled in the art as effective in treating MDS, or improving a symptom thereof. In a further embodiment of the invention, one or more vitamin A, E or K derivatives known to a person skilled in the art, which is effective to treat MDS, or ameliorate a symptom thereof, can be administered to a subject with a vitamin D compound and one or more additional active agents as described herein. Non-limiting examples of a vitamin A, E or K derivative that can be used in the various embodiments of the invention, including the pharmaceutical compositions, dosage forms and kits of the invention, include all-trans-retinoic acid, 13-cis-retinoic acid, tocopherol and menatetrenone. In yet another embodiment of the invention, a vitamin D compound of the invention can be administered with an agent that specifically binds to biological targets related to MDS. The agent that specifically binds to biological targets related to MDS can be any agent that specifically binds to biological targets related to MDS known to a person skilled in the art, that are effective in treating MDS, or ameliorating a symptom thereof. In a further embodiment of the invention, one or more agents that specifically bind to biological targets related to MDS known to a person skilled in the art to be effective in treating MDS, or ameliorating a symptom thereof, can be administered to a patient. subject with a vitamin D compound and one or more additional active agents as described herein. Non-limiting examples of an agent that specifically binds to the biological targets related to MDS that can be used in the various embodiments of the invention, including the pharmaceutical compositions, dosage forms, and kits of the invention, include anti- VEGF, gemtuzumab ozogamicin, and T FR: Fe. In yet another embodiment of the invention, a vitamin D compound of the invention can be administered with a signal transduction inhibitor. The signal transduction inhibitor can be any inhibitor of signal transduction, known to a person skilled in the art as effective in treating MDS, or improving a symptom thereof. In a further embodiment of the invention, one or more signal transduction inhibitors, known to a person skilled in the art, which is effective to treat MDS or ameliorate a symptom thereof, can be administered to a subject with a compound of vitamin D and one or more additional active agents as described herein. Non-limiting examples of such signal transduction inhibitors that can be used in various embodiments of the invention, including the pharmaceutical compositions, dosage forms, and kits of the invention, include the farnesyl transferase inhibitors such as for example Zarnestra ™ and Sarasar1® and tyrosine kinase inhibitors such as, for example, SU5416, SU6668 and PTK787 / ZK222584. In yet another embodiment of the invention, a vitamin D compound of the invention can be administered with an aminothiol. The aminothiol can be any aminothiol known to a person skilled in the art, which is effective in treating MDS, or improving a symptom thereof. In a further embodiment of the invention, one or more aminothiols known to a person skilled in the art, which is effective to treat MDS, or ameliorate a symptom thereof, can be administered to a subject with a vitamin D compound and one or more additional active agents as described herein. A non-limiting example of an aminothiol which can be used in the various embodiments of the invention, including pharmaceutical compositions, dosage forms and kits of the invention, is amifostine. In yet another embodiment of the invention, a vitamin D compound of the invention can be administered with an arsenic-containing compound. The arsenic-containing compound can be any compound containing arsenic, known to a person skilled in the art, which is effective in treating MDS or improving a symptom thereof. In a further embodiment of the invention, one or more arsenic-containing compounds, known to a person skilled in the art, which is effective to treat MDS or ameliorate a symptom thereof, can be administered to a subject with a compound of vitamin D and one or more additional active agents as described herein. A non-limiting example of an arsenic-containing compound that can be used in the various embodiments of the invention, including pharmaceutical compositions, dosage forms and equipment of the invention is arsenic trioxide.

METHODS FOR TREATING MYELODISPLASTIC SYNDROMES The invention provides methods for treating MDS, or improving a symptom thereof, in a subject in need of such treatment or improvement. This- also covers methods for treating subjects who have been previously treated for MDS, as well as those who have not been previously treated for MDS. Because subjects with MDS have heterogeneous clinical manifestations and varying clinical signs, it has become apparent that it is necessary to classify subjects according to their prognosis and therapeutic approach depending on the severity and stage. Of course, the methods of this invention can be used in various treatment stages for subjects with one or more types of MDS, including but not limited to refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with blasts in excess (RAEB), RAEB in transformation (RAEB-T), or chronic myelomonocytic leukemia (CMML). In addition, the methods of the invention can be used in various stages of treatments for subjects with one or more types of MDS including, but not limited to, low risk MDS, intermediate risk 1, intermediate risk 2, or high risk. The present invention provides methods for therapeutically administering effective doses of the vitamin D compounds, while minimizing the risk of hypercalcemia for the treatment of myelodysplastic syndromes, the improvement of a symptom thereof. In certain embodiments, the methods comprise administering a therapeutically effective dose of the vitamin D compounds in the treatment of MDS, or the amelioration of a symptom thereof. In additional embodiments, the methods incorporate administration of the vitamin D compounds intermittently at high doses. Intermittent administration of the vitamin D compounds allows high doses to be administered to a subject, while minimizing or eliminating hypercalcemia. In additional embodiments, the methods incorporate the use of oral formulations of the vitamin D compound. In other embodiments, the methods incorporate the use of oral, stable, vitamin D compound formulations with improved bioavailability and rapid onset of blood levels. maximums of the vitamin D compounds. In other additional embodiments, the methods incorporate the use of oral formulations of the vitamin D compound in the form of a pre-concentrate emulsion. In other embodiments, the methods incorporate the use of intravenous (i.v.) formulations of the vitamin D compound. In certain embodiments, the vitamin D compounds are administered as a monotherapy. In other embodiments, the vitamin D compounds and formulations are administered in combination with one or more additional active agents. In other embodiments, the vitamin D compounds and formulations are administered in combination with one or more hematopoietic growth factors or cytokines. In certain embodiments, the methods of the invention encompass the administration of a therapeutically effective dose of the vitamin D compounds while minimizing the risk of hypercalcemia, for the treatment of myelodysplastic syndromes, or the improvement of a symptom of the same. In certain embodiments, the methods of the invention encompass the administration of a therapeutically effective dose of the vitamin D compounds for the treatment of anemia associated with MDS. In other embodiments, the methods of the invention encompass the administration of a therapeutically effective dose of the vitamin D compounds to increase the plasma concentrations of hemoglobin of a subject with MDS. In other additional embodiments, the methods of the invention encompass the administration of a therapeutically effective dose of the vitamin D compounds to reduce the transfusion requirements of a subject with MDS. In other modalities, the methods of the invention encompass the administration of a therapeutically effective dose of vitamin D compounds for the treatment of thrombocytopenia associated with MDS. In other embodiments, the methods of the invention encompass administration of a therapeutically effective dose of the vitamin D compounds to reduce fatigue of a subject with MDS. In other embodiments, the methods of the invention encompass the administration of a therapeutically effective dose of vitamin D compounds to decrease the frequency and severity of contusions of a subject with MDS. In other embodiments, the methods of the invention encompass the administration of a therapeutically effective dose of vitamin D compounds to reduce the frequency and severity of bleeding episodes of a subject with MDS. In other embodiments, the methods of the invention encompass the administration of a therapeutically effective dose of vitamin D compounds to reduce the frequency and severity of fevers suffered by a subject with MDS. In other embodiments, the methods of the invention encompass the administration of a therapeutically effective dose of vitamin D compounds for the treatment of neutropenia associated with MDS. In other embodiments, the methods of the invention encompass the administration of a therapeutically effective dose of vitamin D compounds to reduce the frequency and severity of infections in a subject with MDS. In other embodiments, the methods of the invention encompass the administration of a therapeutically effective dose of vitamin D compounds to delay the progression of MDS to leukemia in a subject with MDS. In other embodiments, the methods of the invention encompass the administration of a therapeutically effective dose of vitamin D compounds to extend the survival of a subject with MDS. Without intending to be compromised by any particular theory or mechanism of action, it is believed that vitamin D compounds and other effective therapeutic agents for treating MDS may act in complementary or synergistic ways in the treatment of MDS, or the improvement of a symptom of the same. Therefore, one embodiment of the invention encompasses a method for treating MDS, or improving a symptom thereof, which comprises administering to a patient in need of such treatment and / or improvement, a therapeutically effective dose of a vitamin D compound. , or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in a therapeutically effective dose of one or more additional active agents, as described herein. A person of skill in the art will recognize that any of the methods of treatment described herein may be further utilized for the prevention of the onset or recurrence of MDS in a subject in whom such prevention is desired.

Administration and Dosage of the Compounds of Vitamin D in the Treatment of the Syndrome Myelodysplastic The high systemic levels of the vitamin D compounds can be achieved without the onset of hypercalcemia, by intermittently administering the vitamin D compounds according to the methods of the invention. High doses of vitamin D compounds include doses greater than about 3 as discussed in the following sections. Therefore, in certain embodiments of the invention, methods for the treatment of MDS, or the improvement of a symptom thereof, encompass intermittently administering high doses of vitamin D compounds. High doses of vitamin D compounds can be administered before, concurrently with, after or in cycles with other therapies, including but not limited to pharmacotherapy. The administration of the vitamin D compounds can also occur in cyclic regimes such that the administration of the vitamin D compound can occur before, concurrently with, after, or at any cyclic regimen with other treatments within a cyclic series of such treatments. The frequency of intermittent administration may be limited by a number of factors, including but not limited to the pharmacokinetic parameters of the compound or formulation and the pharmacodynamic effects of the vitamin D compound on the subject. For example, subjects with MDS who have impaired renal function may require less frequent administration of vitamin D compounds because of the decreased ability of those subjects to excrete calcium. The following is exemplary only and serves merely to illustrate that the term "intermittent" may encompass any administration regime designed by a person of ordinary skill in the art. In one example, the vitamin D compound can be administered no more than once every three days. Administration can continue for one, two, three or four weeks or one, two, three, four, five or six months, or one year, or longer. In certain embodiments, the vitamin D compound can be administered until the anemia associated with MDS is improved. Optionally, after a rest period, the vitamin D compound can be administered under the same or a different scheme. The rest period may be one, two, three or four weeks, or longer, according to the pharmacokinetic effects of the vitamin D compound on the subject. In yet another example, the vitamin D compound can be administered no more than once every four days.

