US20030207810A1 - Method of treating malignancy associated hypercalcemia using active vitamin D analogues - Google Patents
Method of treating malignancy associated hypercalcemia using active vitamin D analogues Download PDFInfo
- Publication number
- US20030207810A1 US20030207810A1 US10/441,731 US44173103A US2003207810A1 US 20030207810 A1 US20030207810 A1 US 20030207810A1 US 44173103 A US44173103 A US 44173103A US 2003207810 A1 US2003207810 A1 US 2003207810A1
- Authority
- US
- United States
- Prior art keywords
- compound
- accordance
- vitamin
- hydrogen
- dihydroxyvitamin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 0 [1*]C([2*])(C)C([3*])(C)C(C)C(C)C(C)C1CCC2C(C/C=C3/C[C@@H](C)C[C@H](O)c3[y])CCCC21C Chemical compound [1*]C([2*])(C)C([3*])(C)C(C)C(C)C(C)C1CCC2C(C/C=C3/C[C@@H](C)C[C@H](O)c3[y])CCCC21C 0.000 description 8
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- This invention relates generally to a method of treating malignancy-associated hypercalcemia (MAH), and in particular, to the use of active forms of vitamin D to reduce hypercalcemia associated with inhibit the hyperproliferative diseases.
- MAH malignancy-associated hypercalcemia
- Vitamin D 1 ⁇ ,25-dihydroxyvitamin D 3
- LNCaP human prostatic carcinoma cell line
- Vitamin D receptors have also been described for many other neoplastic cells, e.g., carcinomas of the breast and carcinomas of the colon.
- vitamin D compounds and analogues are potent inhibitors of malignant cell proliferation and are inducers/stimulators of cell differentiation.
- U.S. Pat. No. 4,391,802 issued to Suda et al. discloses that 1 ⁇ -hydroxyvitamin D compounds, specifically 1 ⁇ ,25-dihydroxyvitamin D 3 and 1 ⁇ -hydroxyvitamin D 3 , possess potent antileukemic activity by virtue of inducing the differentiation of malignant cells (specifically leukemia cells) to nonmalignant macrophages (monocytes), and are useful in the treatment of leukemia.
- PTHrP Parathyroid hormone related protein
- PTH parathyroid hormone
- PTHrP is one of the main causative substances of such hypercalcemia, and is overproduced by malignant cells.
- 1,25-dihydroxyvitamin D 3 has been found to repress the transcription of the PTHrP gene in cells, however, the 1,25-dihydroxyvitamin D 3 compounds themselves increase serum calcium levels. Therefore a need exists for compounds with greater specific activity and selectivity of action, i.e., vitamin D compounds with antiproliferative and differentiating effects but which have less calcemic activity.
- the present invention provides a method of treating malignancy-associated hypercalcemia (MAH) such as that associated with hyperproliferative cell growth and/or abnormal cell differentiation.
- the method includes use of active vitamin D compounds to treat hypercalcemia and reduce serum parathyroid hormone related protein (PTHrP) levels.
- PTHrP serum parathyroid hormone related protein
- a method of treating malignancy-associated hypercalcemia from the hyperproliferative activity of human neoplastic or hyperplastic cells comprising treating the cells with an effective amount of a hypocalcemic hydroxyvitamin D compound having a hydrocarbon moiety substituted at the C-24 position on the sidechain of the molecule.
- the treating step includes inhibiting proliferation of, and inducing and enhancing differentiation in such cells.
- a hydroxyvitamin D compound in accordance with the present invention is an active vitamin D and is suitably represented by the formula (I) described hereafter.
- Suitable compounds of formula (I) are 1 ⁇ ,24-dihydroxyvitamin D 2 , 1 ⁇ ,24-dihydroxyvitamin D 4 , 1 ⁇ ,25-dihydroxyvitamin D 4 , 1 ⁇ ,25-dihydroxyvitamin D 2 , 1 ⁇ -hydroxyvitamin D 2 and 1 ⁇ -hydroxyvitamin D 4 .
- the effective or therapeutic amount of the hypocalcemic hydroxyvitamin D compounds administrable in accordance with the present invention to patients in need on a daily basis per kilogram of body weight ranges from 0.01 ⁇ g/kg/day to 2.0 ⁇ g/kg/day.
- lowering serum parathyroid hormone related protein (PTHrP) levels in patients suffering from hypercalcemia is accomplished by a method comprising, administering to these patients an effective amount of a hypocalcemic vitamin D compound, to lower the serum parathyroid hormone related protein (PTHrP) level.
- the hypocalcemic vitamin D compounds are also valuable for the treatment of breast, prostate and colon cancer, as well as other neoplasms such as pancreatic cancer, endometrial cancer, testicular cancer, small cell and non-small cell cancer of the lung (including squamous, adneocarcinoma and large cell types), squamous cell of the head and neck, bladder, ovarian and cervical cancers, myeloid and lymphocyltic leukemia, lymphoma, hepatic tumors, medullary thyroid carcinoma, multiple myeloma, retinoblastoma, and sarcomas of the soft tissue and bone, i.e. neoplasms that express a vitamin D receptor.
- neoplasms that express a vitamin D receptor.
- the hypocalcemic vitamin D compounds when effective amounts of the hypocalcemic vitamin D compounds are administered to patients with MAH, significantly redeuced hypercalcemia is observed than is observed after the same amount of an activated vitamin D 3 (e.g., 1 ⁇ -OH D 3 , 1 ⁇ ,25-(OH) 2 D 3 ) is administered in previously known formulations.
- an activated vitamin D 3 e.g., 1 ⁇ -OH D 3 , 1 ⁇ ,25-(OH) 2 D 3
- the compound in accordance with the present invention has an improved therapeutic index relative to active forms of vitamin D 3 analogues.
- another aspect of the invention is a method of treating malignancy associated hyercalcemia comprising administering to a subject who is suffering therefrom an effective amount of active vitamin D compound which has, or attains through metabolism in vivo, a vitamin D receptor (VDR) binding affinity substantially equivalent to the binding affinity of 1 ⁇ ,25-dihydroxyvitamin D 3 and has a hypercalcemia risk substantially lower that that of 1 ⁇ ,25-dihydroxyvitamin D 3 , to normalize or reduce serum calcium levels.
- VDR vitamin D receptor
- the active vitamin D is suitably administered alone as an active ingredient in a pharmaceutical composition, or is co-administered with an anticancer agent.
- a hypocalcemic vitamin D compound with a cytotoxic or anticancer agent.
- agents suitably include antimetabolites (e.g., 5-fluoro-uracil, methotrexate, fludarabine), antimicrotubule agents (e.g., vincristine, vinblastine, taxanes such as paclitaxel, docetaxel), an alkylating agent (e.g., cyclophasphamide, melphalan, biochoroethylnitrosurea, hydroxyurea), platinum agents (e.g.
- cisplatin carboplatin, oxaliplatin, JM-216, CI-973
- anthracyclines e.g., doxrubicin, daunorubicin
- antibiolitics e.g., mitomycin, idarubicin, adriamycin, daunomycin
- topoisomerase inhibitiors e.g., etoposide, camptothecins
- any other antineoplastic agents estramustine phosphate, prednimustine.
- the active vitamin D compounds used in combination with various anticancer drugs can give rise to a significantly enhanced cytotoxic effect on cancerous cells, thus providing an increased therapeutic effect.
- a significantly increased growth-inhibitory effect is obtained with the above disclosed combinations utilizing lower concentrations of the anticancer drugs compared to the treatment regimes in which the drugs are used alone, there is the potential to provide therapy wherein adverse side effects associated with the anticancer drugs are considerably reduced than normally observed with the anticancer drugs used alone in larger doses.
- Possible dose ranges of these co-administered anticancer agents are about 0.1 to 20 mg/kg/day.
- a hypocalcemic vitamin D compound in conjunction with administration of hormones or other agents, e.g., estrogens, which are known to ameliorate bone diseases or disorders.
- hormones or other agents e.g., estrogens
- prostate cancer often metastasizes to bone, causing bone loss and associated pain.
- bone agents may include conjugated estrogens or their equivalents, calcitonin, bisphosphonates, calcium supplements, cobalamin, pertussis toxin and boron.
- the invention is a pharmaceutical composition which includes an anticancer agent which is an active hypocalcemic vitamin D compound; an agent selected from the group consisting of (i) an anticancer agent, (ii) a bone agent, and combinations thereof; and a physiologically acceptable carrier.
- an anticancer agent which is an active hypocalcemic vitamin D compound
- an agent selected from the group consisting of (i) an anticancer agent, (ii) a bone agent, and combinations thereof and a physiologically acceptable carrier.
- the present invention provides an effective method for the treatment of hypercalcemia, i.e. unphysiologically high and deleterious blood calcium levels, associated with neoplastic and hyperproliferative diseases.
- the present invention relates to therapeutic methods for ameliorating or alleviating the hypercalcemia associated with the hyperproliferative cellular activity of malignant and neoplastic diseases, as well as inducing, enhancing or promoting cell differentiation in the diseased cells.
- the present invention provides a novel treatment of a patient suffering from a hyperproliferative disease with an active hypocalcemic vitamin D compound.
- the active vitamin D analogue is a hydroxyvitamin D compound and is suitably represented by formula (I) as described hereinbelow.
- the active vitamin D analogue is provided to the patient without itself causing dose-limiting hypercalcemia and hypercalciuria, and in fact, reduces the hypercalcemia caused by the malignancy. These attributes are achieved through specific chemical properties of the hypocalcemic vitamin D compounds as described.
- hypocalcemic active vitamin D compounds when effective amounts of the hypocalcemic active vitamin D compounds are administered to patients with malignant diseases, the hypercalcemia is reduced, the PTHrP serum level is reduced, and the proliferative activity of the abnormal cells is inhibited, redeuced, or stabilized, and cell differentiation is induced, promoted or enhanced.
- the hypocalcemic vitamin D compounds of the present invention have an improved therapeutic index relative to active forms of vitamin D 3 analogues.
- activated vitamin D or “active vitamin D” is intended to refer to a vitamin D compound or analogue that has been hydroxylated in at least the C-1, C-24 or C-25 position of the molecule and either the compound itself or its metabolites in the case of a prodrug, such as 1 ⁇ -hydroxyvitamin D 2 , binds the vitamin D receptor (VDR).
- prodrugs are vitamin D compounds which are hydroxylated in the C-1. Such compounds undergo further hydroxylation in vivo and their metabolites bind the VDR.
- hypocalcemic vitamin D compound is in reference to active vitamin D analogs which demonstrate hypocalcemic activity, i.e. have low calcemic activity relative to that of 1 ⁇ ,25-dihydroxyvitamin D 3 , including 24-hydroxyvitamin D compounds, 25-hydroxyvitamin compounds and I a-hydroxyvitamin compounds.
- alkyl alkenyl acyl, or cycloalkyl
- lower as a modifier for alkyl, alkenyl acyl, or cycloalkyl is meant to refer to a straight or branched, saturated or unsaturated hydrocarbon radical having 1 to 4 carbon atoms.
- hydrocarbon radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, ethenyl, propenyl, butenyl, isobutenyl, isopropenyl, formyl, acetyl, propionyl, butyryl or cyclopropyl.
- aromatic acyl is meant to refer to a unsubstituted or substituted benzoyl group.
- hydrocarbon moiety refers to a lower alkyl, a lower alkenyl, a lower acyl group or a lower cycloalkyl, i.e., a straight or branched, saturated or unsaturated C 1 -C 4 hydrocarbon radial.
- the compound in accordance with the present invention is an active hypocalcemic vitamin D compound.
- the active vitamin D provided is such that the compound has a hydrocarbon moiety at the C-24 position, e.g. a lower alkyl, alkenyl or acyl group as the C-24 position.
- the active vitamin D in accordance with the present invention may have an unsaturated sidechain, e.g., there is suitably a double bond between C-22 and C-23, between C-25 and C-26 or between C-26 and C-27.
