Prevention of Thrombotic Disorders with Active Vitamin D Compounds or Mimics Thereof

• US 20080069814A1
• Filed: 03/26/2007
• Published: 03/20/2008
• Est. Priority Date: 01/05/2005
• Status: Abandoned Application

• Current Assignee: Novacea, Inc. (Paratek Pharmaceuticals Incorporated)
• Original Assignee: Novacea, Inc. (Paratek Pharmaceuticals Incorporated)
• Inventors: HENNER, William, CURD, John, GOODWIN, Bradford, LALANI, Alshad, BEER, Tomasz
• Application Number:
  US11/691,271
• Publication Number:
  US 20080069814A1
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/355 Tocopherols, e.g. vitamin E
• CPC Class Codes: A61K 31/59 Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
• CPC Class Codes: A61K 31/593 9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
• CPC Class Codes: A61K 38/16 Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 41/00 Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Abstract

The present invention relates to a method for preventing, treating, or ameliorating thrombotic disorders in an animal comprising administering to the animal an active vitamin D compound or a mimic thereof. According to the invention, the active vitamin D compound or the mimic thereof may be administered by HDPA so that high doses of the active vitamin D compound or the mimic thereof can be administered to an animal without inducing severe symptomatic hypercalcemia. The invention also relates a method for preventing, treating, or ameliorating thrombotic disorders in an animal comprising administering to the animal an active vitamin D compound or a mimic thereof in combination with one or more other therapeutic agents.

Claims

1. A method for preventing, treating or ameliorating a thrombotic disorder comprising administering by high dose pulse administration (HDPA) to an animal in need of such a treatment a pharmaceutical composition comprising an effective amount of active vitamin D compound or a mimic thereof.

2. The method of claim 1, wherein said active vitamin D compound is selected from the group consisting of calcitriol, 1α

-calcidol and calcifediol.

3. The method of claim 1, wherein said active vitamin D compound is calcitriol.

4. The method of claim 1, wherein said active vitamin D compound is 1α

-calcidol.

5. The method of claim 1, wherein said active vitamin D compound is calcifediol.

6. The method of claim 2, wherein said active vitamin D compound is administered as a unit dosage form comprising about 10 μ

g to about 75 μ

g of calcitriol, about 50% MIGLYOL 812 and about 50% tocopherol PEG-1000 succinate (vitamin E TPGS).

7. The method of claim 6, wherein said active vitamin D compound is administered as a unit dosage form comprising about 45 μ

g of calcitriol, about 50% MIGLYOL 812, about 50% vitamin E TPGS, BHA, and BHT.

8. The method of claim 6, wherein said unit dosage form is a capsule wherein the total volume of ingredients in said capsule is between about 10 μ

L to about 1000 μ

L.

9. The method of claim 1, wherein said HDPA is administered no more frequently than once in three days.

10. The method of claim 1, wherein said active vitamin D compound is administered orally, intravenously, parenterally, rectally, sublingually, intramuscularly, topically, nasally or transdermally.

11. The method of claim 1, further comprising administering one or more therapeutic agents.

12. The method of claim 11, wherein said one or more therapeutic agent is a chemotherapeutic agent, an anti-angiogenic factor, or a combination thereof.

13. The method of claim 11, wherein said one or more therapeutic agents are a contributing cause to said thrombosis.

14. The method of claim 13, wherein said one or more therapeutic agents are selected from the group consisting of anti-angiogenic factors, vasodilators, immunosuppressants, anti-inflammatories, and collagen synthetase inhibitors, actinomycin D, irinotecan, vincristine, vinblastine, vinorelbine, SN-38, azacitidine, thalidomide, methotrexate, azathioprine, fluorouracil, doxorubicin, mitomycin, nitrates, calcium channel blockers, hirudin, iloprost, sirolimus, everolimus, A24, tranilast, dexamethasone, tacrolimus, halofuginone, propyl hydroxylase, C-proteinase inhibitor, metalloproteinase inhibitor, corticosteroids, non-steroidal anti-inflammatory drugs, 17β

-estradiol, angiotensin converting enzyme inhibitors, colchicine, fibroblast growth factor antagonists, histamine antagonists, lovastatin, nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, thioprotease inhibitors, platelet-derived growth factor antagonists, nitric oxide, angiopeptin and antineoplastic agents comprising paclitaxel and docetaxel.

15. The method of claim 12 or 14, wherein said anti-angiogenic factor is selected from the group consisting of bevacizumab, VEGF-TRAP, anti-VEGF-receptor antibodies, angiostatin, endostatin, batimastat, captopril, cartilage derived inhibitor, genistein, interleukin 12, lavendustin, medroxypregesterone acetate, recombinant human platelet factor 4, tecogalan, thrombospondin, TNP-470, VEGF antagonists, anti-VEGF monoclonal antibodies, soluble VEGF-receptor chimaeric proteins, antisense oligonucleotides, antisense oligodexoynucleotides, siRNAs, anti-VEGF aptamers, pigment epithelium derived factor, tyrosine kinase inhibitors, inhibitors of epidermal-derived growth factor, inhibitors of fibroblast-derived growth factor, inhibitors of platelet derived growth factor, matrix metalloprotease inhibitors, integrin blockers, interferon-α

, pentosan polysulfate, cyclooxygenase inhibitors, carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, troponin-1, indolinethiones, pyridopyrimidines, quinoazolines, phenyl-pyrrolo-pyrimidines, trastuzumab, calcium influx inhibitors, neomycin, squalamine, marimastat, prinomastat, metastat and cinnoline derivatives.

16. The method of claim 11, wherein said one or more therapeutic agent is an erythropoiesis-stimulating agent, alone or in combination with a chemotherapeutic agent, an anti-angiogenic factor, a radiotherapeutic agent, or combinations thereof.

17. The method of claim 16, wherein said erythropoiesis-stimulating agent is erythropoietin, dabepoetin alfa, or epoetin alfa.

19. The method of claim 11, wherein said one or more therapeutic agents are anti-thrombotic agents.

20. The method of claim 19, wherein said one or more therapeutic agents are selected from the group consisting of anticoagulants, anti-platelet agents, anti-thrombins, heparin, aspirin, blockers of IIb/IIIa receptors hirudin, platelet-derived growth factor antagonists, coumarin, bishydroxycoumarin, warfarin, acid citrate dextrose, lepirudin, ticlopidine, clopidogrel, tirofiban, argatroban, and eptifibatide.

21. The method of claim 11, wherein said one or more therapeutic agents is a taxane.

22. The method of claim 21, wherein said taxane is paclitaxel or docetaxel.

23. The method of claim 1, wherein said thrombotic disorder is selected from the group consisting of venous and arterial thrombosis, congestive heart failure, transient ischemic attacks, stroke, pulmonary embolism, arterial embolism, atherosclerosis, myocardial ischemia, myocardial infarction, cerebral thrombosis and ischemia, atherosclerosis and arteriosclerosis, angina, peripheral vascular disease, preeclampsia, and restenosis following angioplasty, carotid endarterectomy or anastomosis of vascular grafts.

18. A method for preventing, treating, or ameliorating a thrombotic disorder associated with administration of one or more erythropoiesis-stimulating agents to an animal, comprising administering to said animal an effective amount of active vitamin D compound or a mimic thereof.