The administration may continue for one, two, three or four weeks or - one, "two, three, four, five or six months, or one year, or longer." In certain modalities, the vitamin D compound may be administered until the anemia associated with MDS is improved.Optionally, after a rest period, the vitamin D compound can be administered under the same or a different scheme.The rest period can be one, two, three or four weeks, or longer, according to the pharmacokinetic effects of the vitamin D compound on the subject.In yet another example, the vitamin D compound can be administered no more than once every five days.The administration may continue for one, two, three or four weeks or one, two, three, four, five or six months, or one year, or longer.In certain modalities, the vitamin D compound can be administered until the anemia associated with MDS is improved. after a period of decay nso, the vitamin D compound can be administered under the same or a different scheme. The rest period may be one, two, three or four weeks, or longer, according to the pharmacokinetic effects of the vitamin D compound on the subject. In yet another example, the vitamin D compound can be administered no more than once every six days. The administration can continue for one, two, three or four weeks or one, two, three, four, five or six months, or a year, or longer. In certain embodiments, the vitamin D compound can be administered until the anemia associated with MDS is improved. Optionally, after a rest period, the vitamin D compound can be administered under the same or a different scheme. The rest period may be one, two, three or four weeks, or longer, according to the pharmacokinetic effects of the vitamin D compound on the subject. In yet another example, the vitamin D compound can be administered no more than once every seven days. Administration can continue for one, two, three or four weeks or one, two, three, four, five or six months, or one year, or longer. In certain embodiments, the vitamin D compound can be administered until the anemia associated with MDS is improved. Optionally, after a rest period, the vitamin D compound can be administered under the same or a different scheme. The rest period may be one, two, three or four weeks, or longer, according to the pharmacokinetic effects of the vitamin D compound on the subject. In another example, the vitamin D compound can be administered no more than once every eight days. Administration can continue for one, two, three or four weeks or one, two, three, four, five or six months, or one year, or longer. In certain embodiments, the vitamin D compound can be administered until the anemia associated with MDS is improved. Optionally, after a rest period, the vitamin D compound can be administered under the same or a different scheme. The rest period may be one, two, three or four weeks, or longer, according to the pharmacokinetic effects of the vitamin D compound on the subject. In yet another example, the vitamin D compound can be administered no more than once every nine days. Administration can continue for one, two, three or four weeks or one, two, three, four, five or six months, or one year, or longer. In certain embodiments, the vitamin D compound can be administered until the anemia associated with MDS is improved. Optionally, after a rest period, the vitamin D compound can be administered under the same or a different scheme. The rest period may be one, two, three or four weeks, or longer, according to the pharmacokinetic effects of the vitamin D compound on the subject. In yet another example, the vitamin D compound can be administered no more than once every ten days. Administration can continue for one, two, three or four weeks or one, two, three, four, five or six months, or one year, or longer. In certain embodiments, the vitamin D compound can be administered until the anemia associated with MDS is improved. Optionally, after a rest period, the vitamin D compound can be administered under the same or a different scheme. The rest period may be one, two, three or four weeks, or longer, according to the pharmacokinetic effects of the vitamin D compound on the subject. In yet another example, the vitamin D compound can be administered once a week for three months. Optionally, after a rest period, the vitamin D compound can be administered under the same or a different scheme. The rest period may be one, two, three or four weeks, or longer, according to the pharmacodynamic effects of the vitamin D compound on the subject. In yet another example, the vitamin D compound can be administered once every three weeks for one year. Optionally, after a rest period, the vitamin D compound can be administered under the same or a different scheme. The rest period may be one, two, three or four weeks, or | longer, according to the pharmacodynamic effects of the vitamin D compound on the subject. In a preferred example, the vitamin D compound can be administered once a week for 3 weeks of each 4 week cycle. After a period of one week of rest, the vitamin D compound can be administered under the same or a different scheme. Additional examples of the dosage scheme that can be used in the methods of the present invention are provided in U.S. Patent No. 6,521,608, which is incorporated by reference herein in its entirety. The administration schemes described above are provided for illustrative purposes only, and should not be considered as limiting. A person of ordinary skill in the art will readily understand that all vitamin D compounds are within the scope of the invention; that calcitriol and its analogs, homologs, derivatives, precursors and vitamin D compounds are preferred; and that the exact dose and schedule of administration of the vitamin D compounds may vary due to many factors. The amount of a therapeutically effective dose of a pharmaceutical agent in the acute or chronic management of a disease or disorder may vary depending on factors including, but not limited to, the disease or disorder being treated, the specific pharmaceutical disorders and the administration route. According to the methods of the invention, a therapeutically effective dose of a Vitamin D compound is any dose of the vitamin D compound effective to treat MDS or ameliorate a symptom thereof. A high dose of a vitamin D compound can be a dose of about 3 μ9 to about 300 g or any dose within these ranges as discussed below. The dose, dose frequency, duration or any combination may also vary according to the subject's age, body weight, response and past medical history, as well as the route of administration, pharmacokinetic effects and pharmacodynamics of the pharmaceutical agent. These factors are routinely considered by a person skilled in the art. The rates of absorption and clearance of the vitamin D compounds are affected by a variety of factors that are well known to those of ordinary skill in the art. As discussed above, the pharmacokinetic properties of vitamin D compounds limit the maximum concentration of vitamin D compounds that can be obtained in the blood, without inducing the onset of hypercalcemia and preferably without inducing the onset of clinical hypercalcemia. The speed and degree of absorption, distribution, binding or localization in the tissues, biotransformation and excretion of the vitamin D compound can all affect the frequency at which the pharmaceutical agent can be administered. In certain embodiments, the vitamin D compounds are administered intermittently in high doses as a method of treatment of MDS, or the improvement of a symptom thereof, according to the dosage scheme described above. In certain embodiments of the invention, the methods comprise administering a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof in a dose of about 3, 4, 5, 6, 7, 8 , 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 76, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125 , 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250 , 255, 260, 265, 270, 275, 280, 285, 290, 295 or 300 μg, or any dose range in these. In certain embodiments, the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof in a dose of about 0.12 μg / kg to about 3 μg. / kg. In other embodiments, the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof in a dose of about 3 pg / kg to about 300 pg. / kg. In other embodiments, the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof in a dose of about 5 pg / kg to about 200 g. / kg. In other embodiments, the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof in a dose of about 5 pg / kg to about 105 pg. / kg. In other embodiments, the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof in a dose of about 15 μg / kg to about 105 pg. / kg. In other embodiments, the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof in a dose of about 15 pg / kg to about 90 g. / kg. In other embodiments, the methods of the invention comprise administering a dose of a vitamin D compound, or a salt, solvate, hydrate, stereoisomer, clathrate or prodrug 7.9 pharmaceutically acceptable thereof in a dose of about 20 μ9 / 1¾ to about 80 μ9 /? 9. In other embodiments, the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof in a dose of about 30 9 / L "? to approximately 60 μg / kg. In other embodiments, the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof in a dose of about 30 gfkq to about 75 μg / kg. . In other embodiments, the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof in a dose of about 45 μg / kg. A person skilled in the art will recognize that these standard doses are for an adult of average size of approximately 70 kg, and can be adjusted for the factors routinely considered as stated above. While not intended to be compromised by any particular theory or mechanism of action, it is believed that doses of vitamin D compounds of up to 105 μg can be administered without substantially increasing the half-life and -the associated toxicity of the vitamin compounds. D. Therefore, in a preferred embodiment, the dose of the vitamin D compound is 105 xq or less. In certain embodiments, the methods of the invention comprise administering a dose of a vitamin D compound or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof in a dose that reaches maximum plasma concentrations of the vitamin D compound of approximately 0.1 nM, 0.2 nM, 0.3 nM, 0.4 nM, 0.5 nM, 0.6 nM, 0.7 nM, 0.8 nM, 0.9 nM, 1 nM, 2 nM, 3 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, 10 nM, 12 nM, 15 nM, 17 nM, or 20 nM, or any concentration range in these. In other embodiments, the methods of the invention comprise administering a dose of a vitamin D compound or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in a dose that reaches maximum plasma concentrations of the vitamin D compound. that exceed 0.5 nM. In other embodiments, the methods of the invention comprise administering a dose of a vitamin D compound or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in a dose that reaches maximum plasma concentrations of the vitamin D compound. from about 0.5 nM to about 20 nM. In other embodiments, the methods of the invention comprise administering a dose of a vitamin D compound or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in a dose that reaches maximum plasma concentrations of the vitamin D compound. from about 1 nM to about 10 nM. In other embodiments, the methods of the invention comprise administering a dose of a vitamin D compound or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in a dose that reaches maximum plasma concentrations of the vitamin D compound. from about 1 nM to about 7 nM. In other embodiments, the methods of the invention comprise administering a dose of a vitamin D compound or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in a dose that reaches maximum plasma concentrations of the vitamin D compound. from about 3 nM to about 7 nM. In other embodiments, the methods of the invention comprise administering a dose of a vitamin D compound or a salt, solvate, hydrate, stereoisomer, clathrate or pharmaceutically acceptable prodrug thereof, in a dose reaching maximum plasma concentrations of the vitamin D compound from about 5 nM to about 7 nM. In other embodiments, the methods of the invention comprise administering a dose of a vitamin D compound or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in a dose that reaches maximum plasma concentrations of the vitamin compound. D from about 3 riM to about 5 nM. In certain embodiments, the methods of the invention further comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof which rapidly reaches peak plasma concentrations, for example four hours. In further embodiments, the methods of the invention comprise administering a dose of a vitamin D compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof that is rapidly eliminated, for example, with a half-life of elimination less than 12 hours. In other aspects, the methods of the invention encompass administering intermittently high doses of vitamin D compounds to a subject with MDS and monitoring the subject for symptoms associated with hypercalcemia. In certain embodiments, the methods of the invention encompass administering intermittently high doses of vitamin D compounds to a subject with MDS and monitoring the renal function of the subject. In other embodiments, the methods of the invention encompass administering intermittently high doses of vitamin D compounds to a subject with MDS and monitoring the subject for calcification of soft tissues, such as, for example, cardiac tissue. In other embodiments, the methods of the invention encompass administering intermittently high doses of vitamin D compounds to a subject with MDS and monitoring the subject for increased bone density. In other embodiments, the methods of the invention encompass administering intermittently high doses of vitamin D compounds to a subject with MDS and monitoring the subject for hypercalcemic nephropathy. In other embodiments, the methods of the invention encompass intermittently administering high doses of vitamin D compounds to a subject with MDS and monitoring the subject's blood calcium concentration to ensure that the blood calcium level is less than about 10.5 mg / dL. In certain modalities, high blood levels of vitamin D compounds can be safely obtained in conjunction with reduced calcium transport to the blood. In one embodiment, higher concentrations of 1, 25-dihydroxy-vitamin D are obtainable safely without the onset of hypercalcemia, when administered in conjunction with a diet low in calcium. In one example, calcium can be trapped by an adsorbent, absorber, ligand, chelate or other binding portion that can not be transported into the blood through the small intestine. In yet another example, the activation rate of the osteoclasts can be inhibited by the administration, for example, of a bisphosphonate such as, for example, pamidronate, or ZOMETA (Novartis Pharmaceuticals Corp., East Hanover, NJ) in conjunction with the Vitamin D compound. In certain modalities, high blood levels of vitamin D compounds are safely obtained in conjunction with maximizing the rate of calcium clearance. In one example, the excretion of calcium can be increased by ensuring adequate hydration and adequate salt intake. In yet another example, diuretic therapy can be used to increase calcium excretion.