- hypocalcemic hydroxyvitamin D of the present invention suitably has the general formula described in formula (I)
- a 1 and A 2 each are hydrogen or a carbon-carbon bond, thus forming a double bond between C-22 and C-23;
- R 1 and R 2 are identical or different and are hydrogen, hydroxyl, lower alkyl, lower fluoroalkyl, O-lower alkyl, lower alkenyl, lower fluoroalkenyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl, lower cycloalkyl with the proviso that R 1 and R 2 cannot both be alkenyl, or taken together with the carbon to which they are bonded, form a C 3 -C 8 cyclocarbon ring;
- R 3 is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl;
- X 1 is hydrogen or hydroxyl,
- a 1 ⁇ -hydroxyvitamin D compound of formula (I) is characterized by the general formula (II):
- a 1 and A 2 each are hydrogen or a carbon-carbon bond, thus forming a double bond between C-22 and C-23;
- R 1 and R 2 are identical or different and are hydrogen, hydroxyl, lower alkyl, lower fluoroalkyl, O-lower alkyl, lower alkenyl, lower fluoroalkenyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl, lower cycloalkyl with the proviso that R 1 and R 2 cannot both be an alkenyl, or taken together with the carbon to which they are bonded, form a C 3 -C 8 cyclocarbon ring;
- R 3 is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl;
- X 1 is hydrogen or hydroxyl
- 1 ⁇ -hydroxyvitamin D compounds in accordance with the present invention are characterized by the general formula (III):
- a 1 and A 2 each are hydrogen or a carbon-carbon bond, thus forming a double bond between C-22 and C-23;
- R 1 and R 2 are identical or different and are hydrogen, hydroxyl, lower alkyl, lower fluoroalkyl, O-lower alkyl, lower alkenyl, lower fluoroalkenyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl, lower cycloalkyl with the proviso that R 1 and R 2 cannot both be an alkenyl, or taken together with the carbon to which they are bonded, form a C 3 -C 8 cyclocarbon ring;
- R 3 is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl;
- X 1 is hydrogen or hydroxyl
- hypocalcemic hydroxyvitamin D compounds of the present invention are those that have effective antiproliferative and cell differentiation activity (i.e., reversal of malignant transformation), but have a lower tendency or inability to cause hypercalcemia and/or hypercalciuria i.e. they are hypocalcemic compounds that have low calcemic activity relative to that of 1 ⁇ ,25-dihydroxyvitamin D 3 .
- the compounds of the present invention can be administered at dosages that allow them to act as antiproliferative agents and cell differentiation agents when exposed to malignant or other hyperproliferative cells and can reduce hypercalcemia associated with the maligancy.
- hypocalcemic vitamin D compounds useful and preferred antihypercalcemic agents as well as safely inhibiting hyperproliferation and promoting malignant or hyperplastic cell differentiation.
- the compounds of the present invention overcome the shortcomings of the known active vitamin D 3 compounds described above, and can be considered preferred agents for the control and treatment of malignant diseases such breast, prostate, testicular and colon cancer, as well as other neoplasms such as pancreatic cancer, endometrial cancer, small cell and non-small cell cancer of the lung (including squamous, adneocarcinoma and large cell types), squamous cell of the head and neck, bladder, ovarian and cervical cancers, myeloid and lymphocyltic leukemia, lymphoma, hepatic tumors, medullary thyroid carcinoma, multiple myeloma, melanoma retinoblastoma, and sarcomas of the soft tissue and bone, i.e. neo
- Suitable hypocalcemic vitamin D compounds in accordance with the present invention include: 1 ⁇ ,24-dihydroxyvitamin D 2 , 1 ⁇ ,24-dihydroxyvitamin D 4 , 1 ⁇ ,25-dihydroxyvitamin D 2 , 1 ⁇ ,25-dihydroxyvitamin D 4 , 1 ⁇ -hydroxyvitamin D 2 , and 1 ⁇ -hydroxyvitamin D 4 .
- compounds of formula (I) that have a chiral center in the sidechain, such as at C-24, it is understood that both epimers (e.g., R and S) and the racemic mixture are within the scope of the present invention.
- the present invention provides a method of treating hypercalcemia associated with malignant cells with an effective amount of a hypocalcemic vitamin D compound.
- the effective dosage amount on a daily basis per kilogram of body weight of the patient ranges from about 0.01 ⁇ g/kg/day to about 2.0 ⁇ g/kg/day.
- the compounds of formula (I) can be prepared as described, e.g., in U.S. Pat. No. 5,488,120 issued to Knutson et al., U.S. Pat. Nos. 4,670,190 and 4,554,106 issued to DeLuca et al., U.S. Pat. No. 5,486,636 issued to DeLuca et al., and Slitnell et al., 310 Biochem. J. ( 1995) pp. 233-241, all of which are incorporated herein by reference.
- the biopotencies of the compounds of formula (I) have been studied and compared to that of 1 ⁇ ,25-dihydroxyvitamin D 3 , the active hormonal form of vitamin D and the standard against which all vitamin D compounds and analogues are measured.
- VDR vitamin D receptor
- the vitamin D receptor (VDR) binding affinities of the compounds of formula (I), or their active metabolites are substantially equivalent to (i.e., equal to or up to 3 times weaker than) the affinity of 1 ⁇ ,25-dihydroxyvitamin D 3 .
- Such receptor binding affinities are indicative of potent biological activity.
- 1 ⁇ -hydroxyvitamin D 2 has the same biopotency as 1 ⁇ -hydroxyvitamin D 3 and 1 ⁇ ,25-dihydroxyvitamin D 3 but is much less toxic. Even dosages up to 10 ⁇ g/day of 1 ⁇ -hydroxyvitamin D 2 in women with postmenopausal osteoporosis elicited only mild hypercalciuria (U.Ca>300 mg/24 hrs), and no marked hypercalcemia (S. Ca>1 1.0 mg/dL) solely due to 1 ⁇ -hydroxyvitamin D 2 was evident.
- the compound did not adversely affect kidney function, as determined by creatinine clearance and BUN; nor did it increase urinary excretion of hydroxyproline, indicating the absence of any stimulatory effect on bone resorption.
- Administration of 1 ⁇ -hydroxyvitamin D 2 to healthy adult males in dosages up to 8 ⁇ g/day showed no clinically significant hypercalcemia or other adverse effects.
- hypocalcemic vitamin D compounds of the present invention are useful as active compounds in pharmaceutical compositions having reduced side effects and low toxicity as compared with the known analogues of active forms of vitamin D 3 .
- the pharmacologically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, e.g., mammals including humans.
- the hypocalcemic vitamin D compounds can be employed in admixtures with conventional excipients, e.g., pharmaceutically acceptable carrier substances suitable for enteral (e.g., oral), parenteral or topical application which do not deleteriously react with the active compounds.
- Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils (e.g., almond oil, corn oil, cottonseed oil, peanut oil, olive oil, coconut oil), mineral oil, fish liver oils, oily esters such as Polysorbate 80, polyethylene glycols, gelatine, carbohydrates (e.g., lactose, amylose or starch), magnesium stearate, talc, silicic acid, viscous paraffin, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxy methylcellulose, polyvinyl pyrrolidone, etc.
- vegetable oils e.g., almond oil, corn oil, cottonseed oil, peanut oil, olive oil, coconut oil
- mineral oil e.g., fish liver oils
- oily esters such as Polysorbate 80, polyethylene glycols, gelatine, carbohydrates (e.g., lactose, amylose or starch), magnesium
- the pharmaceutical preparations can be sterilized and, if desired, be mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or one or more other active compounds, for example, vitamin D 3 and its 1 ⁇ -hydroxylated metabolites, conjugated estrogens or their equivalents, anti-estrogens, calcitonin, biphosphonates, calcium supplements, cobalamin, pertussis toxin and boron.
- auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or one or more other active compounds, for example, vitamin D 3 and its 1 ⁇ -hydroxylated metabolites, conjugated estrogens or their equivalents, anti-estrogens, calcitonin, biphosphon
- parenteral application particularly suitable are injectable, sterile solutions, preferably oily or aqueous solution, as well as suspensions, emulsions, or implants, including suppositories.
- Parenteral administration suitably includes subcutaneous, intramuscular, or intravenous injection, nasopharyngeal or mucosal absorption, or transdermal absorption. Ampoules are convenient unit dosages.
- Suitable enteral application particularly suitable are tablets, dragees, liquids, drops, suppositories, lozenges, powders, or capsules.
- a syrup, elixir, or the like can be used if a sweetened vehicle is desired.
- suitable nonsprayable viscous, semi-solid or solid forms can be employed which include a carrier compatible with topical application and having a dynamic viscosity preferably greater than water, for example, mineral oil, almond oil, self-emulsifying beeswax, vegetable oil, white soft paraffin, and propylene glycol.
- Suitable formulations include, but are not limited to, creams, ointments, lotions, solutions, suspensions, emulsions, powders, liniments, salves, aerosols, transdermal patches, etc., which are, if desired, sterilized or mixed with auxiliary agents, e.g., preservatives, stabilizers, demulsifiers, wetting agents, etc.
- a cream preparation in accordance with the present invention suitably includes, for example, mixture of water, almond oil, mineral oil and self-emulsifying beeswax; an ointment preparation suitably includes, for example, almond oil and white soft paraffin; and a lotion preparation suitably includes, for example, dry propylene glycol.
- Topical preparations of the compound in accordance with the present invention useful for the treatment of skin disorders may also include epithelialization-inducing agents such as retinoids (e.g., vitamin A), chromanols such as vitamin E, ⁇ -agonists such as isoproterenol or cyclic adenosine monophosphate (cAMP), anti-inflammatory agents such as corticosteroids (e.g., hydrocortisone or its acetate, or dexamethasone) and keratoplastic agents such as coal tar or anthralin.
- epithelialization-inducing agents such as retinoids (e.g., vitamin A), chromanols such as vitamin E, ⁇ -agonists such as isoproterenol or cyclic adenosine monophosphate (cAMP), anti-inflammatory agents such as corticosteroids (e.g., hydrocortisone or its acetate, or dexamethasone) and kera
- Effective amounts of such agents are, for example, vitamin A about 0.003 to about 0.3% by weight of the composition; vitamin E about 0.1 to about 10%; isoproterenol about 0.1 to about 2%; cAMP about 0.1 to about 1%; hydrocortisone about 0.25 to about 5%; coal tar about 0.1 to about 20%; and anthralin about 0.05 to about 2%.
- the compound is formed into a pharmaceutical composition containing a suppository base such as cacao oil or other triglycerides.
- a suppository base such as cacao oil or other triglycerides.
- the composition advantageously includes an antioxidant such as ascorbic acid, butylated hydroxyanisole or hydroquinone.
- the compound of this invention is dispensed by unit dosage form comprising about 0.5 ⁇ g to about 25 ⁇ g in a pharmaceutically acceptable carrier per unit dosage.
- the dosage of the compound according to this invention generally is about 10 ⁇ g to 200 ⁇ g/day.
- the dosage of the compound of the present invention in a topical composition generally is about 0.01 ⁇ g to about 50 ⁇ g per gram of composition.
- the dosage of the hypocalcemic vitamin D compound in a locally applied composition generally is about 0.01 ⁇ g to 100 ⁇ g per gram composition.
- dosing of the hypocalcemic compounds in accordance with the present invention can also be done on an episodic basis, in which case higher doses can be used generally about 20 ⁇ g to about 200 ⁇ g given once every 2 to 7 days.
- the dose can be given as a single dose or a divided dose in 2 to 5 subdoses, the subdoses given, e.g., one every hour until the total dose is taken.
- a hypocalcemic vitamin D compound with a anticancer agent, e.g., a cytotoxic agent
- agents suitably include antimetabolites (e.g., 5-fluoro-uracil, methotrexate, fludarabine), antimicrotubule agents (e.g., vincristine, vinblastine, taxanes such as paclitaxel, docetaxel), an alkylating agent (e.g., cyclophasphamide, melphalan, biochoroethylnitrosurea, hydroxyurea), platinum agents (e.g.
- cisplatin carboplatin, oxaliplatin, JM-216, CI-973
- anthracyclines e.g., doxrubicin, daunorubicin
- antibiolitics e.g., mitomycin, idarubicin, adriamycin, daunomycin
- topoisomerase inhibitors e.g., etoposide, camptothecins
- any other antineoplastic agents estramustine phosphate, prednimustine.
- co-administration is meant to refer to any administration route in which two or more agents are administered to a patient or subject.
- the agents may be administered together, or before or after each other.
- the agents may be administered by different routes, e.g., one agent may be administered intravenously while the second agent is administered intramuscularly, intravenously or orally.
- the agents may be administered simultaneously or sequentially, as long as they are given in a manner sufficient to allow both agents to achieve effective concentrations in the body.
- the agents also may be in an admixture, as, for example, in a single tablet.
- one agent may directly follow administration of the other or the agents may be give episodically, i.e., one can be given at one time and the other at a later time, typically within a week.
- An example of a suitable co-administration regimen is where a hypocalcemic vitamin D compound is administered from 0.5 to 7 days prior to administration of a cytotoxic agent.
- analogue of formula (I) in conjunction with administration of hormones or other agents, e.g., estrogens, which are known to ameliorate bone diseases or disorders.
- hormones or other agents e.g., estrogens
- prostate cancer often metastasizes to bone, causing bone loss and associated pain.
- bone agents may include conjugated estrogens or their equivalents, calcitonin, bisphosphonates, calcium supplements, cobalamin, pertussis toxin and boron. It is contemplated that these bone agents also have an antihypercalcemic effect and may enhance the treatment of malignancy-associated hypercalcemia. Possible dose ranges for these co-administered bone agents are provided in Table 1.
- 1 ⁇ ,24-(OH) 2 D 2 had a very similar affinity for bovine thymus VDR as did 1 ⁇ ,25-(OH) 2 D 3 , indicating that 1 ⁇ ,24-(OH) 2 D 2 has potent biological activity.
- the VDR affinity binding of 1 ⁇ ,24-(OH) 2 D 4 was investigated.
- the 1 ⁇ ,24-(OH) 2 D 4 was incubated with vitamin D receptor and radiolabeled tracer 1 ⁇ ,25-(OH) 2 D 3 . After incubation, the amount of radioactivity bound to the receptor was determined and compared with the amount bound after co-incubation of unlabeled and labeled 1 ⁇ ,25-(OH) 2 D 3 . It was found that 50 pg/tube of 1 ⁇ ,24-(OH) 2 D 4 was equivalent to approximately 20 pg 1 ⁇ ,25-(OH) 2 D 3 .
- VDR binding of vitamin D compounds by prostate cells is demonstrated using the techniques of Skowronski et al., 136 Endocrinology ( 1995) 20-26, which is incorporated herein by reference.
- Prostate-derived cell lines are cultured to near confluence, washed and harvested by scraping. Cells are washed by centrifugation, and the cell pellet resuspended in a buffered salt solution containing protease inhibitors. The cells are disrupted by sonication while cooling on ice. The supernatant obtained from centrifuging the disrupted cells at 207,000 ⁇ g for 35 min at 4EC is assayed for binding.
- Example 3 The procedure of Example 3 is repeated using the active vitamin D analogue 1 ⁇ ,24-(OH) 2 D 4 , and the specific binding is determined. The results demonstrate that 1 ⁇ ,24-(OH) 2 D 4 has strong affinity for prostate VDR, indicating that 1 ⁇ ,24-(OH) 2 D 4 has potent biological activity in respect of prostate cells.
- Example 3 The procedure of Example 3 is repeated using the active vitamin D analogue 1 ⁇ ,25-(OH) 2 D 4 , and the specific binding is determined. The results demonstrate that 1 ⁇ ,25-(OH) 2 D 4 has strong affinity for prostate VDR, indicating that 1 ⁇ ,25-(OH) 2 D 4 has potent biological activity in respect of prostate cells.
- One plasmid contained the gene for Growth Hormone (GH) under the control of the vitamin D responsive element (VDRE) and the other plasmid contained the structural gene for the vitamin D receptor (VDR).
- GH Growth Hormone
- VDRE vitamin D responsive element
- VDR vitamin D receptor
- Table 2 below shows the results of this assay: TABLE 2 Induction of Growth Hormone by Vitamin D Compounds Concentration Growth Hormone Compound Used (M) Induction (ng/ml) 1,25-(OH) 2 D 3 1 ⁇ 10 ⁇ 10 39 1,25-(OH) 2 D 3 5 ⁇ 10 ⁇ 10 248 1,24-(OH) 2 D 4 5 ⁇ 10 ⁇ 10 165 1,24-(OH) 2 D 4 1 ⁇ 10 ⁇ 9 628 1,24-(OH) 2 D 4 5 ⁇ 10 ⁇ 9 1098
- Example 6 The gene expression study described in Example 6 was conducted to compare the biological activity in vitro of chemically synthesized 1 ⁇ ,24(S)-(OH) 2 D 2 and 1 ⁇ ,24(R)-(OH) 2 D 2 , with 1 ⁇ ,25-(OH) 2 D 3 and 25-OH-D 3 .
- the vitamin D-dependent transcriptional activation model system was used in which plasmids pSG5-hVDR1/3 and p(CT4) 4 TKGH were co-transfected into Green monkey kidney, COS-1 cells.
- the medium is removed, the cells are rinsed, precipitated with cold 5% trichloroacetic acid, and washed with cold ethanol.
- the cells are solubilized with 0.2 N sodium hydroxide, and the amount of DNA determined by standard procedures. The results show that cultures incubated with 1 ⁇ ,24-(OH) 2 D 2 in accordance with the present invention have significantly fewer cells than the control cultures.
- Example 8 The procedure of Example 8 is repeated using the active vitamin D analogue 1 ⁇ ,24-(OH) 2 D 4 , and the cell number is determined. Cultures incubated with 1 ⁇ ,24-(OH) 2 D 4 have significantly fewer cells than the control cultures.
- Example 8 The procedure of Example 8 is repeated using the active vitamin D analogue 1 ⁇ ,25-(OH) 2 D 4 , and the cell number is determined. Cultures incubated with 1 ⁇ ,25-(OH) 2 D 4 have significantly fewer cells than the control cultures.
- cells of the cell line, LNCaP which is derived from a human metastatic prostate adenocarcinoma and known to express PSA
- LNCaP which is derived from a human metastatic prostate adenocarcinoma and known to express PSA
- the medium is replenished with medium containing vehicle or the active vitamin D analogue, 1 ⁇ ,24-(OH) 2 D 2 , at concentrations from 10 ⁇ 11 M to 10 ⁇ 7 M. After 6-7 days, the medium is removed and stored at ⁇ 20EC for prostate specific antigen (PSA) analysis.
- PSA prostate specific antigen
- Example 12 The procedure of Example 12 is repeated except the active vitamin D analogue is 1 ⁇ ,24-(OH) 2 D 4 .
- the PSA is measured and cultures incubated with 1 ⁇ ,24-(OH) 2 D 4 have significantly more PSA than control cultures when expressed as mass of PSA/cell.
- Example 12 The procedure of Example 12 is repeated except the active vitamin D analogue is 1 ⁇ ,25-(OH) 2 D 4 .
- the PSA is measured and cultures incubated with 1 ⁇ ,25-(OH) 2 D 4 have significantly more PSA than control cultures when expressed as mass of PSA/cell.
- Patients with malignancy-associated hypercalcemia participate in an open-label study of a hypocalcemic vitamin D compound in accordance with the present invention. Patients are restricted to daily calcium intake of about 400-500 mg. Each patient is also asked to drink 4-6 cups of fluid more than usual intake to assure adequate oral hydration.
- Each subject is monitored at regular intervals for: (1) hypercalcemia, serum PTHrP levels, hyperphosphatemia, hypercalciuria, hyperphosphaturia and other toxicity; (2) evidence of changes in the progression of metastatic disease; and (3) compliance with the prescribed test drug dosage.
- the dosing regimen is typically on a daily dose basis of 10 ⁇ g or 20 ⁇ g per day to about 100 ⁇ g/day for 10 weeks.
- a non-daily dosing regimen can be used, e.g., 40 ⁇ g given every other day, 100 ⁇ g given once a week.
- the route of administration can vary from oral to intravenous to regional delivery (e.g., arterial infusion, via the portal vein). Oral is, of course, the easiest and most cost effective route.
- Regional delivery permits high dosing and generally avoids any production of hypercalcemia.
- the compound of the present invention the compound is substantially hypocalcemic.
- CAT, scans, X-rays and bone scans used for evaluating the progress of metastatic disease show stable disease or partial remission in many patients treated at the lower dosage, and stable disease and partial or complete remission in many patients treated at the higher dosage.
- Serum calcium levels are in the normal range and serum levels of PTHrP are redeuced.
Abstract
Methods utilizing active vitamin D analogs for the treatment of malignancy-associated hypercalcemia. Methods comprise the application of an effective amount of a hypocalcemic vitamin D compound to alleviate hypercalcemia, lower serum parathyroid hormone related protein (PTHrP) levels.
Description
- This application is a continuation-in-part of U.S. application Ser. No. 09/596,149 filed Feb. 23, 1998, which is a continuation-in-part of U.S. application Ser. No. 08/781,910, filed Dec. 20, 1996, now U.S. Pat. No. 5,763,429, all of which are incorporated herein by reference.
- Not Applicable
- This invention relates generally to a method of treating malignancy-associated hypercalcemia (MAH), and in particular, to the use of active forms of vitamin D to reduce hypercalcemia associated with inhibit the hyperproliferative diseases.
- Extensive research during the past two decades has established important biologic roles for vitamin D apart from its classic role in bone and mineral metabolism. Specific nuclear receptors for 1α,25-dihydroxyvitamin D3, the hormonally active form of vitamin D, are present in cells from diverse organs not involved in calcium homeostasis. For example, specific, biologically active vitamin D receptors have been demonstrated in the human prostatic carcinoma cell line, LNCaP, (Miller et al., 52 Cancer Res. (1992) 515-520); Vitamin D receptors have also been described for many other neoplastic cells, e.g., carcinomas of the breast and carcinomas of the colon.
- It has been reported that certain vitamin D compounds and analogues are potent inhibitors of malignant cell proliferation and are inducers/stimulators of cell differentiation. For example, U.S. Pat. No. 4,391,802 issued to Suda et al. discloses that 1α-hydroxyvitamin D compounds, specifically 1α,25-dihydroxyvitamin D3 and 1α-hydroxyvitamin D3, possess potent antileukemic activity by virtue of inducing the differentiation of malignant cells (specifically leukemia cells) to nonmalignant macrophages (monocytes), and are useful in the treatment of leukemia. Antiproliferative and differentiating actions of 1α,25-dihydroxyvitamin D3 and other vitamin D3 analogues have been reported with respect to cancer cell lines. More recently, an association between vitamin D receptor gene polymorphism and cancer risk has been reported, suggesting that vitamin D receptors may have a role in the development, and possible treatment, of cancer.
- These previous studies have focused exclusively on vitamin D3 compounds. Even though these compounds may indeed be highly effective in promoting differentiation in malignant cells in culture, their practical use in differentiation therapy as anticancer agents is severely limited because of their equally high potency as agents affecting calcium metabolism. At the levels required in vivo for effective use as, for example, antileukemic agents, these same compounds can induce markedly elevated and potentially dangerous blood calcium levels by virtue of their inherent calcemic activity. That is, the clinical use of 1α,25-dihydroxyvitamin D3 and other vitamin D3 analogues as anticancer agents is precluded, or severely limited, by the risk of hypercalcemia.
- Hyperalcemia is frequently associated with malignancy (MAH), and is often a major contributor to morbidity and complicates clinical management of the malignancy. Parathyroid hormone related protein (PTHrP) is closely related to parathyroid hormone (PTH) and binds to the same receptor as PTH as well as other receptors. PTHrP is one of the main causative substances of such hypercalcemia, and is overproduced by malignant cells. 1,25-dihydroxyvitamin D3 has been found to repress the transcription of the PTHrP gene in cells, however, the 1,25-dihydroxyvitamin D3 compounds themselves increase serum calcium levels. Therefore a need exists for compounds with greater specific activity and selectivity of action, i.e., vitamin D compounds with antiproliferative and differentiating effects but which have less calcemic activity.
- The present invention provides a method of treating malignancy-associated hypercalcemia (MAH) such as that associated with hyperproliferative cell growth and/or abnormal cell differentiation. The method includes use of active vitamin D compounds to treat hypercalcemia and reduce serum parathyroid hormone related protein (PTHrP) levels.
- The foregoing, and other advantages of the present invention, are realized in one aspect thereof in a method of treating malignancy-associated hypercalcemia from the hyperproliferative activity of human neoplastic or hyperplastic cells, comprising treating the cells with an effective amount of a hypocalcemic hydroxyvitamin D compound having a hydrocarbon moiety substituted at the C-24 position on the sidechain of the molecule. The treating step includes inhibiting proliferation of, and inducing and enhancing differentiation in such cells.