Administration of Vitamin D Compounds in Combination with other Therapeutic Agents The methods of the present invention also provide the combination therapies comprising administering one or more vitamin D compounds in combination with one or more additional active agents that are not vitamin D compounds. The additional active agents can be any agents having a therapeutic effect for treating MDS, or improving a symptom thereof, which are known to a person skilled in the art, without limitation. The proposed mechanisms for these active agents can be found in the art (see, for example, Hardman et al., Eds., 1996, Goodman &Gilman's The Pharmacological Basis of Therapeutics 10th Ed., McGraw-Hill, New York at pages 643-754, 1381-1484, 1649-1678, and Physician's Desk Reference (PDR) 55th Ed., 2001, Medical Economics Co., Inc., Montvale, NJ In certain embodiments, combination therapies of the present invention comprise administering one or more additional active agents which improve the therapeutic effects of the vitamin D compounds by producing a synergistic or additive effect In accordance with the present invention, the combination therapies are advantageously used for the treatment of MDS, or the improvement of a symptom of the same One or more compounds of vitamin D can be administered before (for example, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours , 48 hours, 5 days, 1 week, 2 weeks, 1 month or more before), after (for example, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 5 days, 1 week, 2 weeks, 1 month or more after), concurrently with, or in any cyclical regime involving the administration of one or more additional active agents. In embodiments where additional active agents are administered less frequently than vitamin D compounds, one or more vitamin D compounds are preferably administered about one day before one or more additional active agents. In certain embodiments, additional active agents that are not vitamin D compounds may be one or more growth factors. The growth factors can be administered before, concurrently with, after or in cycles with a vitamin D compound in the methods of the present invention, to benefit from the ability of the vitamin D compound to sensitize the cells to the actions of the growth factors. In this way, less growth factor can be used in the treatment of MDS, or the improvement of a symptom of the same. In other modalities, cyclic therapy is used to inhibit the development of resistance or reduce resistance to one or more of the therapies, to avoid or reduce the side effects of the therapies and / or to improve the effectiveness of the treatments. In certain modalities, one more growth factor can be cytokines. The cytokines can be administered before, concurrently with, after or in cycles with a vitamin D compound, according to the methods of the present invention. In other embodiments, one or more growth factors may be hematopoietic growth factors. Hematopoietic growth factors can be administered before, concurrently with, after or in cycles with a vitamin D compound according to the methods of the present invention. In certain embodiments, the hematopoietic growth factor administered before, concurrently with, after or in cycles with a vitamin D compound may be EPO, for example, rHuEPO, or a pharmacologically active mutant or derivative thereof. In other embodiments, the hematopoietic growth factor that can be administered before, concurrently with, after or in cycles with a vitamin D compound can be G-CSF, for example., r-metHuG-CSF, or a mutant or pharmacologically active derivative thereof. In other embodiments, the hematopoietic growth factors that can be administered before, concurrently with, after or in cycles with a vitamin D compound can be a combination of EPO and HuG-CSF, or the mutants or pharmacologically active derivatives thereof. In other embodiments, the vitamin D compound can be administered as a preconcentrate emulsion in combination with EPO, G-CSF or a mutant or pharmacologically active derivative thereof, or a combination thereof. In certain embodiments, the range of a r-HuEPO, or a mutant or pharmaceutically active derivative thereof, administered to a subject to treat MDS, or to improve an 8 symptom thereof, it can be from about 1 Unit / kg to about 2000 Units / kg three times a week (TIW), preferably from about 10 Units / kg to about 1000 Units / kg TIW, and more preferably from approximately 25 Units / kg to approximately 500 Units / kg of TIW. In other embodiments, r-HuEPO can be administered to a subject to treat MDS, or improve a symptom thereof, at a dose of about 1, 10, 20, 50, 100, 200, 300, 400, 500, 750, 1000, 1250, 1500, 1750, 2000 Units / kg or any dose interval in these. In other embodiments, r-HuEPO can be administered in combination with one or more vitamin D compounds, wherein one or more vitamin D compounds are administered according to the doses and schedules described herein. In certain embodiments, the range of r-metHuG-CSF, or a mutant or pharmacologically active derivative thereof, administered to a subject to treat MDS, or ameliorate a symptom thereof, may be from about 1 μg / kg / day to about 100 μg / kg / day, preferably "from about 3 μg / kg / day to about 75 M € f / kg / day, and more preferably from about 5 lg / kg / day to about 50 μg / kg / day. other embodiments, r-metHuG-CSF can be administered to a subject to treat DS, or improve a symptom thereof, at a dose of about 1, 5, 10, 20, 30, 40, 50, 60, 70, 80 , 90, 100 g / kg or any dose range in these In other embodiments, r-metHuG-CSF or a mutant or pharmacologically active derivative thereof, may be administered in combination with one or more vitamin D compounds, in where one or more vitamin D compounds are administered according to the doses and schedules described in p In other embodiments, a vitamin D compound can be administered in combination with r-HuEPO, r-metHuG-CSF, a mutant or pharmacologically active derivative thereof, or a combination thereof, wherein r-HuEPO, r-metHuG-CSF, or its mutants or pharmacologically active derivatives, are administered in the doses described above, respectively. In certain embodiments, the hematopoietic growth factor is r-HuEPO and is administered before, concurrently with, after or in cycles with the administration of a vitamin D compound, wherein the administration interval of r-HuEPO is approximately 50 Units / kg up to approximately 100 Units / kg of TIW. In other embodiments, the hematopoietic growth factor is r-metHuG-CSF and is administered before, concurrently with, after or in cycles with a vitamin D compound, wherein the administration interval of r-metHuG-CSF is about 5. μg / kg / day to approximately 25 ug / kg / day. In other embodiments, the hematopoietic growth factors are a combination of r-HuEPO and r-metHuG-CSF and are administered before, concurrently with, after or in cycles with a vitamin D compound, wherein the administration interval is about 25 Units / kg up to approximately 500 Units / kg TIW for r-HuEPO and from approximately 5 μg / kg / day to approximately 25 ^ fk ^ / á-a. for r-metHuG-CSF. In other embodiments, the growth factor administered before, concurrently with, after or in cycles with a vitamin D compound may be one of IL-1, IL-2, IL-3, IL-4, IL-6, IL- 8, IL-11, IL-12, IFN-alpha, GM-CSF, TPO or a mutant or pharmacologically active derivative thereof. In other additional embodiments, the growth factors administered before, concurrently with, after or in cycles with a vitamin D compound may be more than one of IL-1, IL-2, IL-3, IL-4, IL-6. , IL-98, IL-11, IL-12, IFN-alpha, GM-CSF, TPO, or a mutant or pharmacologically active derivative thereof. In other embodiments, the vitamin D compound can be administered as a pre-concentrate emulsion in combination with one or more of r-HuEPO, r-metHuG-CSF, IL-1, IL-2, IL-3, IL-4, IL-6, IL-8, IL-11, IL-12, IFN-alpha, GM-CSF, TPO, a mutant or pharmacologically active derivative thereof, or a combination thereof. In other embodiments, additional active agents that are not vitamin D compounds can be immunomodulatory. The immunomodulators may be administered before, concurrently with, after or in cycles with a vitamin D compound according to the methods of the present invention. In certain embodiments, the immunomodulator may be one of ATG, ALG, thalidomide, prednisone, CyA, dexamethasone, or pentoxifylline. In other embodiments, the immunomodulators may be more than one ATG, ALG, thalidomide, prednisone, CyA, dexamethasone or pentoxifylline. In other embodiments, the vitamin D compound can be administered as a preconcentrate in emulsion in combination with one or more of ATG, ALG, thalidomide, prednisone, CyA, dexamethasone, or pentoxifylline, or a combination thereof. In a particular embodiment, the immunomodulator is ATG, wherein the range of administration of ATG is from about 10 mg / kg / day to about 100 mg / kg / day. In a preferred embodiment, the immunomodulator is ATG, wherein the range of administration of ATG is from about 35 mg / kg / day to about 45 mg / kg / day. In another specific modality, the immunomodulator 9 is thalidomide, wherein the administration interval of thalidomide is from about 50 mg / day to about 500 mg / day. In a preferred embodiment, the immunomodulator is thalidomide, wherein the thalidomide administration range is from about 100 mg / day to about 400 mg / day. In other embodiments, additional active agents that are not vitamin D compounds can be cytotoxic agents. The cytotoxic agents can be administered before, concurrently with, after or in cycles with a vitamin D compound according to the methods of the present invention. In certain embodiments, the cytotoxic agent can be an antimetabolite, an anti-microtubule agent, an alkylating agent, a platinum agent, an anthracycline, an antibiotic agent, or a topoisomerase inhibitor. In other embodiments, the cytotoxic agents may be more than one of an antimetabolite, an anti-microtubule agent, an alkylating agent, a platinum agent, an anthracycline, an antibiotic agent, or a topoisomerase inhibitor. In other embodiments, the vitamin D compound can be administered as a pre-concentrate emulsion in combination with one or more than one of an antimetabolite, an anti-microtubule agent, an alkylating agent, a platinum agent, an anthracycline, an antibiotic agent, or a topoisomerase inhibitor. or a combination thereof. In additional embodiments, the cytotoxic agent can be one of cytarabine, melphalan, topotecan, fludarabine, etoposide, idarubicin, daunorubicin, mitoxantrone, cisplatin, paclitaxel or cyclophosphamide. In other embodiments, the cytotoxic agents may be more than one cytarabine, melphalan, topotecan, fludarabine, etoposide, idarubicin, daunorubicin, mitoxantrone, cisplatin, paclitaxel or cyclophosphamide. In other embodiments, the vitamin D compound can be administered as a pre-concentrate emulsion in combination with one or more of cytarabine, melphalan, topotecan, fludarabine, etoposide, idarubicin, daunorubicin, mitoxantrone, cisplatin, paclitaxel or cyclophosphamide, or a combination of them. In a particular embodiment, the cytotoxic agent is cytarabine, wherein the interval of administration of cytarabine is from about 10 mg / m2 / day to about 1 g / m2 / day. In a preferred embodiment, the cytotoxic agent is cytarabine, wherein the interval of administration of the cytarabine is from about 5 mg / m2 / day to about 20 g / m2 / day. In a particular embodiment, the cytotoxic agent is idarubicin, wherein the administration interval of idarubicin is from about 9 mg / m2 / day to about 18 g / m2 / day.

In another specific embodiment, the cytotoxic agent is melphalan, wherein the melphalan administration range is from about 1 mg / day to about 100 mg / day. In another specific embodiment, the cytotoxic agent is melphalan, wherein the melphalan administration range is from about 1 mg / day to about 5 mg / day. In a particular embodiment, the cytotoxic agent is topotecan, wherein the administration interval of the topotecan is from about 1 mg / m2 / day to about 100 g / m2 / day. In a particular embodiment, the cytotoxic agent is topotecan, wherein the administration interval of the topotecan is from about 1 mg / m2 / day to about 5 g / m2 / day. In still further embodiments, additional active agents that are not vitamin D compounds may be one or more agents that affect RNA transcription. Agents that affect RNA transcription can be administered before, concurrently with, after, or in cycles with a vitamin D compound according to the methods of the present invention. In certain embodiments, the agent that affects RNA transcription may be one of decitabine, 5-azacytidine, depsipeptides, or phenylbutyrate. In other modalities, the agents that affect the transcription of the RNA can be more than one of decitabine, 5-azacytidine, depsipeptides, or phenylbutyrate. In other embodiments, the vitamin D compound may be administered as a pre-concentrate emulsion in combination with one or more of decitabine, 5-azacytidine or depsipeptides, or a combination thereof. In a particular embodiment, the agent that affects RNA transcription is decitabine, wherein the interval of administration of decitabine is from about 10 mg / m2 / day to about 200 mg / m2 / day. In a particular embodiment, the agent that affects RNA transcription is decitabine, wherein the interval of administration of decitabine is from about 45 mg / m2 / day to about 100 mg / m2 / day. In another specific embodiment the agent that affects RNA transcription is 5-azacytidine, wherein the administration interval of 5-azacytidine is from about 5 mg / m2 / day to about 200 mg / m2 / day. In a preferred embodiment, the agent that affects RNA transcription is 5-azacytidine, wherein the range of administration of 5-azacytidine is from about 10 mg / m / day to about 75 mg / m2 / day. In other embodiments, additional active agents that are not vitamin D compounds can be vitamin A, E or K derivatives. The derivatives of vitamin A, E, or K can be administered before, concurrently with, after, or in cycles with a vitamin D compound according to the methods of the present invention. In certain embodiments, the vitamin A, E, or K derivative can be one of AT A, 13-cis-retinoic acid, tocopherol or menatetrenone. In other embodiments, vitamin A, E or K derivatives may be more than one of ATRA, 13-cis-retinoic acid, tocopherol or menatetrenone. In still other embodiments, the vitamin D compound can be administered as a pre-concentrate emulsion in combination with one or more of ATRA, 13-cis-retinoic acid, tocopherol or menatetrenone or a combination thereof. In a particular embodiment, the vitamin A derivative, and O K is ATRA, wherein the administration interval of ATRA is from about 10 mg / m2 / day to about 200 mg / m2 / day. In a preferred embodiment, the vitamin A, E or K derivative is ATRA, wherein the range of administration of ATRA is from about 25 mg / m2 / day to about 80 mg / m2 / day. In another specific embodiment, the vitamin A, E or K derivative is 13-cis-retinoic acid, wherein the administration interval of 13-cis-retinoic acid is from about 5 mg / m2 / day to about 200 mg / m2 / day. In another specific embodiment, the vitamin A, E or K derivative is 13-cis-retinoic acid, wherein the administration interval of 13-cis-retinoic acid is from about 10 mg / m2 / day to about 100 mg / m2 / day. In another specific embodiment, the vitamin A, E or K derivative is menatetrenone, wherein the administration interval of menatetrenone is from about 5 mg / day to about 200 mg / day. In a preferred embodiment, the vitamin A, E or K derivative is menatetrenone, wherein the administration interval of menatetrenone is from about 10 mg / day to about 100 mg / day. In another particular embodiment, the vitamin A, E or K derivative is tocopherol, wherein the administration range of the tocopherol is from about 400 IU / day to about 3000 IU / day. In one embodiment, the vitamin A, E or K derivative is tocopherol, wherein the range of administration of the tocopherol is from about 800 IU / day to about 2000 IU / day. In other embodiments, additional active agents that are not vitamin D compounds may be agents that specifically bind to biological purposes related to DS. Agents that specifically bind to biological targets related to MDS can be administered before, concurrently with, after, or in cycles with a vitamin D compound according to the methods of the present invention. In certain modalities, the age¾te that is specifically linked to the biological objectives related to MDS can be one of anti-VEGF, gemtuzumab ozogamicin, or TNFRrFc. In other embodiments, the agents that specifically bind to the biological targets related to MDS may be more than one of anti-VEGF, gemtuzumab ozogamicin, or TNFR: Fe. In other embodiments, the vitamin D compound can be administered as a pre-concentrate emulsion in combination with one or more of anti-VEGF, gemtuzumab ozogamicin, or TNFR: Fe, or a combination thereof. In a particular embodiment, the agent that specifically binds to the biological targets related to MDS is gemtuzumab ozogamicin, wherein the administration interval of gemtuzumab ozogamicin is from about 5 mg / m2 / week to about 20 mg / m2 / week. In other embodiments, additional active agents that are not vitamin D compounds may be inhibitors of signal transduction. Inhibitors of signal transduction can be administered before, concurrently with, after, or in cycles with a vitamin D compound according to the methods of the present invention. In certain embodiments, inhibitors of signal transduction may be one or more farnesyl transferase inhibitors. In other embodiments, the farnesyl transferase inhibitor may be one of Zarnestra "and Sarasar ™ 1. In other embodiments, the farnesyl transferase inhibitor may be more than one of Zarnestra1 and Sarasar." In other embodiments, the vitamin D compound can be administered as a pre-concentrate in emulsion in combination with one or more of Zarnestram and Sarasar "11 or a combination thereof In other embodiments, inhibitors of signal transduction can to be tyrosine kinase inhibitors Tyrosine kinase inhibitors can be administered before, concurrently with, after, or in cycles with a vitamin D compound according to the methods of the present invention In certain embodiments, the inhibitor of the tyrosine kinase can be one of SU5416, SU6668 or PT 787 / ZK22258. In other embodiments, the tyrosine kinase inhibitors can be more than one of SU5416, SU6668, or PTK787 / ZK222584. In other embodiments, the compound Vitamin D can be administered as a pre-concentrate emulsion in combination with one or more of SU5416, SU6668, PTK787 / ZK222584, or a combination thereof. Additional ingredients that are not vitamin D compounds can be aminothiols. The aminothiols can be administered before, concurrently with, after, or in cycles with a vitamin D compound according to the methods of the present invention. In a specific embodiment, aminothiol is amifostine. In another specific embodiment, the vitamin D compound can be administered as a pre-concentrate in combination with amifostine. In another particular embodiment, the aminothiol is amifostine, wherein the administration range of amifostine is from about 50 mg / m2 / day to about 600 mg / m2 / day when administered on multiple days, or about 600 mg / m2 up to approximately 1.2 mg / m2 when administered in a single dose. In a preferred embodiment, the aminothiol is amifostine, wherein the range of administration of amifostine is from about 100 mg / m2 to about 400 mg / m2 / day when administered on multiple days, or from about 740 mg / m2 to about 910 mg / m2 when administered in a single dose. In other embodiments, additional active agents that are not vitamin D compounds can be arsenic-containing compounds. Arsenic-containing compounds can be administered before, concurrently with, after, or in cycles with a vitamin D compound according to the methods of the present invention. In a specific embodiment, the arsenic-containing compound is arsenic trioxide. In another specific embodiment, the vitamin D compound can be administered as a pre-concentrate in emulsion in combination with arsenic trioxide.