- A hydroxyvitamin D compound in accordance with the present invention is an active vitamin D and is suitably represented by the formula (I) described hereafter. Suitable compounds of formula (I) are 1α,24-dihydroxyvitamin D2, 1α,24-dihydroxyvitamin D4, 1α,25-dihydroxyvitamin D4, 1α,25-dihydroxyvitamin D2, 1α-hydroxyvitamin D2 and 1α-hydroxyvitamin D4.
- The effective or therapeutic amount of the hypocalcemic hydroxyvitamin D compounds administrable in accordance with the present invention to patients in need on a daily basis per kilogram of body weight ranges from 0.01 μg/kg/day to 2.0 μg/kg/day.
- In another aspect of the invention, lowering serum parathyroid hormone related protein (PTHrP) levels in patients suffering from hypercalcemia is accomplished by a method comprising, administering to these patients an effective amount of a hypocalcemic vitamin D compound, to lower the serum parathyroid hormone related protein (PTHrP) level.
- The hypocalcemic vitamin D compounds are also valuable for the treatment of breast, prostate and colon cancer, as well as other neoplasms such as pancreatic cancer, endometrial cancer, testicular cancer, small cell and non-small cell cancer of the lung (including squamous, adneocarcinoma and large cell types), squamous cell of the head and neck, bladder, ovarian and cervical cancers, myeloid and lymphocyltic leukemia, lymphoma, hepatic tumors, medullary thyroid carcinoma, multiple myeloma, retinoblastoma, and sarcomas of the soft tissue and bone, i.e. neoplasms that express a vitamin D receptor.
- In accordance with the present invention, when effective amounts of the hypocalcemic vitamin D compounds are administered to patients with MAH, significantly redeuced hypercalcemia is observed than is observed after the same amount of an activated vitamin D3 (e.g., 1α-OH D3, 1α,25-(OH)2 D3) is administered in previously known formulations. Thus, the compound in accordance with the present invention has an improved therapeutic index relative to active forms of vitamin D3 analogues.
- Accordingly, another aspect of the invention is a method of treating malignancy associated hyercalcemia comprising administering to a subject who is suffering therefrom an effective amount of active vitamin D compound which has, or attains through metabolism in vivo, a vitamin D receptor (VDR) binding affinity substantially equivalent to the binding affinity of 1α,25-dihydroxyvitamin D3 and has a hypercalcemia risk substantially lower that that of 1α,25-dihydroxyvitamin D3, to normalize or reduce serum calcium levels.
- For treatment for malignancy-associated hypercalcemia and the underlying malignant condition in accordance with the present invention, the active vitamin D is suitably administered alone as an active ingredient in a pharmaceutical composition, or is co-administered with an anticancer agent.
- Further, included within the scope of the present invention is the co-administration of a hypocalcemic vitamin D compound with a cytotoxic or anticancer agent. Such agents suitably include antimetabolites (e.g., 5-fluoro-uracil, methotrexate, fludarabine), antimicrotubule agents (e.g., vincristine, vinblastine, taxanes such as paclitaxel, docetaxel), an alkylating agent (e.g., cyclophasphamide, melphalan, biochoroethylnitrosurea, hydroxyurea), platinum agents (e.g. cisplatin, carboplatin, oxaliplatin, JM-216, CI-973), anthracyclines (e.g., doxrubicin, daunorubicin), antibiolitics (e.g., mitomycin, idarubicin, adriamycin, daunomycin), topoisomerase inhibitiors (e.g., etoposide, camptothecins) or any other antineoplastic agents. (estramustine phosphate, prednimustine).
- It is anticipated that the active vitamin D compounds used in combination with various anticancer drugs can give rise to a significantly enhanced cytotoxic effect on cancerous cells, thus providing an increased therapeutic effect. Specifically, as a significantly increased growth-inhibitory effect is obtained with the above disclosed combinations utilizing lower concentrations of the anticancer drugs compared to the treatment regimes in which the drugs are used alone, there is the potential to provide therapy wherein adverse side effects associated with the anticancer drugs are considerably reduced than normally observed with the anticancer drugs used alone in larger doses. Possible dose ranges of these co-administered anticancer agents are about 0.1 to 20 mg/kg/day.
- Also included within the scope of the present invention is the co-administration of effective dosages of a hypocalcemic vitamin D compound in conjunction with administration of hormones or other agents, e.g., estrogens, which are known to ameliorate bone diseases or disorders. For example, prostate cancer often metastasizes to bone, causing bone loss and associated pain. Such bone agents may include conjugated estrogens or their equivalents, calcitonin, bisphosphonates, calcium supplements, cobalamin, pertussis toxin and boron.
- In another aspect, the invention is a pharmaceutical composition which includes an anticancer agent which is an active hypocalcemic vitamin D compound; an agent selected from the group consisting of (i) an anticancer agent, (ii) a bone agent, and combinations thereof; and a physiologically acceptable carrier.
- Other advantages and a fuller appreciation of specific adaptations, compositional variations, and physical attributes will be gained upon an examination of the following detailed description of preferred embodiments, taken in conjunction with the appended claims.
- Not Applicable
- The present invention provides an effective method for the treatment of hypercalcemia, i.e. unphysiologically high and deleterious blood calcium levels, associated with neoplastic and hyperproliferative diseases. Particularly, the present invention relates to therapeutic methods for ameliorating or alleviating the hypercalcemia associated with the hyperproliferative cellular activity of malignant and neoplastic diseases, as well as inducing, enhancing or promoting cell differentiation in the diseased cells. The present invention provides a novel treatment of a patient suffering from a hyperproliferative disease with an active hypocalcemic vitamin D compound. Preferably, the active vitamin D analogue is a hydroxyvitamin D compound and is suitably represented by formula (I) as described hereinbelow. The active vitamin D analogue is provided to the patient without itself causing dose-limiting hypercalcemia and hypercalciuria, and in fact, reduces the hypercalcemia caused by the malignancy. These attributes are achieved through specific chemical properties of the hypocalcemic vitamin D compounds as described.
- In accordance with the present invention, when effective amounts of the hypocalcemic active vitamin D compounds are administered to patients with malignant diseases, the hypercalcemia is reduced, the PTHrP serum level is reduced, and the proliferative activity of the abnormal cells is inhibited, redeuced, or stabilized, and cell differentiation is induced, promoted or enhanced. Thus, the hypocalcemic vitamin D compounds of the present invention have an improved therapeutic index relative to active forms of vitamin D3 analogues.
- It is known that vitamin D3 must be hydroxylated in the C-1 and C-25 positions before it is activated, i.e., before it will produce a biological response. A similar metabolism appears to be required to activate other forms of vitamin D, e.g., vitamin D2 and vitamin D4. Therefore, as used herein, the term “activated vitamin D” or “active vitamin D” is intended to refer to a vitamin D compound or analogue that has been hydroxylated in at least the C-1, C-24 or C-25 position of the molecule and either the compound itself or its metabolites in the case of a prodrug, such as 1α-hydroxyvitamin D2, binds the vitamin D receptor (VDR). For example, “prodrugs” are vitamin D compounds which are hydroxylated in the C-1. Such compounds undergo further hydroxylation in vivo and their metabolites bind the VDR.
- The term “hypocalcemic vitamin D compound” is in reference to active vitamin D analogs which demonstrate hypocalcemic activity, i.e. have low calcemic activity relative to that of 1α,25-dihydroxyvitamin D3, including 24-hydroxyvitamin D compounds, 25-hydroxyvitamin compounds and I a-hydroxyvitamin compounds.
- Also, as used herein, the term “lower” as a modifier for alkyl, alkenyl acyl, or cycloalkyl is meant to refer to a straight or branched, saturated or unsaturated hydrocarbon radical having 1 to 4 carbon atoms. Specific examples of such hydrocarbon radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, ethenyl, propenyl, butenyl, isobutenyl, isopropenyl, formyl, acetyl, propionyl, butyryl or cyclopropyl. The term “aromatic acyl” is meant to refer to a unsubstituted or substituted benzoyl group.
- As used herein, the term “hydrocarbon moiety” refers to a lower alkyl, a lower alkenyl, a lower acyl group or a lower cycloalkyl, i.e., a straight or branched, saturated or unsaturated C1-C4 hydrocarbon radial.
- The compound in accordance with the present invention is an active hypocalcemic vitamin D compound. The active vitamin D provided is such that the compound has a hydrocarbon moiety at the C-24 position, e.g. a lower alkyl, alkenyl or acyl group as the C-24 position. Further, the active vitamin D in accordance with the present invention may have an unsaturated sidechain, e.g., there is suitably a double bond between C-22 and C-23, between C-25 and C-26 or between C-26 and C-27.
-
- wherein A1 and A2 each are hydrogen or a carbon-carbon bond, thus forming a double bond between C-22 and C-23; R1 and R2 are identical or different and are hydrogen, hydroxyl, lower alkyl, lower fluoroalkyl, O-lower alkyl, lower alkenyl, lower fluoroalkenyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl, lower cycloalkyl with the proviso that R1 and R2 cannot both be alkenyl, or taken together with the carbon to which they are bonded, form a C3-C8 cyclocarbon ring; R3 is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl; X1 is hydrogen or hydroxyl, X2 is hydrogen or hydroxyl, or, may be taken with R1 or R2, to constitute a double bond, and X3 is hydrogen or hydroxyl provided that at least one of X1, X2, or X3 is hydroxyl, and Y is a methylene group if the bond to Y is a double bond or is a methyl group or hydrogen if the bond to Y is a single bond.
-
- wherein A1 and A2 each are hydrogen or a carbon-carbon bond, thus forming a double bond between C-22 and C-23; R1 and R2 are identical or different and are hydrogen, hydroxyl, lower alkyl, lower fluoroalkyl, O-lower alkyl, lower alkenyl, lower fluoroalkenyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl, lower cycloalkyl with the proviso that R1 and R2 cannot both be an alkenyl, or taken together with the carbon to which they are bonded, form a C3-C8 cyclocarbon ring; R3 is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl; X1 is hydrogen or hydroxyl, X2 is hydrogen or hydroxyl, or, may be taken with R1 or R2, to constitute a double bond, and Y is a methylene group if the bond to Y is a double bond or is a methyl group or hydrogen if the bond to Y is a single bond.
-
- wherein A1 and A2 each are hydrogen or a carbon-carbon bond, thus forming a double bond between C-22 and C-23; R1 and R2 are identical or different and are hydrogen, hydroxyl, lower alkyl, lower fluoroalkyl, O-lower alkyl, lower alkenyl, lower fluoroalkenyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl, lower cycloalkyl with the proviso that R1 and R2 cannot both be an alkenyl, or taken together with the carbon to which they are bonded, form a C3-C8 cyclocarbon ring; R3 is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl; X1 is hydrogen or hydroxyl, and X2 is hydrogen or hydroxyl, or, may be taken with R1 or R2, to constitute a double bond.
- The hypocalcemic hydroxyvitamin D compounds of the present invention are those that have effective antiproliferative and cell differentiation activity (i.e., reversal of malignant transformation), but have a lower tendency or inability to cause hypercalcemia and/or hypercalciuria i.e. they are hypocalcemic compounds that have low calcemic activity relative to that of 1α,25-dihydroxyvitamin D3. In other words, the compounds of the present invention can be administered at dosages that allow them to act as antiproliferative agents and cell differentiation agents when exposed to malignant or other hyperproliferative cells and can reduce hypercalcemia associated with the maligancy. This selectivity and specificity of action makes the hypocalcemic vitamin D compounds useful and preferred antihypercalcemic agents as well as safely inhibiting hyperproliferation and promoting malignant or hyperplastic cell differentiation. The compounds of the present invention, thus, overcome the shortcomings of the known active vitamin D3 compounds described above, and can be considered preferred agents for the control and treatment of malignant diseases such breast, prostate, testicular and colon cancer, as well as other neoplasms such as pancreatic cancer, endometrial cancer, small cell and non-small cell cancer of the lung (including squamous, adneocarcinoma and large cell types), squamous cell of the head and neck, bladder, ovarian and cervical cancers, myeloid and lymphocyltic leukemia, lymphoma, hepatic tumors, medullary thyroid carcinoma, multiple myeloma, melanoma retinoblastoma, and sarcomas of the soft tissue and bone, i.e. neoplasms that express vitamin D receptors.