Dosages, dose frequencies, and administration durations of any combination set forth above may also vary according to the subject's age, body weight, response, and medical history, as well as the route of administration, pharmacokinetic effects. and pharmacodynamics of the pharmaceutical agent. These factors are routinely considered by a person skilled in the art. Examples of other dosage schemes and factors considered by a person skilled in the art when designing a dosage scheme are discussed above.

METHODS OF ADMINISTRATION In the methods of the invention, the vitamin D compound can be administered by any method known to those skilled in the art. In certain embodiments, vitamin D compounds can be administered by any route known to a person skilled in the art who can achieve the rapid onset of peak plasma concentrations of vitamin D compounds. In other embodiments, vitamin D compounds they are administered orally, mucosally or parenterally. For example, mucosal administration of vitamin D compounds may include nasal, sublingual, vaginal, buccal or rectal administration, while parenteral administration of vitamin D compounds may include intravenous, intramuscular or intraarterial administration. Where the vitamin D compound is administered intravenously or intraarterially, the vitamin D compound can be administered either as a bolus injection or as an infusion in several minutes to hours. In preferred embodiments, the vitamin D compounds can be administered either orally or intravenously. The timing of the administration of the vitamin D compound may also vary. The vitamin D compound can be administered, notwithstanding the dosage form, as a co-therapy either before, concurrently with, after, or in cycles with the administration of one or more additional active agents. Administration of the vitamin D compounds and formulations may also appear in a cyclic treatment regimen such as administration of the vitamin D compound between or concurrently with other treatments within a cyclic series of these other treatments. In certain embodiments, the vitamin D compounds may be administered intermittently according to periodic continuous or non-continuous schedules. In addition, where the methods of the invention additionally comprise the administration of one or more additional active agents, the additional active agents can be administered by any method known to a person skilled in the art.

PHARMACEUTICAL FORMULATIONS OF VITAMIN D COMPOUNDS For use in the present invention, the pharmaceutical agent may comprise one or more vitamin D compounds or optionally one or more vitamin D compounds in combination with one or more additional active agents. The pharmaceutical agent can be administered in combination with one or more additional active agents as well, such as haematopoietic growth factors or cytokines in the treatment of MDS. The pharmaceutical agent can be in the form of any pharmaceutical formulation known to those skilled in the art. Typically, the pharmaceutical formulations and dosage forms of the present invention comprise at least one vitamin D compound or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. The pharmaceutical compositions and dosage forms of the invention may further comprise one or more excipients, diluents or any other components known to those skilled in the art and suitable for the formulation methods of the present invention. The pharmaceutical formulations and dosage forms of the present invention may further comprise other active ingredients that are not vitamin D compounds. In addition, the pharmaceutical formulations of the present invention can be used to prepare simple unit dosage forms. The composition, form and type of dosage forms may typically vary depending on their use. For example, a dosage form used in the acute treatment of a disease may comprise larger amounts of the pharmaceutical agents than a dosage form used in the chronic treatment of the same disease. Similarly, a parenteral dosage form can comprise smaller amounts of the pharmaceutical agents of an oral dosage form used to treat the same disease. These and other ways in which the specific dosage forms may vary will be readily apparent to those skilled in the art. See, for example, Remington's Phar aceutical Sciences, 18 ed. , Mack Publishing, Easton PA (1990). The dosage forms are suitable for oral administration; mucosal such as nasal, sublingual, vaginal, buccal or rectal; or parenteral such as 5 intravenous, intramuscular or intraarterial administration. Where the vitamin D compound is administered intravenously or intraarterially, the vitamin D compound can be administered either as a bolus injection or as an infusion in several minutes to hours. Examples of dosage forms include but are not limited to tablets, capsules such as hard and soft gelatin capsules, sachets, troches, lozenges, dispersions, suppositories, ointments, poultices (plasters), pastes, powders, dressings, creams, solutions , patches, aerosols such as nasal sprays or inhalers, and gels. Liquid dosage forms suitable for oral or mucosal administration include, but are not limited to, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, water-in-oil emulsions, solutions and elixirs. Liquid doses include, but are not limited to, the reconstitution of sterile solids, which may be crystalline or amorphous, in liquid dosage forms suitable for parenteral administration. Preferred dosage forms of the present invention include oral dosage forms and intravenous dosage forms. Where the vitamin D compounds are administered intermittently orally, the vitamin D compounds are preferably administered in the form of pre-concentrates in emulsion. In a preferred embodiment of an oral dosage form of a vitamin D compound, the oral dosage form is a pre-concentrate emulsion of a vitamin D compound comprising approximately 15 μg of calcitriol in addition to the following excipients with the amount given in approximate percentage by weight: 65% of Migliol 812N®, 30% Gelucire 44 / 14®, 5% vitamin E TPGS and approximately 0.05% each of butylated idroxytoluene (BHT) and butylated hydroxyanisole (BHA). In the most preferred embodiment of an intravenous dosage form of a vitamin D compound, the intravenous dosage form is Calcijex, which may comprise 1 μg of calcitriol, 4 mg of Polysorbate 20, 2.5 mg of sodium ascorbate and optionally either HCl or NaOH for pH adjustment. Typical pharmaceutical formulations and dosage forms comprise one or more excipients. Suitable excipients are well known to those skilled in the art. Technical and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable or not for incorporation into a pharmaceutical formulation or dosage form, that depends on a variety of factors well known in the art including, but not limited to, the route by which the dosage form is administered. . In one example, oral dosage forms such as tablets may contain excipients not suitable for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific pharmaceutical agent in the dosage form. In certain embodiments, the pharmaceutical formulations and the dosage forms can be anhydrous, since water, as well as heat, can facilitate the degradation of some compounds. In this way, the effect of water as well as heat on a formulation can be of great significance since moisture is commonly found during the manufacture, handling, packaging, storage, shipping and use of the formulations. Anhydrous pharmaceutical formulations and anhydrous dosage forms can be prepared using ingredients that contain low moisture or anhydrous ingredients, and low humidity conditions. In a preferred embodiment, anhydrous pharmaceutical formulations are prepared, stored and packaged to preserve the anhydrous environment by using materials capable of preventing exposure to water and facilitating the production of suitable formulation equipment. Examples of suitable materials include, but are not limited to, hermetically sealed metallic papers, plastics, and unit dose containers such as flasks, blister packs, and packets in strips. In certain embodiments, the pharmaceutical formulations and dosage forms comprise one or more stabilizers, which are compounds that reduce the rate at which an active ingredient will decompose, and include but are not limited to antioxidants such as ascorbic acid, pH buffers , or saline shock absorbers. The pharmaceutical formulations of the present invention can be, for example, in a semi-solid formulation or in a liquid formulation. The semisolid formulations of the present invention can be any semisolid formulation known to those of ordinary skill in the art including, for example, gels, pastes, creams and ointments. In certain embodiments, the pharmaceutical formulations can comprise preparations of the vitamin D compounds that are currently in clinical use. Examples of such preparations of vitamin D compound and the like include but are not limited to dihydrotachysterol (DHT ™, Roxane; e Hytakerol®, Sanofi Winthrop P arm); calcitriol (Rocaltrol®, Roche; and Calcijex®, Abbot); Calcifediol (Calderol®, Organon); ergocalciferol (Calciferol, Schwarz Pharma; and Drisdol, Sanofi Pharm), -Colecalciferol (Delta-D® and vitamin D3, Freeda); paracalcitol (Zemplar®, Abbott); doxercalciferol (Hectorol®, Bone Care Int'l); and alfacalcidol (AlfaD® and One-Alfa). Rocaltrol is a formulation of calcitriol currently in clinical use and available as capsules containing 0.25 and 0.5 g of calcitriol and as an oral solution - containing 1 μ9 / t? 1 of calcitriol. Dosage forms of Rocaltrol® may contain additional components such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) as antioxidants. The capsules may also contain a fractionated triglyceride of coconut oil and the oral solution contains a fractionated triglyceride of palm kernel oil. See Physicians' Desk Reference 2991 (56th ed., 2002).