- Suitable hypocalcemic vitamin D compounds in accordance with the present invention include: 1α,24-dihydroxyvitamin D2, 1α,24-dihydroxyvitamin D4, 1α,25-dihydroxyvitamin D2, 1α,25-dihydroxyvitamin D4, 1α-hydroxyvitamin D2, and 1α-hydroxyvitamin D4. Among those compounds of formula (I) that have a chiral center in the sidechain, such as at C-24, it is understood that both epimers (e.g., R and S) and the racemic mixture are within the scope of the present invention.
- Thus, the present invention provides a method of treating hypercalcemia associated with malignant cells with an effective amount of a hypocalcemic vitamin D compound. The effective dosage amount on a daily basis per kilogram of body weight of the patient ranges from about 0.01 μg/kg/day to about 2.0 μg/kg/day.
- The compounds of formula (I) can be prepared as described, e.g., in U.S. Pat. No. 5,488,120 issued to Knutson et al., U.S. Pat. Nos. 4,670,190 and 4,554,106 issued to DeLuca et al., U.S. Pat. No. 5,486,636 issued to DeLuca et al., and Strugnell et al., 310Biochem. J. (1995) pp. 233-241, all of which are incorporated herein by reference.
- The biopotencies of the compounds of formula (I) have been studied and compared to that of 1α,25-dihydroxyvitamin D3, the active hormonal form of vitamin D and the standard against which all vitamin D compounds and analogues are measured. For example, it has been found that the vitamin D receptor (VDR) binding affinities of the compounds of formula (I), or their active metabolites, are substantially equivalent to (i.e., equal to or up to 3 times weaker than) the affinity of 1α,25-dihydroxyvitamin D3. Such receptor binding affinities are indicative of potent biological activity.
- At the same time, it has been found that compounds of formula (I) are significantly less toxic than their corresponding vitamin D3 analogues. For example, in parent co-pending application, Ser. No. 08/265,438, the disclosure of which is incorporated herein by reference, the LD50 for 1α-hydroxyvitamin D4 was found to be 1.0 mg/kg in males and 3.0 mg/kg in females, i.e., substantially less toxic than 1α-hydroxyvitamin D3 (LD50˜0.2 mg/kg). Further, in the parent U.S. Pat. No. 5,403,831, and its grandparent U.S. Pat. No. 5,104,864, both of which are incorporated herein by reference, it has been shown that 1α-hydroxyvitamin D2 has the same biopotency as 1α-hydroxyvitamin D3 and 1α,25-dihydroxyvitamin D3 but is much less toxic. Even dosages up to 10 μg/day of 1α-hydroxyvitamin D2 in women with postmenopausal osteoporosis elicited only mild hypercalciuria (U.Ca>300 mg/24 hrs), and no marked hypercalcemia (S. Ca>1 1.0 mg/dL) solely due to 1α-hydroxyvitamin D2 was evident. Additionally, the compound did not adversely affect kidney function, as determined by creatinine clearance and BUN; nor did it increase urinary excretion of hydroxyproline, indicating the absence of any stimulatory effect on bone resorption. Administration of 1α-hydroxyvitamin D2 to healthy adult males in dosages up to 8 μg/day showed no clinically significant hypercalcemia or other adverse effects.
- The hypocalcemic vitamin D compounds of the present invention are useful as active compounds in pharmaceutical compositions having reduced side effects and low toxicity as compared with the known analogues of active forms of vitamin D3.
- The pharmacologically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, e.g., mammals including humans. For example, the hypocalcemic vitamin D compounds can be employed in admixtures with conventional excipients, e.g., pharmaceutically acceptable carrier substances suitable for enteral (e.g., oral), parenteral or topical application which do not deleteriously react with the active compounds.
- Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils (e.g., almond oil, corn oil, cottonseed oil, peanut oil, olive oil, coconut oil), mineral oil, fish liver oils, oily esters such as Polysorbate 80, polyethylene glycols, gelatine, carbohydrates (e.g., lactose, amylose or starch), magnesium stearate, talc, silicic acid, viscous paraffin, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxy methylcellulose, polyvinyl pyrrolidone, etc.
- The pharmaceutical preparations can be sterilized and, if desired, be mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or one or more other active compounds, for example, vitamin D3 and its 1α-hydroxylated metabolites, conjugated estrogens or their equivalents, anti-estrogens, calcitonin, biphosphonates, calcium supplements, cobalamin, pertussis toxin and boron.
- For parenteral application, particularly suitable are injectable, sterile solutions, preferably oily or aqueous solution, as well as suspensions, emulsions, or implants, including suppositories. Parenteral administration suitably includes subcutaneous, intramuscular, or intravenous injection, nasopharyngeal or mucosal absorption, or transdermal absorption. Ampoules are convenient unit dosages.
- For enteral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, lozenges, powders, or capsules. A syrup, elixir, or the like can be used if a sweetened vehicle is desired.
- For topical application, suitable nonsprayable viscous, semi-solid or solid forms can be employed which include a carrier compatible with topical application and having a dynamic viscosity preferably greater than water, for example, mineral oil, almond oil, self-emulsifying beeswax, vegetable oil, white soft paraffin, and propylene glycol. Suitable formulations include, but are not limited to, creams, ointments, lotions, solutions, suspensions, emulsions, powders, liniments, salves, aerosols, transdermal patches, etc., which are, if desired, sterilized or mixed with auxiliary agents, e.g., preservatives, stabilizers, demulsifiers, wetting agents, etc. A cream preparation in accordance with the present invention suitably includes, for example, mixture of water, almond oil, mineral oil and self-emulsifying beeswax; an ointment preparation suitably includes, for example, almond oil and white soft paraffin; and a lotion preparation suitably includes, for example, dry propylene glycol.
- Topical preparations of the compound in accordance with the present invention useful for the treatment of skin disorders may also include epithelialization-inducing agents such as retinoids (e.g., vitamin A), chromanols such as vitamin E, β-agonists such as isoproterenol or cyclic adenosine monophosphate (cAMP), anti-inflammatory agents such as corticosteroids (e.g., hydrocortisone or its acetate, or dexamethasone) and keratoplastic agents such as coal tar or anthralin. Effective amounts of such agents are, for example, vitamin A about 0.003 to about 0.3% by weight of the composition; vitamin E about 0.1 to about 10%; isoproterenol about 0.1 to about 2%; cAMP about 0.1 to about 1%; hydrocortisone about 0.25 to about 5%; coal tar about 0.1 to about 20%; and anthralin about 0.05 to about 2%.
- For rectal administration, the compound is formed into a pharmaceutical composition containing a suppository base such as cacao oil or other triglycerides. To prolong storage life, the composition advantageously includes an antioxidant such as ascorbic acid, butylated hydroxyanisole or hydroquinone.
- For treatment of hypercalcemia associated with maligancy, oral administration of the pharmaceutical compositions of the present invention is preferred. Generally, the compound of this invention is dispensed by unit dosage form comprising about 0.5 μg to about 25 μg in a pharmaceutically acceptable carrier per unit dosage. The dosage of the compound according to this invention generally is about 10 μg to 200 μg/day.
- For topical treatment of skin disorders, the dosage of the compound of the present invention in a topical composition generally is about 0.01 μg to about 50 μg per gram of composition. For treatment of skin cancers, the dosage of the hypocalcemic vitamin D compound in a locally applied composition generally is about 0.01 μg to 100 μg per gram composition.
- It is noted that dosing of the hypocalcemic compounds in accordance with the present invention can also be done on an episodic basis, in which case higher doses can be used generally about 20 μg to about 200 μg given once every 2 to 7 days. The dose can be given as a single dose or a divided dose in 2 to 5 subdoses, the subdoses given, e.g., one every hour until the total dose is taken.
- Those of ordinary skill in the art will readily optimize effective doses and coadministration regimens as determined by good medical practice and the clinical condition of the individual patient. Regardless of the manner of administration, it will be appreciated that the actual preferred amounts of active compound in a specific case will vary according to the efficacy of the specific compound employed, the particular compositions formulated, the mode of application, and the particular situs and organism being treated. For example, the specific dose for a particular patient depends on age, body weight, general state of health, on diet, on the timing and mode of administration, on the rate of excretion, and on medicaments used in combination and the severity of the particular disorder to which the therapy is applied. Dosages for a given host can be determined using conventional considerations, e.g., by customary comparison of the differential activities of the subject compounds and of a known agent, such as by means of an appropriate conventional pharmacological protocol.
- Further, included within the scope of the present invention is the co-administration of a hypocalcemic vitamin D compound with a anticancer agent, e.g., a cytotoxic agent, Such agents suitably include antimetabolites (e.g., 5-fluoro-uracil, methotrexate, fludarabine), antimicrotubule agents (e.g., vincristine, vinblastine, taxanes such as paclitaxel, docetaxel), an alkylating agent (e.g., cyclophasphamide, melphalan, biochoroethylnitrosurea, hydroxyurea), platinum agents (e.g. cisplatin, carboplatin, oxaliplatin, JM-216, CI-973), anthracyclines (e.g., doxrubicin, daunorubicin), antibiolitics (e.g., mitomycin, idarubicin, adriamycin, daunomycin), topoisomerase inhibitors (e.g., etoposide, camptothecins) or any other antineoplastic agents. (estramustine phosphate, prednimustine). It is anticipated that the hypocalcemic vitamin D compounds used in combination with various anticancer drugs can give rise to a significantly enhanced cytotoxic effect on cancerous cells, thus providing an increased therapeutic effect. Specifically, as a significantly increased growth-inhibitory effect is obtained with the above disclosed combinations utilizing lower concentrations of the anticancer drugs compared to the treatment regimes in which the drugs are used alone, there is the potential to provide therapy wherein adverse side effects associated with the anticancer drugs are considerably reduced than normally observed with the anticancer drugs used alone in larger doses. Possible dose ranges of these co-administered anticancer agents are about 0.1 to 20 mg/kg/day.
- The term “co-administration” is meant to refer to any administration route in which two or more agents are administered to a patient or subject. For example, the agents may be administered together, or before or after each other. The agents may be administered by different routes, e.g., one agent may be administered intravenously while the second agent is administered intramuscularly, intravenously or orally. The agents may be administered simultaneously or sequentially, as long as they are given in a manner sufficient to allow both agents to achieve effective concentrations in the body. The agents also may be in an admixture, as, for example, in a single tablet. In sequential administration, one agent may directly follow administration of the other or the agents may be give episodically, i.e., one can be given at one time and the other at a later time, typically within a week. An example of a suitable co-administration regimen is where a hypocalcemic vitamin D compound is administered from 0.5 to 7 days prior to administration of a cytotoxic agent.
- Also included within the scope of the present invention is the co-administration of effective dosages of the analogue of formula (I) in conjunction with administration of hormones or other agents, e.g., estrogens, which are known to ameliorate bone diseases or disorders. As noted above, prostate cancer often metastasizes to bone, causing bone loss and associated pain. Such bone agents may include conjugated estrogens or their equivalents, calcitonin, bisphosphonates, calcium supplements, cobalamin, pertussis toxin and boron. It is contemplated that these bone agents also have an antihypercalcemic effect and may enhance the treatment of malignancy-associated hypercalcemia. Possible dose ranges for these co-administered bone agents are provided in Table 1.
TABLE 1 Possible Oral Dose Ranges for Various Bone Agents Co-Administered With 1α-Hydroxyvitamin D of Formula (I) Dose Ranges Most Agent Broad Preferred Preferred Conjugated Estrogens or 0.3-5.0 0.4-2.4 0.6-1.2 Equivalent (mg/day) Sodium Fluoride (mg/day) 5-150 30-75 40-60 Calcitonin (IU/day) 5-800 25-500 50-200 Bisphosphonates (mg/day) 0.5-20 1-15 5-10 Calcium Supplements 250-2500 500-1500 750-1000 (mg/day) Cobalamin (μg/day) 5-200 20-100 30-50 Pertussis Toxin (mg/day) 0.1-2000 10-1500 100-1000 Boron (mg/day) 0.10-3000 1-250 2-100 - The present invention is further explained by the following examples which should not be construed by way of limiting the scope of the present invention.
- The affinity of 1α,24-(OH)2D2 for the mammalian vitamin D receptor (VDR) was assessed using a commercially available kit of bovine thymus VDR and standard 1,25-(OH)2D3 solutions from Incstar (Stillwater, Minn.). The half-maximal binding of chemically synthesized 1α,24-(OH)2D2 was approximately 150 pg/ml whereas that of 1α,25-(OH)2D3 was 80 pg/ml. Thus, the 1α,24-(OH)2D2 had a very similar affinity for bovine thymus VDR as did 1α,25-(OH)2D3, indicating that 1α,24-(OH)2D2 has potent biological activity.
- The VDR affinity binding of 1α,24-(OH)2D4 was investigated. The 1α,24-(OH)2D4 was incubated with vitamin D receptor and radiolabeled tracer 1α,25-(OH)2D3. After incubation, the amount of radioactivity bound to the receptor was determined and compared with the amount bound after co-incubation of unlabeled and labeled 1α,25-(OH)2D3. It was found that 50 pg/tube of 1α,24-(OH)2D4 was equivalent to approximately 20 pg 1α,25-(OH)2D3.
- These results show that 1α,24-(OH)2D4 binds slightly less tightly to the vitamin D receptor than does 1α,25-(OH)2D3. Such data mean that 1α,24-(OH)2D4 has high affinity for the VDR and significant biological activity, similar to that of 1α,25-(OH)2D3. These data are consistent with gene expression studies done (described below) with 1α,24-(OH)2D4 which demonstrate that 1α,24-(OH)2D4 is only slightly less active than is 1α,25-(OH)2D3.
- These results are surprising and unexpected in view of the prior art. They are contrary to the normative wisdom in the vitamin D art regarding the very low degree of biological activity of vitamin D4 compounds.
- VDR binding of vitamin D compounds by prostate cells is demonstrated using the techniques of Skowronski et al., 136Endocrinology (1995) 20-26, which is incorporated herein by reference. Prostate-derived cell lines are cultured to near confluence, washed and harvested by scraping. Cells are washed by centrifugation, and the cell pellet resuspended in a buffered salt solution containing protease inhibitors. The cells are disrupted by sonication while cooling on ice. The supernatant obtained from centrifuging the disrupted cells at 207,000×g for 35 min at 4EC is assayed for binding. 200 TL of soluble extract, (1-2 mg protein/ml supernatant) is incubated with a 1 nM 3H-1α,25-(OH)2D3 and increasing concentrations of 1α,24-(OH)2-D2 (0.01-100 nM) for 16-20 hr at 4EC. Bound and free hormones are separated with hydroxylapatite using standard procedures. Specific binding is calculated by subtracting nonspecific binding obtained in the presence of a 250-fold excess of nonradioactive 1α,25-(OH)2D3 from the total binding measured. The results demonstrate that 1α,24-(OH)2D2 has strong affinity for prostate VDR, indicating that 1α,24-(OH)2D2 has potent biological activity in respect of prostate cells.
- The procedure of Example 3 is repeated using the active vitamin D analogue 1α,24-(OH)2D4, and the specific binding is determined. The results demonstrate that 1α,24-(OH)2D4 has strong affinity for prostate VDR, indicating that 1α,24-(OH)2D4 has potent biological activity in respect of prostate cells.
- The procedure of Example 3 is repeated using the active vitamin D analogue 1α,25-(OH)2D4, and the specific binding is determined. The results demonstrate that 1α,25-(OH)2D4 has strong affinity for prostate VDR, indicating that 1α,25-(OH)2D4 has potent biological activity in respect of prostate cells.
- Using the plasmids p(CT4)4TKGH, a vitamin D receptor (VDR)-expressing plasmid, and pSG5-hVDR1/3, a plasmid containing a Growth Hormone (GH) gene, under the control of a vitamin D-responsive element (VDRE), experiments were conducted to explore the ability of 1α,24-(OH)2D4 to induce vitamin D-dependent growth hormone acting as a reporter gene compared to that of 1α,25-(OH)2D3. Cells in culture were transfected with these two plasmids. One plasmid contained the gene for Growth Hormone (GH) under the control of the vitamin D responsive element (VDRE) and the other plasmid contained the structural gene for the vitamin D receptor (VDR). These transfected cultures were incubated with 1α,24-(OH)2D4 or 1α,25-(OH)2D3, and the production of growth hormone was measured. Table 2 below shows the results of this assay:
TABLE 2 Induction of Growth Hormone by Vitamin D Compounds Concentration Growth Hormone Compound Used (M) Induction (ng/ml) 1,25-(OH)2D3 1 × 10−10 39 1,25-(OH)2D3 5 × 10−10 248 1,24-(OH)2D4 5 × 10−10 165 1,24-(OH)2D4 1 × 10−9 628 1,24-(OH)2D4 5 × 10−9 1098 - These data show that the ability of 1α,24-(OH)2D4 to stimulate vitamin D-dependent growth hormone is nearly equivalent to that of 1α,25-(OH)2D3. Such results are truly surprising and would not have been expected by following the teachings of the prior art.
- The gene expression study described in Example 6 was conducted to compare the biological activity in vitro of chemically synthesized 1α,24(S)-(OH)2D2 and 1α,24(R)-(OH)2D2, with 1α,25-(OH)2D3 and 25-OH-D3. The vitamin D-dependent transcriptional activation model system was used in which plasmids pSG5-hVDR1/3 and p(CT4)4TKGH were co-transfected into Green monkey kidney, COS-1 cells.
- Transfected cells were incubated with vitamin D metabolites and growth hormone production was measured. As shown in Table 3, both 1α,24(S)-(OH)2D2 and its epimer, 1α,24(R)-(OH)2D2, had significantly more activity in this system than 25-OH-D3, with 1α,24(S)-(OH)2D2 having nearly the same activity as 1α,25-(OH)2D3.
TABLE 3 Vitamin D-Inducible Growth Hormone Production In Transfected COS-1 Cells Vitamin DClnducible Growth Hormone Production Net vitamin Total GH DCinducible Molar Production* GH-production Inducer Concentration (ng/ml) (ng/ml) Ethanol 44 0 25-OH-D3 1 × 10−7 245 201 1 × 10−6 1100 1056 1 × 10−5 775 731 1α,25-(OH)2D3 1 × 10−10 74 30 1 × 10−9 925 881 1 × 10−8 1475 1441 1α,24(S)-(OH)2D2 5 × 10−10 425 381 5 × 10−9 1350 1306 5 × 10−8 1182 1138 1α,24(R)-(OH)2D2 1 × 10−9 80 36 1 × 10−8 1100 1056 1 × 10−7 1300 1256 - Inhibition of cell proliferation is demonstrated using the techniques of Skowronski et al., 132Endocrinology (1993) 1952-1960 and 136 Endocrinology (1995) 20-26, both of which are incorporated herein by reference. The cell lines, LNCaP and PC-3, which are derived from human prostate adenocarcinoma, are seeded in six-well tissue culture plates at a density of about 50,000 cells/plate. After the cells have attached and stabilized, about 2-3 days, the medium is replenished with medium containing vehicle or the active vitamin D analogue 1α,24-(OH)2D2, at concentrations from 10−11 M to 10−7 M. Medium containing test analogue or vehicle is replaced every three days. After 6-7 days, the medium is removed, the cells are rinsed, precipitated with cold 5% trichloroacetic acid, and washed with cold ethanol. The cells are solubilized with 0.2 N sodium hydroxide, and the amount of DNA determined by standard procedures. The results show that cultures incubated with 1α,24-(OH)2D2 in accordance with the present invention have significantly fewer cells than the control cultures.
- The procedure of Example 8 is repeated using the active vitamin D analogue 1α,24-(OH)2D4, and the cell number is determined. Cultures incubated with 1α,24-(OH)2D4 have significantly fewer cells than the control cultures.
- The procedure of Example 8 is repeated using the active vitamin D analogue 1α,25-(OH)2D4, and the cell number is determined. Cultures incubated with 1α,25-(OH)2D4 have significantly fewer cells than the control cultures.
- Using the techniques of Skowronski et al., 132Endocrinology (1993) 1952-1960 and 136 Endocrinology (1995) 20-26, both of which are incorporated herein by reference, cells of the cell line, LNCaP, which is derived from a human metastatic prostate adenocarcinoma and known to express PSA, are seeded in six-well tissue culture plates at a density of about 50,000 cells/plate. After the cells have attached and stabilized, about 2-3 days, the medium is replenished with medium containing vehicle or the active vitamin D analogue, 1α,24-(OH)2D2, at concentrations from 10−11 M to 10−7 M. After 6-7 days, the medium is removed and stored at −20EC for prostate specific antigen (PSA) analysis.
- The cells from parallel cultures are rinsed, precipitated, and the amount of DNA determined by standard procedures. PSA is measured by standard known methods. Cultures incubated with 1α,24-(OH)2D2 have significantly more PSA than control cultures when expressed as mass of PSA/cell.
- The procedure of Example 12 is repeated except the active vitamin D analogue is 1α,24-(OH)2D4. The PSA is measured and cultures incubated with 1α,24-(OH)2D4 have significantly more PSA than control cultures when expressed as mass of PSA/cell.
- The procedure of Example 12 is repeated except the active vitamin D analogue is 1α,25-(OH)2D4. The PSA is measured and cultures incubated with 1α,25-(OH)2D4 have significantly more PSA than control cultures when expressed as mass of PSA/cell.
- Patients with malignancy-associated hypercalcemia participate in an open-label study of a hypocalcemic vitamin D compound in accordance with the present invention. Patients are restricted to daily calcium intake of about 400-500 mg. Each patient is also asked to drink 4-6 cups of fluid more than usual intake to assure adequate oral hydration.
- Each subject is monitored at regular intervals for: (1) hypercalcemia, serum PTHrP levels, hyperphosphatemia, hypercalciuria, hyperphosphaturia and other toxicity; (2) evidence of changes in the progression of metastatic disease; and (3) compliance with the prescribed test drug dosage.
- The dosing regimen is typically on a daily dose basis of 10 μg or 20 μg per day to about 100 μg/day for 10 weeks. Alternatively, a non-daily dosing regimen can be used, e.g., 40 μg given every other day, 100 μg given once a week. The route of administration can vary from oral to intravenous to regional delivery (e.g., arterial infusion, via the portal vein). Oral is, of course, the easiest and most cost effective route. Regional delivery permits high dosing and generally avoids any production of hypercalcemia. Although, in the case of the compound of the present invention, the compound is substantially hypocalcemic.
- After the treatment period, CAT, scans, X-rays and bone scans used for evaluating the progress of metastatic disease show stable disease or partial remission in many patients treated at the lower dosage, and stable disease and partial or complete remission in many patients treated at the higher dosage. Serum calcium levels are in the normal range and serum levels of PTHrP are redeuced.
- The procedure of example 14 is carried out using 1α,24-(OH)2D2. The results show serum calcium levels in the normal range and serum levels of PTHrP reduced.
- The procedure of example 14 is carried out using 1α-OH-D2. The results show serum calcium in the normal range and serum PTHrP levels reduced.
- While the present invention has now been described and exemplified with some specificity, those skilled in the art will appreciate the various modifications, including variations, additions, and omissions, that may be made in what has been described. Accordingly, it is intended that these modifications also be encompassed by the present invention and that the scope of the present invention be limited solely by the broadest interpretation lawfully accorded the appended claims.
Claims (33)
1. A method of treating hypercalcemia associated with malignant or neoplastic cells, comprising treating the cells with an effective amount of a hypocalcemic vitamin D compound having a hydrocarbon moiety at the C24 position.
2. The method of claim 1 , wherein the cells are cancers of the breast, colon, lung, neck and head, pancreas, endometrium, bladder, cervix, testes, ovaries, squamous cell carcinoma, myeloid and lymphocytic leukemia, lymphoma, medullary thyroid carcinoma, melanoma, multiple myeloma, retinoblastoma or sarcomas of the soft tissues and bone.