Oral Dosage Forms In certain embodiments, the pharmaceutical agents can be administered orally. Pharmaceutical formulations that are suitable for oral administration may be presented as discrete dosage forms including, but not limited to, tablets such as chewable tablets, capsules and liquids such as flavored syrups. Such dosage forms contain predetermined amounts of a pharmaceutical agent and can be prepared by pharmacy methods well known to those skilled in the art. See generally, Remington's Phazmaceutical Sciences, 18th ed. , Mack Publishing, Easton PA (1990). Typical oral dosage forms are prepared by combining a pharmaceutical agent with at least one excipient according to conventional pharmaceutical composition techniques. The excipients can take a variety of forms. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms such as powders, tablets, capsules include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrating agents. In certain embodiments, suitable forms of the binders include, but are not limited to, corn starch, potato starch, other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, tragacanth in powder, guar gum, cellulose and its derivatives. Examples of cellulose derivatives include, but are not limited to, ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose. Other binders include, but are not limited to polyvinylpyrrolidone, methylcellulose, pre-gelatinized starch, hydroxypropylmethylcellulose, microcrystalline cellulose and mixtures thereof. Suitable forms of microcrystalline cellulose include, but are not limited to, those commercially known as Avicel®, Avicel-PH-101®, Avicel-PH-103®, Avicel RC-581®, Avicel-PH-105® (the products Avicel® are available from FMC Corporation, American Viseose Division, Avicel Sales, Marcus Hook, PA) and mixtures thereof. In certain embodiments, the binder may be a mixture of microcrystalline cellulose and sodium carboxymethylcellulose sold as Avicel RC-581®. Suitable anhydrous and low moisture excipients or additives include Avicel-PH-103® and Starch 1500 LM®. In certain embodiments, suitable fillers include, but are not limited to, talcum, calcium carbonate, microcrystalline cellulose, cellulose powder, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelled starch and mixtures thereof. The binder or filler is typically present from about 50 to about 99 weight percent of the pharmaceutical formulation or dosage form. In certain modalities, the disintegrators can be used in the formulations to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant can disintegrate in storage, while those that contain too little can not disintegrate at a desired rate or under the desired conditions. In this way, a sufficient amount of the disintegrator that is neither too much nor too little to alter to the detriment of the release of the pharmaceutical agent, should be used to form the solid oral dosage forms. The amount of disintegrator varies based on the type of formulation and is easily determined by those skilled in the art. In certain embodiments, the pharmaceutical formulations comprise from about 0.5 to about 15 weight percent disintegrant. In a preferred embodiment, the pharmaceutical formulations comprise from about 1 to about 5 weight percent of disintegrant. In other modalities, suitable disintegrants include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, potassium polacrilin, sodium starch glycolate, potato starch or tapioca starch. , others, starches, pregelatinized starch, other starches, clays, other alginates, other celluloses, gums and mixtures thereof. In certain embodiments, suitable lubricants include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, and hydrogenated vegetable oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil. In other embodiments, suitable lubricants include, but are not limited to, zinc stearate, ethyl oleate, ethyl laureate, agar and mixtures thereof. In other embodiments, suitable lubricants include, but are not limited to, a siloidal silica gel such as Aerosil 200 (manufactured by WR Grace Co. of Baltimore, MD), a synthetic silica coagulated aerosol (available from Degussa Co. , TX), cab-O-Sil® (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA.) And mixtures thereof. When lubricants are used, they are typically present in an amount of less than about 1 weight percent of the pharmaceutical formulations or dosage forms. In certain embodiments, the oral dosage form may be tablets and capsules. The tablets and capsules may comprise solid excipients and represent the most advantageous oral dosage unit forms due to their ease of distribution. The tablets can be coated by standard aqueous or non-aqueous techniques, if desired. Such dosage forms can be prepared by any pharmaceutical method. In general, pharmaceutical formulations and dosage forms are prepared by uniformly and intimately mixing the pharmaceutical agents with liquid carriers, finely divided solid carriers, or both, and then forming the product into the desired form. For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing the pharmaceutical agents, and optionally excipients, in a suitable machine. The molded tablets can likewise be processed by molding a mixture of the pharmaceutical agents, and optionally excipients, moistened with an inert liquid diluent with a suitable machine. In certain embodiments, the unit dosage form of the composition is a capsule, and the total amount of the ingredients is preferably in the range of about 10 μ? up to approximately 1000 μ? . In a preferred embodiment, the total amount of the ingredients present in the capsule is in the range of approximately 100 μ? to approximately 300 μ? . The relative proportion of the ingredients in the formulations may vary according to the particular type of composition, the particular function of the ingredients, the particular ingredients and the desired physical characteristics of the product. For example, a composition can be a free flowing liquid or a paste for topical use. The determination of the treatable proportions in any particular case is within the capacity of a person of ordinary skill in the art. All the indicated proportions and the relative weight ranges described below are indicative of the preferred teachings, and are not intended to be limiting in any way. Calcitriol can be sensitive to light and especially prone to oxidation. In addition, calcitriol and other active vitamin D compounds are lipophilic, which means that they are soluble in lipids and some organic solvents, but only sparingly soluble in a polar medium such as water. As a result of the lipophilic nature of the active vitamin D compounds, the dispersion of such compounds in aqueous solutions, for example, the gastric fluids of the stomach, is significantly limited. Accordingly, the pharmacokinetic parameters of the formulations of currently available vitamin D active compounds are suboptimal. As a result, currently available formulations of active vitamin D compounds tend to exhibit substantial absorption variability in the small intestine. However, in certain preferred embodiments of the present invention, the vitamin D compounds can be formulated as emulsion pre-concentrates to improve stability, even at elevated temperatures, to improve pharmacokinetic parameters and to reduce variability in absorption in small intestine. Preferably, the method provides dosage forms of the active vitamin D compounds, such as calcitriol, in sufficiently high concentrations to allow convenient use. The dosage forms are stable at a variety of temperatures and rapidly become a nanodispersion in polar media including, but not limited to, gastric fluids, while functioning within the required pharmacokinetic parameters. At high doses, the pre-concentrates in emulsion show a high blood concentration of a vitamin D compound, which is at least 1.5-2 times higher than the maximum blood concentration observed with Rocaltrol, a half-life of elimination that is half or less than the elimination half-life observed with Rocaltrol®, and a time for maximum plasma concentration that is shorter than the time for the maximum plasma concentration observed with Rocaltrol®. These pharmacokinetic characteristics are beneficial in achieving high blood levels of vitamin D compounds without the onset of hypercalcemia and preferably without the onset of clinical hypercalcemia. In certain embodiments, the emulsion pre-concentrates form an emulsion after dilution with a polar phase component such as a liquid or solution, e.g. polar medium, including but not limited to water. The ratio of the polar medium to the pre-concentrate in emulsion is preferably 1: 1 or greater. In one example, the ratio of water to composition may be in the range of about 1: 1 to about 5000: 1. In another example, the water to composition ratio may be about 1: 1, 2: 1, 3: 1, 4: 1, 5: 1, 10: 1, 200: 1, 300: 1, 500: 1 , 1000: 1, or 5000: 1, or any range of proportions in this. The person skilled in the art can determine the appropriate proportion for the desired application.

In other embodiments, the emulsion may be an emulsion of submicron droplets, wherein submicron droplet emulsions possess one or more of the following characteristics: (1) the spontaneous formation of the emulsion when the components are contacted despite the absence of an energy source such as heat, high cut or other substantial agitation, (2) thermodynamic stability and (3) a single phase state. The droplets or particles within submicron droplet emulsions can have a variety of shapes including, but not limited to, spheres and liquid crystals with lamellar, hexagonal or isotropic symmetries. The submicron droplet emulsions comprise droplets or particles having an average diameter in the range of generally from about 50 nm to about 1000 nm, preferably from about 100 nm to about 750 nm, and more preferably from about 200 nm to about 400 nm. In certain embodiments, the emulsion has an absorbance range of from about 0.3 to about 15.0 to 400 nm after dilution of the pre-concentrate emulsion with a polar medium such as water. In other embodiments, the emulsion has an absorbance in the range of about 0.3 to about 8.0 at 400 nm. In certain embodiments, the absorbance may be in the range of about 0.4, 0.5, 0.6, 1.0, 1.2, 1.6, 2.0, 2.2, 2.4, 2.5, 3.0 or 4.0, or any range of absorbances therein at 400 nm. In a preferred embodiment, the emulsion is formed with a 100: 1 dilution of water with the emulsion pre-concentrate and has an absorbance in the range of about 0.3 to about 4.0 to 400 nm. Methods for determining the absorbance of a liquid solution are well known to those skilled in the art. The person skilled in the art may be able to evaluate and adjust the relative proportions of the ingredients of. the emulsion pre-concentrates of the invention, in order to obtain, after dilution with a polar medium such as water, an emulsion having any particular absorbance encompassed within the scope of the invention. In certain embodiments, the emulsion pre-concentrates comprise: (a) one or more components in the lipophilic phase, (b) one or more surfactants, and (c) one or more vitamin D compounds; wherein the composition is a pre-concentrate emulsion, which after dilution with a polar medium such as water, for example, in a water ratio to the composition of about 1: 1 or more, forms an emulsion having a absorbance greater than 0.3 to 400 nm. In certain embodiments, the emulsion pre-concentrates may further comprise either one or more hydrophobic or hydrophilic phase components. The vitamin D compounds of the emulsion pre-concentrates are described above. The vitamin D compounds can be active vitamin D compounds or compounds that can be converted to active vitamin D compounds when administered. The lipophilic phase components can be any pharmaceutically acceptable solvent, which is not miscible with water. Typically, the lipophilic phase component comprises mono-, di- or triglycerides which include but are not limited to those derived from fatty acids of 6, 8, 10, 12, 14, 16, 18, 20 and 22 carbon atoms. Exemplary diglycerides include, in particular, diolein, dipalmitolein and mixed capriline-caprine glycerides. Preferred triglycerides include, but are not limited to, vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, synthetic triglycerides, modified triglycerides, fractionated triglycerides, medium and long chain triglycerides, structured triglycerides and mixtures thereof. Preferred triglycerides include, but are not limited to, almond oil, babassu oil, borage oil, cassis seed oil, canola oil, castor oil, coconut oil, corn oil, cottonseed oil, donkey herb oil, grape seed oil, oil peanuts, mustard seed oil, olive oil, palm oil, palm kernel oil, safflower oil, sesame oil, shark liver oil, soybean oil, sunflower oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated palm oil, hydrogenated soybean oil, hydrogenated vegetable oil, hydrogenated cottonseed and castor oil, partially hydrogenated soybean oil, partially hydrogenated soybean and cottonseed oil, glyceryl tricaproate, glyceryl tricaprylate, glyceryl tricaprate, glyceryl triodecanoate, glyceryl trilaurate, glyceryl trioleate, glyceryl trilinoleate, glyceryl trilinolenate, tricaprylate / glyceryl caprate, tricap rilate / caprate / glyceryl laurate, tricaprylate / caprate / glyceryl linoleate and tricaprylate / caprate / glycerol stearate. In certain embodiments, the preferred triglyceride may be a medium chain triglyceride commercially known as Labrafac CC®. Other preferred triglycerides include, for example, neutral oils such as neutral vegetable oils and in particular, fractionated coconut oils such as commercially available Miglyol®, which includes but is not limited to Miglyol 810®; Miglyol 812®; Miglyol 818®; and Captex 355®. A preferred lipophilic phase component can be the Miglyol 812® product. See United States Patent No. 5,342,625. Other suitable triglycerides include, but are not limited to caprylic-capric triglycerides such as those which are commercially known as Myritol®, which includes but is not limited to Myritol 813®. Other suitable products of this class include, but are not limited to Capmul MCT®, Captex 200®, Captex 300®, Captex 800®, Neobee MS® and Mazol 1400®. As discussed above, the emulsion pre-concentrates further comprise one or more surfactants. Surfactants that may be used include, but are not limited to, hydrophilic or lipophilic surfactants, which include, but are not limited to, anionic, cationic, nonionic and amphoteric surfactants or mixtures thereof. In preferred embodiments, the surfactants are hydrophilic nonionic and nonionic lipophilic surfactants. In certain embodiments, suitable hydrophilic surfactants include, but are not limited to, reaction products of natural or hydrogenated vegetable oils and ethylene glycol such as castor oil or hydrogenated or naturally occurring polyoxyethylene glycol oils.

The reaction products can be obtained by known methods including but not limited to the reaction of a natural or hydrogenated castor oil with ethylene oxide in a molar ratio of about 1:35 to about 1:60. Optionally, the free polyethylene glycol components can be removed from the product using the methods shown in the German descriptions 1,182,388 and 1,518,819. Other suitable hydrophilic surfactants include, but are not limited to polyoxyethylene-sorbitan fatty acid esters, which include but are not limited to mono- and trilauryl, palmityl, stearyl and oleyl esters such as the following commercially known as Tween®. Tween 20® (polyoxyethylene (20) sorbitanmonolaurate), Tween 40® (polyoxyethylene (20) sorbitan monopalmitate), Tween 60® (polyoxyethylene (20) sorbitanmonostearate), Tween 80® (polyoxyethylene (20) sorbitanmonooleate), Tween 65® (polyoxyethylene ( 20) sorbitan-stearate), Tween 85® (polyoxyethylene (20) sorbitantrioleate), Tween 21® (polyoxyethylene (4) sorbitanmonolaurate), Tween 61® (polyoxyethylene (4) sorbitanmonostearate) and Tween 81® (polyoxyethylene (5) sorbitanmonooleate).

The most preferred products of this class for use in the compositions are Tween 40® and Tween 80®. See Hauer et al., U.S. Patent No. 5,342,625. In other embodiments, suitable hydrophilic surfactants include, but are not limited to, polyoxyethylene alkyl ethers, polyoxyethylene glycol fatty acid esters such as polyoxyethylene-stearic acid esters, polyglycerol fatty acid esters, polyoxyethylene glycerides, polyoxyethylenated vegetable oils and hydrogenated, polyoxyethylenated vegetable oils. Other suitable hydrophilic surfactants include, but are not limited to, the products of the reaction mixtures of polyols and one or more members of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils and sterols; polyoxyethylene-polyoxypropylene copolymers and block copolymers; dioctylsuccinate, dioctylsodiosulfosuccinate, di- [2-ethylhexyl] -succinate or sodium lauryl sulfate; phospholipids, and preferably lecithins such as soybean lecithin; esters of propylene glycol mono- and di-fatty acid, for example, propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol hydroxystearate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate and propylene glycol stearate. More preferably, the fatty acid ester can be the propylene glycol-caprylic-capric acid diester. Other suitable hydrophilic surfactants include, but are not limited to, bile salts such as sodium taurocholate. In certain embodiments, suitable lipophilic surfactants include, but are not limited to, alcohols, polyoxyethylene alkyl ethers, fatty acids, bile acids, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acid esters, esters of polyethylene glycol fatty acids, polyethylene glycol glycerol fatty acid esters, polypropylene glycol fatty acid esters, polyoxyethylene glycerides, lactic acid esters of mono- or di-glycerides, propylene glycol diglycerides, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, transesterified vegetable oils, sterols, sugar esters, sugar ethers, sucroglycerides, polyoxyethylenated vegetable oils, polyoxyethylene-hydrogenated vegetable oils. In other embodiments, the lipophilic surfactants include, but are not limited to, the products of the reaction mixtures of the polyols and one or more members of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils and sterols.