3. The method of claim 1 , wherein the hypocalcemic vitamin D is a compound represented by formula (I)
wherein A1 and A2 each are hydrogen or a carbon-carbon bond, thus forming a double bond between C-22 and C-23; R1 and R2 are identical or different and are hydrogen, hydroxyl, lower alkyl, lower fluoroalkyl, O-lower alkyl, lower alkenyl, lower fluoroalkenyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl, lower cycloalkyl with the proviso that R1 and R2 cannot both be an alkenyl group, or taken together with the carbon to which they are bonded, form a C3-C8 cyclocarbon ring; R3 is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl; X1 is hydrogen or hydroxyl, or, taken with R3, constitutes a bond when R3 is an alkenyl group, and X2 is hydrogen or hydroxyl, or, taken with R1 or R2, constitutes a double bond, and X3 is hydrogen or hydroxyl provided that at least one of X1, X2 and X3 is hydroxyl; and Y is a methylene group if the bond to Y is a double bond or is a methyl group or hydrogen if the bond to Y is a single bond.
4. The method of claim 1 , wherein said hypocalcemic vitamin D is a 1α-hydroxvitamin D compound is represented by formula (I)
wherein A1 and A2 each are hydrogen or a carbon-carbon bond, thus forming a double bond between C-22 and C-23; R1 and R2 are identical or different and are hydrogen, hydroxyl, lower alkyl, lower fluoroalkyl, O-lower alkyl, lower alkenyl, lower fluoroalkenyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl, lower cycloalkyl with the proviso that R1 and R2 cannot both be an alkenyl group, or taken together with the carbon to which they are bonded, form a C3-C8 cyclocarbon ring; R3 is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl; X1 is hydrogen or hydroxyl, or, taken with R3, constitutes a bond when R3 is an alkenyl group, and X2 is hydrogen or hydroxyl, or, taken with R1 or R2, constitutes a double bond.
5. The method of claim 4 , wherein the compound of formula (I) is 1α,24-dihydroxyvitamin D2, 1α,24-dihydroxyvitamin D4, 1α,25-dihydroxyvitamin D2, 1α,25-dihydroxyvitamin D4, 1α-hydroxyvitamin D2 or 1α-hydroxyvitamin D4.
6. A method in accordance with claim 1 , wherein a dosing regimen for the hypocalcemic vitamin D compound is a daily regimen or an episodic regimen.
7. A method in accordance with claim 6 , wherein the espisodic regimen is a dose once every 2 to 7 days.
8. A method in accordance with claim 6 , wherein the hypocalcemic vitamin D compound is administered daily at a dose of about 10 to 100 μg/day.
9. A method in accordance with claim 6 , wherein the hypocalcemic vitamin D compound is orally, intravenously or regionally delivered to a cancer site.
10. A method in accordance with claim 9 , wherein the hypocalcemic vitamin D compound is administered orally.
11. A method in accordance with claim 1 , wherein the hypocalcemic vitamin D compound is co-administered with a cytotoxic agent.
12. A method in accordance with claim 11 , wherein the cytotoxic agent is an antimetabolite, and antimicrotubule agent, an alkyating agent, a platinum agent, an anthracycline, a topoisomase inhibitor, or an antibiotic.
13. A method in accordance with claim 12 , wherein the antimetabolite is 5-fluoro-uracil, methotrexate or fludarabine.
14. A method in accordance with claim 12 , wherein the antimicrotubule agent is vincristine, vinblastine or a taxane.
15. A method in accordance with claim 14 , wherein the taxane is paclitaxel or docetaxel.
16. A method in accordance with claim 12 , wherein the alkylating agent is cyclophasphamide, melphalan, biochoroethylnitrosurea or hydroxyurea.
17. A method in accordance with claim 12 , wherein the platinum agent is cisplatin, carboplatin, oxaliplatin, JM-216 or CI-973.
18. A method in accordance with claim 12 , wherein the anthracycline is doxrubicin or daunorubicin.
19. A method in accordance with claim 12 , wherein the antibiotic is mitomycin, idarubicin, adriamycin or daunomycin.
20. A method in accordance with claim 12 , wherein the topoisomerase inhibitior is etoposide or camptothecins.
21. A method in accordance with claim 12 wherein the cytotoxic agent is estramustine phosphate or prednimustine.
22. A method of treating a human to alleviate hypercalcemia associated with breast cancer, colon cancer, prostate cancer, testicular cancer, pancreatic cancer, endometrial cancer, small cell and non-small cell cancer of the lung (including squamous, adneocarcinoma and large cell types), squamous cell of the head and neck, bladder, ovarian and cervical cancers, myeloid and lymphocyltic leukemia, lymphoma, hepatic tumors, medullary thyroid carcinoma, multiple myeloma, melanoma, retinoblastoma or sarcomas of the soft tissue and bone, comprising administering to the human therapeutic amount of a hypocalcemic vitamin D compound.
23. A method of claim 22 , wherein said hypocalcemic vitamin D is a 1α-hydroxyvitamin D compound represented by formula (III)
wherein A1 and A2 each are hydrogen or a carbon-carbon bond, thus forming a double bond between C-22 and C-23; R1 and R2 are identical or different and are hydrogen, hydroxyl, lower alkyl, lower fluoroalkyl, O-lower alkyl, lower alkenyl, lower fluoroalkenyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl, lower cycloalkyl with the proviso that R1 and R2 cannot both be an alkenyl group, or taken together with the carbon to which they are bonded, form a C3-C8 cyclocarbon ring; R3 is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl; X1 is hydrogen or hydroxyl, or, taken with R3, constitutes a bond when R3 is an alkenyl group, and X2 is hydrogen or hydroxyl, or, taken with R1 or R2, constitutes a double bond.
24. The method of claim 23 , wherein said therapeutic amount is 0.01 μg/kg/day to 2.0 μg/kg/day.
25. The method of claim 23 , wherein the compound of formula (I) is 1α,24-dihydroxyvitamin D2, 1α,24-dihydroxyvitamin D4, 1α,25-dihydroxyvitamin D2, 1(1,25-dihydroxyvitamin D4, 1α-hydroxyvitamin D2 or 1α-hydroxyvitamin D4.
26. A method of treating a human to alleviate hypercalcemia associated with malignant cells, comprising administering to the patient a hypocalcemic vitamin D compound, and a cytotoxic agent.
27. A method in accordance with claim 26 , wherein the hypocalcemic vitamin D compound is administered from 0.5 to 7 days prior to administration of the cytotoxic agent.
28. A method in accordance with claim 26 , wherein the hypocalcemic vitamin D compound is administered 2 to 4 days prior to administration of the cytotoxic agent.
29. A method of claim 26 , wherein said hypocalcemic vitamin D is a 1α-hydroxyvitamin D compound represented by formula (III)
wherein A1 and A2 each are hydrogen or a carbon-carbon bond, thus forming a double bond between C-22 and C-23; R1 and R2 are identical or different and are hydrogen, hydroxyl, lower alkyl, lower fluoroalkyl, O-lower alkyl, lower alkenyl, lower fluoroalkenyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl, lower cycloalkyl with the proviso that R1 and R2 cannot both be an alkenyl group, or taken together with the carbon to which they are bonded, form a C3-C8 cyclocarbon ring; R3 is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl; X1 is hydrogen or hydroxyl, or, taken with R3, constitutes a bond when R3 is an alkenyl group, and X2 is hydrogen or hydroxyl, or, taken with R1 or R2, constitutes a double bond.
30. The method of claim 29 , wherein the therapeutic amount is 0.01 μg/kg/day to 2.0 μg/kg/day.
31. The method of claim 29 , wherein the compound of formula (I) is 1α,24-dihydroxyvitamin D2, 1α,24-dihydroxyvitamin D4, 1α,25-dihydroxyvitamin D2, 1α,25-dihydroxyvitamin D4, 1α-hydroxyvitamin D2 or 1α-hydroxyvitamin D4.
32. A method in accordance with claim 29 , wherein the cytotoxic agent is an antimetabolite, and antimicrotubule agent, an alkyating agent, a platinum agent, an anthracycline, a topoisomase inhibitor, or an antibiotic.
33. A method of lowering serum parathyroid hormone related protein in a human patient by administering to the human an effective amount of a hypocalcemic vitamin D compound.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/441,731 US20030207810A1 (en) | 1996-12-30 | 2003-05-20 | Method of treating malignancy associated hypercalcemia using active vitamin D analogues |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/781,910 US5763429A (en) | 1993-09-10 | 1996-12-30 | Method of treating prostatic diseases using active vitamin D analogues |
US09/596,149 US6537982B1 (en) | 1993-09-10 | 1998-02-23 | Method of treating prostatic diseases using active vitamin D analogues |
US09/891,763 US6566353B2 (en) | 1996-12-30 | 2001-06-26 | Method of treating malignancy associated hypercalcemia using active vitamin D analogues |
US10/441,731 US20030207810A1 (en) | 1996-12-30 | 2003-05-20 | Method of treating malignancy associated hypercalcemia using active vitamin D analogues |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/891,763 Continuation US6566353B2 (en) | 1996-12-30 | 2001-06-26 | Method of treating malignancy associated hypercalcemia using active vitamin D analogues |
Publications (1)
Publication Number | Publication Date |
---|---|
US20030207810A1 true US20030207810A1 (en) | 2003-11-06 |
Family
ID=25398783
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/891,763 Expired - Fee Related US6566353B2 (en) | 1996-12-30 | 2001-06-26 | Method of treating malignancy associated hypercalcemia using active vitamin D analogues |
US10/441,731 Abandoned US20030207810A1 (en) | 1996-12-30 | 2003-05-20 | Method of treating malignancy associated hypercalcemia using active vitamin D analogues |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/891,763 Expired - Fee Related US6566353B2 (en) | 1996-12-30 | 2001-06-26 | Method of treating malignancy associated hypercalcemia using active vitamin D analogues |
Country Status (9)
Country | Link |
---|---|
US (2) | US6566353B2 (en) |
EP (1) | EP1416939A2 (en) |
JP (1) | JP2004535439A (en) |
KR (1) | KR20040015301A (en) |
CN (1) | CN1520301A (en) |
CA (1) | CA2451037A1 (en) |
IL (1) | IL159069A0 (en) |
MX (1) | MXPA03011305A (en) |
WO (1) | WO2003002060A2 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020128240A1 (en) * | 1996-12-30 | 2002-09-12 | Bone Care International, Inc. | Treatment of hyperproliferative diseases using active vitamin D analogues |
US20030191093A1 (en) * | 2001-12-03 | 2003-10-09 | Novacea, Inc. | Pharmaceutical compositions comprising active vitamin D compounds |
US20050222190A1 (en) * | 2004-03-30 | 2005-10-06 | Curd John G | 1,4-bis-N-oxide azaanthracenediones and the use thereof |
WO2005101022A2 (en) * | 2004-04-15 | 2005-10-27 | Bayer Healthcare Ag | Diagnostics and therapeutics for diseases associated with vitamin d (1,25-dihydroxyvitamin d3) receptor 1 (vdr1) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5763429A (en) * | 1993-09-10 | 1998-06-09 | Bone Care International, Inc. | Method of treating prostatic diseases using active vitamin D analogues |
US6566353B2 (en) * | 1996-12-30 | 2003-05-20 | Bone Care International, Inc. | Method of treating malignancy associated hypercalcemia using active vitamin D analogues |
US6087350A (en) * | 1997-08-29 | 2000-07-11 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Use of pretreatment chemicals to enhance efficacy of cytotoxic agents |