In other embodiments, suitable lipophilic surfactants include, but are not limited to, trans-esterification products of triglycerides of natural vegetable oils and polyalkylene polyols. Such trans-esterification products are known in the art and can be obtained using the methods shown in U.S. Patent No. 3,288,824. These transesterification products include, but are not limited to, the reaction mixtures of one or more natural vegetable oils such as corn oil, grain oil, almond oil, peanut oil, olive oil, palm oil with one or more polyethylene glycols. The preferred polyethylene glycols have an average molecular weight of 200 to 800. In a preferred embodiment, the products are obtained by transesterification of a 2: 1 molar ratio of a triglyceride of natural vegetable oil to polyethylene glycol. Various forms of trans-esterification products are commercially known as Labrafil®. In certain embodiments, suitable lipophilic surfactants include, but are not limited to, oil soluble vitamin derivatives such as tocopherol succinate PEG-1000 ("vitamin E TPGS"), monoglycerides, diglycerides, and mixtures thereof; esterification products of caprylic or capric acid with glycerol; fatty acid esters of sorbitan; fatty acid esters of pentaerythritol and pentaerythritol; and polyalkylene glycol esters such as pentaerythritol dioate ethers, distearate, monolaurate, polyglycol; monoglycerides such as glycerol monooleate, glycerol monopalmitate and glycerol monostearate; glycerol triacetate or (1, 2, 3) -triacetin; sterols and derivatives including, but not limited to cholesterols and derivatives thereof, and in particular, phytosterols such as products comprising sitoesterol, campesterol or stigmasterol; and ethylene oxide adducts such as soy steels and derivatives thereof. Those of ordinary skill in the art understand that various commercial surfactant compositions may contain small to moderate amounts of triglycerides. Thus, in certain embodiments, surfactants that are suitable for use in the present pharmaceutical formulations may include surfactants containing triglycerides. Examples of commercial surfactant compositions containing triglycerides include, but are not limited to, Gelucire®, Aisine® and Imwitor. Specific examples of these compounds are saturated polyglycolized glycerides such as Gelucire 44 / 14®, Gelucire 50 / 13®, and Gelucire 53 / 10®; semi-synthetic triglycerides such as Gelucire 33/01, Gelucire 39/01; and other Gelucire surfactant compositions such as 37/06, 43/01, 35/10, 37/02, 46/07, 48/09, 50/02, 62/05, etc. In other embodiments, suitable commercial surfactant compositions include, but are not limited to, linoleic glycerides such as Maisine 35-1® and caprylic / capric glycerides such as Imwitor 742®. See United States Patent No. 6,267,985. Those skilled in the art will recognize that there are other commercial surfactant compositions that have significant triglyceride contents, and will appreciate that compositions containing triglycerides as well as surfactants may be suitable to provide all or part of the lipophilic phase components, as well as all or part of the surfactants. In certain embodiments, the emulsion pre-concentrates of the present invention may optionally comprise one or more hydrophilic phase components. Suitable hydrophilic phase components include, but are not limited to alkanediol ethers and preferably dieters. One or more hydrophilic phase components may comprise, for example, a pharmaceutically acceptable alkyl ether of 1 to 5 carbon atoms or tetrahydrofurfuryl, of a mono- or poly-oxyalkanediol of low molecular weight. The alkanediol may be an oxyalkanediol of 2 to 12 carbon atoms and preferably an oxyalkanediol of 4 carbon atoms. More preferably, the oxy-alkanediol can be straight chain. Exemplary hydrophilic phase components for use in the relation to the present invention are commercially available as Transcutol® and Colycofurol®. See United States Patent No. 5,342,625. In other embodiments, the hydrophilic phase component may include one or more additional ingredients. Preferably, however, the additional ingredients comprise materials in which the vitamin D compound can be sufficiently soluble, such that the function of the hydrophilic phase component as a carrier of the vitamin D compound is not materially impaired. Other possible hydrophilic phase components include, but are not limited to, lower alkanols, such as alkanols of 1 to 5 carbon atoms and preferably ethanol. In a preferred embodiment, the hydrophilic phase component comprises 1,2-propylene glycol. In certain embodiments, any pharmaceutical formulations of the invention, such as a pre-concentrate emulsion, may further comprise one or more additives. Additives that are well known in the art include, but are not limited to, adhesion promoters, anti-foaming agents, buffering agents, antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and tocopherols such as a- tocopherol (vitamin E), preservatives, chelating agents, viscometers, toning agents, flavorings, dyes, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants and mixtures thereof. Those skilled in the art can easily determine the amounts of such additives required to achieve the desired properties. In other embodiments, the additives may also comprise thickening agents and salts thereof. Thickening agents can be included for a variety of reasons including, but not limited to, the provision of a sustained release effect. However, where oral administration is intended, thickening agents in general will not be required and are generally less preferred. Thickening agents are generally indicated for topical application. Suitable thickeners known in the art include, but are not limited to, pharmaceutically acceptable polymeric and inorganic materials. In a preferred embodiment, the thickening agents include but are not limited to polyacrylate copolymer resins and polyacrylate resins, polyacrylic acid resins and polyacrylic acid / methacrylic acid resins, celluloses and cellulose derivatives. In certain embodiments, cellulose derivatives include, but are not limited to, acylated celluloses such as cellulose acetates, cellulose acetate phthalates, cellulose acetatosuccinates and hydroxypropylmethyl cellulose phthalates. Cellulose salts and cellulose derivatives include but are not limited to sodium carboxymethyl cellulose. Preferred cellulose derivatives include, but are not limited to, alkylcelluloses such as methyl-, ethyl- and propyl-celluloses hydroxyalkylcelluloses such as hydroxypropylcelluloses and hydroxypropylalkylcelluloses. Hydroxypropylalkylcelluloses include, but are not limited to, hydroxypropylmethylcelluloses. In certain embodiments, other additives may serve as thickening agents and include, but are not limited to polyvinylpyrrolidones such as poly-N-vinylpyrrolidones and copolymers of vinylpyrrolidones. Vinylpyrrolidone copolymers include, but are not limited to, vinylpyrrolidone-vinyl acetate copolymers, polyvinyl resins such as polyvinylacetates and polyvinylalcohols, and polymeric materials. In other modalities, polymeric additives include, but are not limited to gum tragacanth, gum arabic, alginates such as alginic acid, and alginic acid salts such as sodium alginates. In certain embodiments, the inorganic thickening agents are suitable and include, but are not limited to attapulgite, bentonite and silicates. The silicates include, but are not limited to, hydrophilic silicon dioxide products such as alkylated silica gels and are preferably methylated. In a preferred embodiment, the inorganic thickening agents are colloidal silicon dioxide products. In certain embodiments, the lipophilic phase components may be suitably present in an amount of about 30% to about 90% by weight, based on the total weight of the composition. In a preferred embodiment, the lipophilic phase component may be present in an amount of about 50% to about 85% by weight, based on the total weight of the composition. In other embodiments, one or more surfactants may suitably be present in an amount of about 1% to about 50% by weight based on the total weight of the composition. In a preferred embodiment, one or more surfactants can. to be present in an amount of about 5% to about 40% by weight, based on the total weight of the composition. More preferably, one or more surfactants may be present in an amount of about 10% to about 30% by weight, based on the total weight of the composition.

The amount of vitamin D compound in the compositions may vary according to a variety of factors. Examples of factors that can vary the amount of vitamin D compound include, but are not limited to, the intended route of administration and the degree to which the other components are present. In certain embodiments, the vitamin D compound may be present in an amount of about 0.005% to 20% by weight, based on the total weight of the composition. In other embodiments, the vitamin D compound may be present in an amount of about 0.01% to 15% by weight, based on the total weight of the composition. In a preferred embodiment, the vitamin D compound may be present in an amount of about 0.1% to about 10% by weight, based on the total weight of the composition. In certain embodiments, the hydrophilic phase component may be present in an amount of about 2% to about 20% by weight, based on the total weight of the composition. In other embodiments, the hydrophilic phase component may be present in an amount of about 5% to 15% by weight, based on the total weight of the composition. In a preferred embodiment, the hydrophilic phase component may be present in an amount of about 8% to 12% by weight, based on the total weight of the composition.

In certain embodiments, the pre-concentrate emulsion may be a semi-solid. The semi-solid formulations may comprise, for example, one or more components in a lipophilic phase in an amount of about 60% to about 80% by weight, based on the total weight of the composition, one or more surfactants present in an amount of about 5% to about 35% by weight, based on the total weight of the composition, and one or more vitamin D compounds present in an amount of about 0.01% to about 15% by weight, based on the total weight of the composition. composition. In certain embodiments, the pre-concentrate emulsion may be liquid. The liquid formulations may comprise, for example, one or more lipophilic phase components present in an amount of about 50% to about 60% by weight, based on the total weight of the composition, one or more surfactants present in an amount of about 4% to about 25% by weight, based on the total weight of the composition, or one or more vitamin D compounds present in an amount of about 0.01% to about 15% by weight, based on the total weight of the composition. the composition, and one or more hydrophilic phase components present in an amount of about 5% to about 10% by weight, based on the total weight of the composition.

Additional compositions that can be used include the following, wherein the percentage of each component is by weight, based on the total weight of the composition excluding the active vitamin D compound: Gelucire 44 / about 50% iglyol 812 about 50%; Gelucire 44/14 approximately 50% Vitamin ETPGS approximately 10% Miglyol 812 approximately 40%; Gelucire 44/14 approximately 50% Vitamin E TPGS approximately 20% Miglyol 812 approximately 30%; Gelucire 44/14 approximately 40% Vitamin E TPGS approximately 30% Miglyol 812 approximately 30%; Gelucire 44/14 approximately 40% Vitamin E TPGS approximately 20% Miglyol 812 approximately 40%; Gelucire 44/14 approximately 30% Vitamin E TPGS approximately 20% Miglyol 812 approximately 40% Gelucire 44/14 approximately 20% Vitamin E TPGS approximately 30% Miglyol 812 approximately 50% Vitamin E TPGS approximately 50% Miglyol 812 approximately 50% Gelucire 44/14 approximately 60% Vitamin E TPGS approximately 25% Miglyol 812 approximately 15% Gelucire 50/13 approximately 30% Vitamin E TPGS approximately 5% Miglyol 812 approximately 65%; Gelucire 50/13 approximately 50% Miglyol 812 approximately 50% Gelucire 50/13 approximately 50% Vitamin E TPGS approximately 10% Miglyol 812 approximately 40%; Gelucire 50/13 approximately 50% Vitamin E TPGS approximately 20% Miglyol 812 approximately 30% Gelucire 50/13 approximately 40% Vitamin E TPGS approximately 30% Miglyol 812 approximately 30% Gelucire 50/13 approximately 50% Vitamin E TPGS approximately 20% Miglyol 812 approximately 30% Gelucire 50/13 approximately 30% Vitamin E TPGS approximately 30% Miglyol 812 approximately 40%; Gelucire 50/13 approximately 20% Vitamin E TPGS approximately 30% Miglyol 812 approximately 50%; Gelucire 50/13 approximately 60% Vitamin E TPGS approximately 25% Miglyol 812 approximately 15%; Gelucire 44/14 approximately 50% PEG 4000 approximately 50%; Gelucire 50/13 approximately 50% PEG 4000 approximately 50%; Vitamin E TPGS approximately 50% PEG 4000 approximately 50%; Gelucire 44/14 approximately 33.3% Vitamin E TPGS approximately 33.3% PEG 4000 approximately 33.3% Gelucire 50/13 approximately 33.3% Vitamin E TPGS approximately 33.3% PEG 4000 approximately 33.3% Gelucire 44/14 approximately 50% Vitamin E TPGS approximately 50%; Gelucire 50/13 approximately 50% Vitamin E TPGS approximately 50%; Vitamin E TPGS approximately 5% Miglyol 812 approximately 95%; Vitamin E TPGS approximately 5% Miglyol 812 approximately 65% PEG 4000 approximately 30%; Vitamin E TPGS approximately 10% Miglyol 812 approximately 90%; Vitamin E TPGS approximately 5% Miglyol 812 approximately 85% PEG 4000 approximately 10%; Y Vitamin E TPGS approximately 10% Miglyol 812 approximately 80% PEG 4000 approximately 10%.

Parenteral Dosage Forms In certain embodiments, the pharmaceutical agents can be administered parenterally. Parenteral dosage forms can be administered by various routes including but not limited to intravenous administration, including but not limited to bolus and intramuscular and intra-arterial injections. In preferred embodiments, the parenteral dosage forms are sterile and capable of being sterilized prior to administration to a subject, since they typically bypass the subject's natural defenses against contaminants. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, anhydrous products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection and emulsions. Formulations useful in the present invention include, but are not limited to Calcijex®, which is an example of an intravenous vitamin D compound formulation, currently available which may contain 1 μg of calcitriol, 4 mg of Polysorbate 20, 2.5 mg of sodium ascorbate and optionally either HC1 or NaOH for pH adjustment. Suitable vehicles that can be used to provide the parenteral dosage forms of the invention are well known to those skilled in the art. In certain embodiments, suitable vehicles for parenteral dosage forms include, but are not limited to, water for USP injection; aqueous vehicles including but not limited to Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection and Lactated Ringer's Injection; miscible vehicles in water that include but are not limited to ethyl alcohol, polyethylene glycol and polypropylene glycol; and non-aqueous vehicles including but not limited to corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate. In other embodiments, compounds that increase the solubility of pharmaceutical agents can be incorporated into parenteral dosage forms. For example, cyclodextrin and its derivatives can be used to increase the solubility of a thalidomide analogue and its derivatives. See, for example, U.S. Patent No. 5,134,127, which is incorporated by reference herein in its entirety.

MANUFACTURING ARTICLES The present invention also encompasses a finished packaged and labeled pharmaceutical product. This article of manufacture includes the appropriate unit dosage form in an appropriate container or container such as a glass jar or other container that is hermetically sealed. In the case of dosage forms suitable for parenteral administration, the active ingredient, for example, one or more vitamin D compounds that are preferably active and more preferably calcitrol, is 1 Sterile and suitable for administration as a particulate free solution. In other words, the invention encompasses parenteral solutions and lyophilized powders, each being sterile, and the latter being suitable for reconstitution prior to injection. Alternatively, the unit dosage form may be a solid suitable for oral administration. In certain embodiments, the unit dosage form is suitable for intravenous administration. Thus, the invention also encompasses solutions, which are preferably sterile, suitable for intravenous administration. In a preferred embodiment, the dosage form is a solution suitable for intravenous administration, comprising at least one unit dose form of one or more vitamin D compounds, such as for example Calci ex®. In an equally preferred embodiment, the unit dosage form is a pre-concentrate in oral emulsion and comprises approximately 15 μC of calcitriol in addition to the following excipients with the amount given in approximate weight percentage: 65% Miglyol 821N® 30% Gelucire 44 / 14®, 5% vitamin E TPGS and approximately 0.05% each of butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA).

As with any pharmaceutical product, the packaging material and the container are designed to protect the stability of the product during storage and shipment. For example, the packaging material and the container can be designed to protect the product from light and high temperatures, in order to protect the stability of the product. In addition, the products of the invention include instructions for use or other information material that advises the physician, technician or patient on how to properly treat the disease or disorder in question. In other words, the article of manufacture includes the means of instruction that indicate or suggest a dosage regimen that includes but is not limited to effective doses and monitoring procedures. Specifically, the invention provides an article of manufacture comprising the packaging material such as a box, bottle, tube, bottle, container, intravenous bag (i.v.), envelope and the like; and at least one unit dosage form of a pharmaceutical agent contained within a packaging material, wherein the pharmaceutical agent comprises one or more vitamin D compounds, which are preferably active and more preferably calcitriol, and the packaging material includes the instructional means indicating that the vitamin D compound can be used to treat MDS, or ameliorate a symptom thereof, by administration of the specific doses and the use of the specific dosage regimens described herein. More specifically, the invention provides an article of manufacture comprising the packaging material such as a box, bottle, tube, bottle, container, intravenous bag (i.v.), envelope and the like; and at least one unit dosage form of a pharmaceutical agent contained within the packaging material, wherein the pharmaceutical agent comprises one or more vitamin D compounds, which are preferably active and more preferably calcitriol, and wherein the packaging material includes instructional means indicating that the vitamin D compound can be used to treat MDS by the administration of specific doses and using specific dosage regimens as described herein. The invention provides an article of manufacture comprising the packaging material such as a box, bottle, tube, bottle, container, intravenous bag (i.v.), envelope and the like.; and at least one unit dosage form of a pharmaceutical agent contained within the packaging material, wherein the pharmaceutical agent comprises one or more vitamin D compounds, which are preferably active and more preferably calcitriol, and the other pharmaceutical agent comprises an agent therapeutic composition of a vitamin D compound, and wherein the packaging material includes instructional means indicating that the vitamin D compound can be used to treat MDS by administering specific doses and using specific dosage regimens as described at the moment. More specifically, the invention provides an article of manufacture comprising the packaging material such as a box, bottle, tube, bottle, container, intravenous bag (i.v.), envelope and the like; and at least one unit dosage form of a pharmaceutical agent contained within the packaging material, wherein the pharmaceutical agent comprises one or more vitamin D compounds, and the other pharmaceutical agent comprises a therapeutic agent other than a vitamin D compound and wherein the packaging material includes instructional means indicating that the vitamin D compound can be used to treat MDS by the administration of specific doses and using specific dosage regimens as described herein. the invention provides an article of manufacture comprising the packaging material such as a box, bottle, tube, bottle, container, intravenous bag (i.v.), envelope and the like; and at least one unit dosage form of a pharmaceutical agent contained within the packaging material, wherein the pharmaceutical agent comprises one or more vitamin D compounds, which are preferably active and more preferably calcitriol, and the other pharmaceutical agent comprises one or more haematopoietic growth factors or cytokines, which are preferably r-HuEPO, r-metHuG-CSF or any combination thereof, and wherein the packaging material includes instructional means indicating that the vitamin D compound can be used to treat MDS by administering specific doses and using specific dosing regimens as described herein. More specifically, the invention provides an article of manufacture comprising the packaging material such as a box, bottle, tube, bottle, container, intravenous bag (i.v.) / envelope and the like; and at least one unit dosage form of a pharmaceutical agent contained within the packaging material, wherein the pharmaceutical agent comprises one or more vitamin D compounds, which are preferably active and more preferably calcitriol, and the other pharmaceutical agent comprises one or more haematopoietic growth factors or cytokines, which are preferably r-HuEPO, r-metHuG-CSF or any combination thereof, and wherein the packaging material includes instructional means indicating that the vitamin D compound can be used to treat MDS by administering specific doses and using specific dosing regimens as described above. describes in the present. In a preferred embodiment, the instructional means enclosed in an article of manufacture indicate or suggest that the plasma concentration of calcium be monitored one or more times before and / or after a dose. For example, the instructional means enclosed in an article of manufacture may indicate that the calcium concentration in blood is taken before the first dose and after one or more subsequent doses. In a specific embodiment, the means of instruction enclosed in an article of manufacture indicate that the vitamin D compounds are used to treat DS in a subject, and that the blood calcium concentration in the subject is less than about 10.5 mg / dL. In another specific embodiment, the instructional means enclosed in an article of manufacture indicate that the vitamin D compounds are used to treat MDS anemia, and that the blood calcium concentration in the subject is less than about 10.5 mg / dL. The information material enclosed in an article of manufacture for use in the treatment of MDS, or the improvement of one or more symptoms thereof, also indicates that subjects with hypercalcemia are not administered with a pharmaceutical composition comprising a vitamin compound. D. In a specific embodiment, the information material enclosed in an article of manufacture for use in the treatment of DS, or the improvement of one or more symptoms thereof, also indicates that subjects with Grade 2, Grade 3 or Grade 4 of hypercalcemia are not administered with a pharmaceutical composition comprising a vitamin D compound.

EXAMPLES EXAMPLE 1 PHARMACOKINETICS OF THE ADMINISTRATION OF CALCITRIOL Twelve human subjects received varying amounts of calcitriol in a study designed to determine the pharmacokinetic behavior of the preferred form of oral dose of calcitriol. The preferred oral dosage form ("the preferred formulation") comprises approximately 15 μC of calcitriol in addition to the following excipients with the amount given in approximate weight percentage: 65% Miglyol 812N®, 30% Gelucire 44 / 14®, 5% vitamin E TPGS and approximately 0.05% each of butylated hydroxytoluene (BHT) and butylated hydroxyanisole (???). Three of the subjects received 15 μg, three received 30 g, and six received 60 μ9 of the preferred formulation. Blood samples were obtained pre-dose and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 24.0, 48.0 and 72.0 hours after the initial dose ("post-dose") of the formulation preferred Calcitriol levels were analyzed using a commercial radioimmunoassay. The mean plasma concentration versus time curves were graphically plotted for each group and are shown in Figure 1. The non-compartmental pharmacokinetic parameters were calculated for each subject and then averaged and tabulated in Table 1. Baseline calcitriol values were subtracted from the post-dose values to adjust the endogenous calcitriol. The pharmacokinetic parameters calculated were with the maximum plasma concentration ("CMAX") time at the maximum concentration ("tMAx"), the half-life ("ti / 2"), and the trapezoidal area determined from the concentration versus the time 0 to 24 hours ("AUC0-24"), time 0-72 hours (¾AUC0-72") and time 0 to infinity (" AUC0-8").

Table 1. Pharmacokinetic parameters for the preferred formulation of calcitriol as administered to human subjects in the amounts of 15, 30 and 60 μg.

Parameter Group Dosage 30 μd 60 CMAx, pg ml (± SD) 398.4 (12.9) 898.8 (333.6) 1738.6 (347.2) ÍMAX, hours (median and range) 1.00 (1.00-1.00) 1.50 (1.50-2.00) 4.00 (1.50-4.00) AUC-0.24h, pg h / ml (± SD) 3665.7 (NA) 6955.9 (2825.4) 17480.6 (2989.7) AUC-0 ^ 8i "pg h / ml (+ SD) 5627.3 (637.1) 9792.9 (2323.9) 20999.4 (4762.5) AUC- ^ pg h / ml i + SD) 5464.8 (892.8) 11069.7 (1406.4) 21795.0 (5124.8) tj / 2 hours, (harmonic mean, based on 8.9 16.3 7.3 knife variance) The pharmacokinetic data show that the preferred formulation responds linearly and predictably at increasing doses, and there was no evidence of absorption saturation. In addition, the pharmacokinetic data show that the administered doses of calcitriol reach higher peak plasma concentrations than previously thought possible without induction of hypercalcemia. Thus, the methods of the invention provide a safe and effective method to achieve high peak plasma concentrations of the vitamin D compounds, to treat MDS, or to improve a symptom thereof, without causing hypercalcemia.

EXAMPLE 2 MONOTHERAPY WITH VITAMIN D The following treatment program provides an example of using the methods described above to treat MDS, or improve a symptom thereof. The subjects self-administered the preferred formulation, which comprises approximately 15 μC of calcitriol in addition to the following excipients with the given amount in approximate weight percentage: 65% Miglyol 812N®, 30% Gelucire 44 / 14®, 5 % of vitamin E TPGS and approximately 0.05% of each of butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA). The total dose administered is 45 μg calcitriol, or three 15 μg capsules, once a week, taken all at once. The subjects are monitored every third week, and the frequency of administration or dosage of calcitriol can be modified accordingly during the duration of the treatment. The monitoring of the subjects includes the physical examination, the ECOG functioning status, hematology, anemia progression, blood chemistry, urinalysis, drug administration study, transfusion registry, adverse events, concomitant medications, FACT-An questionnaire , bone marrow aspiration and biopsy, peripheral blood smear, endogenous EPO and iron status.

EXAMPLE 3 TREATMENT PROGRAM IN COMBINATION OF VITAMIN D The following treatment program provides yet another example of using the methods described above to treat MDS, or improve a symptom thereof. The subjects self-administered the preferred formulation, which comprises approximately 15 μC of calcitriol in addition to the following excipients with the given amount in approximate weight percentage: 65% Miglyol 812N®, 30% Gelucire 44 / 14®, 5 % of vitamin E TPGS and approximately 0.05% of each of butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA). The total dose administered is 45 μg calcitriol, or three 15 μg capsules, once a week, taken all at once. The subjects are monitored every third week, and the frequency of administration or dosage of calcitriol can be modified accordingly during the duration of the treatment. The monitoring of the subjects includes the physical examination, the ECOG functioning status, hematology, anemia progression, blood chemistry, urinalysis, drug administration study, transfusion registry, adverse events, concomitant medications, FACT-An questionnaire , bone marrow aspiration and biopsy, peripheral blood smear, endogenous EPO and iron status. The subjects are further monitored to determine whether they are erythroid responders or non-responders to the administration of the vitamin D compound. A larger erythroid responder is a subject with a baseline hemoglobin less than 11 g / dl who experiences an increase of more than or equal to 2 g / dl of the baseline. A minor erythroid responder is a subject with a baseline hemoglobin less than 11 g / dl who experiences an increase of 1 to 2 g / dl from the baseline. Responders continue to receive calcitriol at the same dose and frequency, while non-responders begin taking EPO in combination with vitamin D compounds. The initial dose of EPO is 10, 000 U once per day. If there is no improvement after six weeks, the dose of EPO is increased to 20,000 U once per day. EPO is administered subcutaneously, and the iron status of the subject is also monitored.

EXAMPLE 4 CLINICAL TESTS Patients who are at low risk of MDS and refractory anemia who do not respond to erythropoietin were introduced in a Phase 2 trial to evaluate the effect of high-dose pulse administration of calcitriol. These patients are dependent on transfusion of red blood cells due to severe anemia. Patients were administered weekly with oral calcitriol at a dose of 45 g for 20 consecutive weeks. The calcitriol was formulated in a composition containing the following excipients with the amount given in approximate percentage by weight: 65% of Miglyol 812N®, 30% of Gelucire 44 / 14®, 5% of vitamin E TPGS and approximately 0.05% of each one of butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA). Patients were monitored for calcitriol activity by measuring hemoglobin and hematocrit levels and the number of transfusions administered during the treatment period compared to comparable values obtained during the eight-week pretreatment observation period. Patient # 1 showed an elevation in hemoglobin of more than one gram per deciliter compared to the baseline, constituting a protocol defined as "minor response" (Figure 2A). Patient # 2 demonstrated a 50% decrease in the required transfusions of red blood cells compared to baseline (Figure 2B). Patient # 3 showed an elevation in hemoglobin of more than two grams per deciliter compared to the baseline, constituting a protocol defined as "major response" (Figure 2C). The results from these three patients are indicators of a beneficial effect of high-dose pulse administration of calcitriol by the treatment of MDS. The various modalities have been described. The descriptions and examples are intended to be illustrative of the invention and not limiting. Those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is intended that such equivalents be encompassed by the following claims. All publications, patents and patent applications mentioned in this specification are incorporated herein by reference in the specification, to the same extent, as if each publication, patent or individual patent application was specifically and individually indicated to be incorporated by reference into the present.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (1)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A method for treating myelodysplastic syndrome (MDS), characterized in that it consists in administering a high dose of one or more vitamin D compounds to a subject in need of them. 2. The method according to claim 1, characterized in that one or more vitamin D compounds are administered no more than once every three, four, five, six, seven, eight, new or ten days. 3. The method of compliance with the claim 1, characterized in that one or more vitamin D compounds are administered no more than once every three days. 4. The method according to claim 1, characterized in that one or more vitamin D compounds are administered approximately once a week. 5. The method according to claim 1, characterized in that the high dose of one or more vitamin D compounds is about 3 \ i < 3 to approximately 300 6. The method according to claim 1, characterized in that the high dose of one or more vitamin D compounds is from about 5 μ to about 200 μg. The method according to claim 1, characterized in that the high dose of one or more vitamin D compounds is from about 15 μ9 to about 105 μ < 3. The method according to claim 1, characterized in that the high dose of one or more vitamin D compounds is from about 15 ig to about 90 μ. The method according to claim 1, characterized in that the high dose of one or more vitamin D compounds is from about 20 9 to about 80 μg. The method according to claim 1, characterized in that the high dose of one or more vitamin D compounds is about 35 μ < to approximately 75 The method according to claim 1, characterized in that the high dose of one or more vitamin D compounds is from about 30 μ to about 60 μg. The method according to claim 1, characterized in that the high dose of one or more vitamin D compounds is about 45 μ. The method according to claim 1, characterized in that one or more vitamin D compounds are administered in a dose reaching a maximum plasma concentration of the vitamin D compounds of at least about 0.5 nM. 1 . The method according to claim 1, characterized in that at least one of the vitamin D compounds is calcitriol. 15. The method of compliance with the claim 14, characterized in that the calcitriol is administered in the form of a pre-concentrate in emulsion. 16. The method of compliance with the claim 15, characterized in that the emulsion pre-concentrate comprises one or more lipophilic phase components, one or more surfactants, and one or more vitamin D compounds. 17. The method according to claim 15, characterized in that the pre-concentrate in emulsion it comprises approximately 15 iq of calcitriol, approximately 65% of Miglyol 812N®, and approximately 30% of Gelucire 44 / 14®. 18. The method according to claim 1, characterized in that one or more vitamin D compounds are administered intravenously. 19. A method for treating anemia associated with MDS, characterized in that it comprises administering a high dose of one or more vitamin D compounds to a subject in need thereof 20. The method according to claim 19, characterized in that or more vitamin D compounds are administered no more than once every three days 21. The method according to claim 19, characterized in that one or more vitamin D compounds are administered approximately once a week. according to claim 19, characterized in that the high dose of one or more vitamin D compounds is from about 3 μg to about 300 x 23. The method according to claim 19, characterized in that the high dose of one or more vitamin D compounds is about 15 <; 3 to about 105 μ < 3. The method according to claim 19, characterized in that the high dose of one or more vitamin D compounds is from about 35 μg to about 75 μg. 25. The method according to claim 19, characterized in that the high dose of one or more vitamin D compounds is about 45 μg. 26. The method of compliance with the claim 19, characterized in that one or more vitamin D compounds are administered in a dose reaching a maximum plasma concentration of at least about 0.5 nM. 27. The method according to claim 19, characterized in that at least one of the vitamin D compounds is calcitriol. 28. The method of compliance with the claim 27, characterized in that the calcitriol is administered in the form of a pre-concentrate in emulsion. 29. The method of compliance with the claim 28, characterized in that the emulsion pre-concentrate comprises one or more lipophilic phase components, one or more surfactants, and one or more vitamin D compounds. The method according to claim 28, characterized in that the pre-concentrate in emulsion comprises approximately 15 < of calcitriol, approximately 65% Miglyol 812N®, and approximately 30% Gelucire 44 / 14®. 31. The method according to claim 19, characterized in that one or more vitamin D compounds are administered intravenously. 32. A method for treating myelodysplastic syndrome, characterized in that it comprises a therapeutically effective dose of one or more vitamin D compounds and a therapeutically effective dose of one or more additional active agents that is not a vitamin D compound. 33. The method of according to claim 32, characterized in that one more vitamin D compounds are administered no more than once every three days. 34. The method according to claim 32, characterized in that one or more vitamin D compounds are administered approximately once a week. 35. The method according to claim 32, characterized in that the therapeutically effective dose of one or more vitamin D compounds is from about 3 xq to about 300 36. The method according to claim 32, characterized in that the therapeutically effective dose of one or more vitamin D compounds is from about 15 μ to about 105. 37. The method according to claim 32, characterized in that the therapeutically effective dose of one or more vitamin D compounds is from about 35 μ9 to about 75 38. The method according to claim 3-2, characterized in that the dose Therapeutically effective amount of one or more vitamin D compounds is approximately 5. 39. The method according to claim 32, characterized in that one or more vitamin D compounds are administered in a dose reaching a maximum plasma concentration of the vitamin D compounds of at least about 0.5 nM. 40. The method according to claim 32, characterized in that at least one of the vitamin D compounds is calcitriol. 41. The method according to the claim 40, characterized in that the calcitriol is administered in the form of a pre-concentrate emulsion. 42. The method of compliance with the claim 41, characterized in that the emulsion pre-concentrate comprises one or more lipophilic phase components, one or more surfactants, and one or more vitamin D compounds, wherein at least one vitamin D compound is calcitriol. 43. The method according to claim 41, characterized in that the emulsion pre-concentrate comprises approximately 15 μg calcitriol, approximately 65% Miglyol 812N®, and approximately 30% Gelucire 44 / 14®. 44. The method according to claim 32, characterized in that one or more vitamin D compounds are administered intravenously. 45. The method according to claim 32, characterized in that at least one of the additional active agents is a growth factor. 46. The method according to claim 32, characterized in that at least one of the additional active agents is a haematopoietic growth factor. 47. The method according to claim 32, characterized in that at least one of the additional active agents is a cytokine. 48. The method of compliance with the claim 32, characterized in that at least one of the additional active agents is IL-1, IL-2, IL-3, IL-6, IL-8, IL-ll, IL-12, IFN-alpha, G-CSF, G -CSF, EPO or TPO. 49. The method according to claim 46, characterized in that at least one of the ematopoietic growth factors is recombinant human erythropoietin (r-HuEPO). 50. The method according to claim 46, characterized in that at least one of the hematopoietic growth factors is the stimulation factor of human granulocyte colonies, methionyl, recombinant (r-metHuG-CSF). 51. The method according to claim 49, characterized in that the r-HuEPO is administered in a dose range of about 1 Unit / kg to about 2000 Units / kg. 52. The method according to claim 50, characterized in that r-metHuG-CSF is administered in a dose range of about 1 μg / kg / day to about 100 μg / kg / day. 53. The method according to claim 32, characterized in that at least one of the additional active agents is an immunomodulator. 54. The method of compliance with the claim 53, characterized in that at least one of the additional active agents is one of ATG, ALG, thalidomide, prednisone, CyA, dexamethasone or pentoxifylline. 55. The method according to claim 32, characterized in that at least one of the additional active agents is a cytotoxic agent. 56. The method according to claim 55, characterized in that at least one of the additional active agents is one of cytarabine, melphalan, topotecan, fludarabine, etoposide, idarubicin, daunorubicin or mitoxantrone. 57. The method according to claim 32, characterized in that at least one of the additional active agents is an agent that affects the transcription of the RNA. 58. The method according to claim 57, characterized in that at least one of the additional active agents is one of decitabine, 5-azacytidine, depsipeptides, and phenylbutyrate. 59. The method of compliance with the claim 32, characterized in that at least one of the additional active agents is a vitamin A, E or K derivative. 60. The method according to claim 59, characterized in that at least one of the additional active agents is one of the total acid. trans-retinoic acid, 13-cis-retinoic acid, tocopherol and menatetrenone. 61. The method according to claim 32, characterized in that at least one of the additional active agents is an agent that specifically binds to the biological targets related to MDS. 62. The method according to claim 61, characterized in that at least one of the additional active agents is one of anti-VEGF, gemtuzumab ozogamicin, and TFR: Fc. 63. The method according to claim 32, characterized in that at least one of the additional active agents is a signal transduction inhibitor. 64. The method according to claim 63, characterized in that at least one of the additional active agents is a farnesyl transferase inhibitor. 65. The method according to claim 64, characterized in that at least one of the additional active agents is one of Zarnestra11 or Sarasar "5. 66. The method according to claim 63, characterized in that at least one of the active agents Additional is a tyrosine kinase inhibitor 67. The method according to claim 66, characterized in that at least one of the additional active agents is one of SU5416, SU6668 or PT 787 / ZK222584. 68. The method according to Claim 32, characterized in that at least one of the additional active agents is aminothiol 69. The method according to claim 68, characterized in that at least one of the additional active agents is amifostine 70. The method according to claim 32. , characterized in that at least one of the additional active agents is an arsenic-containing compound 71. The method according to claim 7 0, characterized in that at least one of the additional active agents is arsenic trioxide.