JP2002509888A (en) * | 1998-03-27 | 2002-04-02 | オレゴン ヘルス サイエンシーズ ユニバーシティー | Vitamin D and its analogs in the treatment of tumors and other hyperproliferative diseases |
US20050026877A1 (en) * | 2002-12-03 | 2005-02-03 | Novacea, Inc. | Pharmaceutical compositions comprising active vitamin D compounds |
US20050020546A1 (en) * | 2003-06-11 | 2005-01-27 | Novacea, Inc. | Pharmaceutical compositions comprising active vitamin D compounds |
EP1663250A4 (en) * | 2003-09-24 | 2006-12-20 | Bioxell Spa | Methods for treating bladder dysfunction |
US20060003950A1 (en) * | 2004-06-30 | 2006-01-05 | Bone Care International, Inc. | Method of treating prostatic diseases using a combination of vitamin D analogues and other agents |
US8501717B2 (en) * | 2007-02-09 | 2013-08-06 | Merck, Sharp & Dohme Corp. | Methods to treat and/or prevent mucositis |
US20100028416A1 (en) * | 2008-07-30 | 2010-02-04 | Nitto Denko Corporation | Drug carriers |
CA2909941A1 (en) | 2013-04-24 | 2014-10-30 | Salk Institute For Biological Studies | Vitamin d receptor/smad genomic circuit gates fibrotic response |
BR112015030518A2 (en) * | 2013-06-05 | 2017-08-29 | Salk Inst For Biological Studi | PHARMACEUTICAL COMPOSITION, USE OF ONE OR MORE VITAMIN D RECEPTOR (VDR) E AGONISTS, METHOD FOR REDUCING THE BIOLOGICAL ACTIVITY OF MOTIF C-X-C LIGAND 12 (CXCL12) |
JP6428665B2 (en) * | 2016-02-10 | 2018-11-28 | 三菱電機株式会社 | Aerial video display |
WO2019023149A1 (en) | 2017-07-24 | 2019-01-31 | Salk Institute For Biological Studies | Use of bromodomain-containing protein 9 antagonists in combination with vitamin d receptor agonists in diabetes treatment |
Citations (84)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2383446A (en) * | 1941-06-04 | 1945-08-28 | Du Pont | Antirachitic materials and processes for their production |
US3741996A (en) * | 1971-12-02 | 1973-06-26 | Wisconsin Alumni Res Found | 1{60 -hydroxycholecalciferol |
US4160803A (en) * | 1978-03-23 | 1979-07-10 | Corning Glass Works | Self packaged test kit |
US4195027A (en) * | 1978-01-16 | 1980-03-25 | Wisconsin Alumni Research Foundation | Process for preparing 1α-hydroxylated compounds |
US4202829A (en) * | 1978-01-05 | 1980-05-13 | Wisconsin Alumni Research Foundation | Process for preparing 1α-hydroxylated compounds |
US4260549A (en) * | 1979-05-21 | 1981-04-07 | Wisconsin Alumni Research Foundation | Process for preparing 1α-hydroxylated compounds |
US4391802A (en) * | 1981-03-13 | 1983-07-05 | Chugai Seiyaku Kabushiki Kaisha | Method of treating leukemia or leukemoid diseases |
US4508651A (en) * | 1983-03-21 | 1985-04-02 | Hoffmann-La Roche Inc. | Synthesis of 1α,25-dihydroxyergocalciferol |
US4588716A (en) * | 1984-05-04 | 1986-05-13 | Wisconsin Alumni Research Foundation | Method for treating metabolic bone disease in mammals |
US4661294A (en) * | 1985-03-18 | 1987-04-28 | The General Hospital Corporation | Biologically active 1-thio derivatives of vitamin D |
US4670190A (en) * | 1973-01-10 | 1987-06-02 | Hesse Robert H | 1-α-hydroxy vitamin D compounds and process for preparing same |
US4686104A (en) * | 1985-04-30 | 1987-08-11 | Sloan-Kettering Institute For Cancer Research | Methods of treating bone disorders |
US4689180A (en) * | 1984-01-30 | 1987-08-25 | Wisconsin Alumni Research Foundation | 1α,25-dihydroxy-22Z-dehydroxyvitamin D compound |
US4717721A (en) * | 1985-05-30 | 1988-01-05 | Howard W. Bremer | Sidechain homo-vitamin D compounds with preferential anti-cancer activity |
US4728643A (en) * | 1984-11-02 | 1988-03-01 | The General Hospital Corporation | Method of treating psoriasis |
US4833125A (en) * | 1986-12-05 | 1989-05-23 | The General Hospital Corporation | Method of increasing bone mass |
US4902481A (en) * | 1987-12-11 | 1990-02-20 | Millipore Corporation | Multi-well filtration test apparatus |
US4948789A (en) * | 1989-03-28 | 1990-08-14 | Chugai Seiyaku Kabushiki Kaisha | Suppression of parathyroid hormone synthesis and secretion |
US5037816A (en) * | 1984-11-02 | 1991-08-06 | The General Hospital Corporation | Method of treating psoriasis |
US5087619A (en) * | 1988-01-20 | 1992-02-11 | Hoffman-La Roche Inc. | Vitamin D3 analogs |
US5098899A (en) * | 1989-03-06 | 1992-03-24 | Trustees Of Boston University | Method for therapeutically treating psoriatic arthritis using vitamin D analogues and metabolites |
US5104864A (en) * | 1988-08-02 | 1992-04-14 | Bone Care International, Inc. | Method for treating and preventing loss of bone mass |
US5141719A (en) * | 1990-07-18 | 1992-08-25 | Bio-Rad Laboratories, Inc. | Multi-sample filtration plate assembly |
US5194248A (en) * | 1990-06-21 | 1993-03-16 | Trustees Of Boston University | Compositions comprising vitamin D analog precursors and the use thereof |
US5205989A (en) * | 1991-09-18 | 1993-04-27 | Minnesota Mining And Manufacturing Company | Multi-well filtration apparatus |
US5219528A (en) * | 1989-07-28 | 1993-06-15 | Pierce Chemical Company | Apparatus for rapid immunoassays |
US5232836A (en) * | 1988-05-04 | 1993-08-03 | Ire-Medgenix S.A. | Vitamin D derivatives: therapeutic applications and applications to assays of metabolites of vitamin D |
US5300687A (en) * | 1991-07-18 | 1994-04-05 | Ortho Pharmaceutical Corporation | Trifluoromethylbenzylphosphonates useful in treating osteoporosis |
US5321018A (en) * | 1989-03-09 | 1994-06-14 | Wisconsin Alumni Research Foundation | Use of 1α-hydroxylated-19-nor-vitamin D compounds to treat psoriasis |
US5334740A (en) * | 1991-03-13 | 1994-08-02 | Kurary Co., Ltd. | Cyclohexanetriol derivatives |
US5338532A (en) * | 1986-08-18 | 1994-08-16 | The Dow Chemical Company | Starburst conjugates |
US5417923A (en) * | 1991-04-24 | 1995-05-23 | Pfizer Inc. | Assay tray assembly |
US5486636A (en) * | 1991-05-28 | 1996-01-23 | Wisconsin Alumni Research Foundation | Synthesis of 19-nor vitamin D compounds |
US5488120A (en) * | 1990-09-21 | 1996-01-30 | Lunar Corporation | 1α-hydroxy vitamin D4 and novel intermediates and analogues |
US5512554A (en) * | 1992-10-07 | 1996-04-30 | Hoffmann-La Roche Inc. | Method of treating hyperproliferative skin diseases with fluorinated vitamin D3 analogs |
US5527524A (en) * | 1986-08-18 | 1996-06-18 | The Dow Chemical Company | Dense star polymer conjugates |
US5529991A (en) * | 1992-06-22 | 1996-06-25 | Lunar Corporation | Oral 1α-hydroxyprevitamin D |
US5547947A (en) * | 1993-03-11 | 1996-08-20 | Hoffmann-La Roche Inc. | Methods of treatment |
US5602116A (en) * | 1988-08-02 | 1997-02-11 | Bone Care International, Inc. | Method for treating and preventing secondary hyperparathyroidism |
US5612327A (en) * | 1993-09-01 | 1997-03-18 | Teijin Limited | 1α,24-(OH)2 -cholecalciferol emulsion composition and method for treating psoriasis |
US5637742A (en) * | 1991-07-05 | 1997-06-10 | Duphar International Research B.V. | Vitamin D compound, method of preparing this compound and intermediate therefor |
US5661025A (en) * | 1992-04-03 | 1997-08-26 | Univ California | Self-assembling polynucleotide delivery system comprising dendrimer polycations |
US5739271A (en) * | 1995-06-07 | 1998-04-14 | Gen-Probe Incorporated | Thiocationic lipids |
US5753638A (en) * | 1992-10-07 | 1998-05-19 | Hoffmann-La Roche Inc. | Method of treating hyperproliferative skin disease with Vitamin D3 fluorinated analogs |
US5763428A (en) * | 1990-09-21 | 1998-06-09 | Bone Care International, Inc. | Methods of treating skin disorders with novel 1a-hydroxy vitamin D4 compounds and derivatives thereof |
US5763429A (en) * | 1993-09-10 | 1998-06-09 | Bone Care International, Inc. | Method of treating prostatic diseases using active vitamin D analogues |
US5786397A (en) * | 1996-02-14 | 1998-07-28 | Hoechst Aktinegesellschaft | Foamable molding compositions |
US5786348A (en) * | 1991-01-08 | 1998-07-28 | Bone Care International, Inc. | Methods for preparation and use of 1α,24(S)-dihydroxy vitamin D2 |
US5789399A (en) * | 1995-10-10 | 1998-08-04 | Strube; Marilyn E. | Treatment of pruritus with vitamin D and analogs thereof |
US5795882A (en) * | 1992-06-22 | 1998-08-18 | Bone Care International, Inc. | Method of treating prostatic diseases using delayed and/or sustained release vitamin D formulations |
US5798345A (en) * | 1990-09-21 | 1998-08-25 | Bone Care International, Inc. | Method of inhibiting the hyperproliferation of malignant cells |
US5902806A (en) * | 1996-02-28 | 1999-05-11 | Sumitomo Pharmaceuticals Company, Limited | Crystalline vitamin D derivative |
US5905074A (en) * | 1995-10-30 | 1999-05-18 | Hoffmann-La Roche Inc. | Vitamin D derivative |
US6025346A (en) * | 1990-09-21 | 2000-02-15 | Bone Care International, Inc. | 1α-hydroxy vitamin D4 and novel intermediates and analogues |
US6048845A (en) * | 1993-09-03 | 2000-04-11 | Supergen, Inc. | Pharmaceutical formulation |
US6087350A (en) * | 1997-08-29 | 2000-07-11 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Use of pretreatment chemicals to enhance efficacy of cytotoxic agents |
US6103709A (en) * | 1993-12-23 | 2000-08-15 | The Regents Of The University Of California | Therapeutically effective 1α,25-dihydroxyvitamin D3 analogs and methods for treatment of vitamin D diseases |
US6211168B1 (en) * | 1991-01-08 | 2001-04-03 | Bone Care International, Inc | Methods for preparation and use of 1α,24 (S)-dihydroxy vitamin D2 |
US6218430B1 (en) * | 1998-08-24 | 2001-04-17 | Ligand Pharmaceuticals Incorporated | Vitamin D3 mimics |
US6221911B1 (en) * | 1995-06-07 | 2001-04-24 | Karo Bio Ab | Uses for thyroid hormone compounds or thyroid hormone-like compounds |
US20010002396A1 (en) * | 1998-07-16 | 2001-05-31 | Charles Achkar | Compositions and methods of treating skin conditions |
US20020006917A1 (en) * | 1998-05-21 | 2002-01-17 | Wisconsin Alumni Research Foundation | Method of locking 1alpha-OH of vitamin D compounds in axial orientation |
US6369098B1 (en) * | 1999-10-05 | 2002-04-09 | Bethesda Pharmaceuticals, Inc. | Dithiolane derivatives |
US20020049344A1 (en) * | 1996-04-30 | 2002-04-25 | Andreas Steinmeyer | New vitamin d derivatives with carbo-or heterocyclic substituents at c-25, a process for their production, intermediate products and their use for producing medicaments |
US6395784B1 (en) * | 2000-06-07 | 2002-05-28 | Bristol-Myers Squibb Company | Benzamide ligands for the thyroid receptor |
US20020091109A1 (en) * | 1998-10-23 | 2002-07-11 | Teijin Limited | Vitamin D3 derivative and treating agent for inflammatory respiratory disease using same |
US6432962B2 (en) * | 2000-05-22 | 2002-08-13 | Leo Pharmaceutical Products Ltd. A/S | Benzophenones as inhibitors of IL-1β and TNF-α |
US6503893B2 (en) * | 1996-12-30 | 2003-01-07 | Bone Care International, Inc. | Method of treating hyperproliferative diseases using active vitamin D analogues |
US6521608B1 (en) * | 1998-03-27 | 2003-02-18 | Oregon Health & Science University | Vitamin D and its analogs in the treatment of tumors and other hyperproliferative disorders |
US6521222B1 (en) * | 1999-09-28 | 2003-02-18 | Societe L'oreal S.A. | Inorganic/organic complexes for reducing skin irritation |
US6524594B1 (en) * | 1999-06-23 | 2003-02-25 | Johnson & Johnson Consumer Companies, Inc. | Foaming oil gel compositions |
US6538037B2 (en) * | 1991-01-08 | 2003-03-25 | Bone Care International, Inc. | Methods for preparation and use of 1α,24(S)-dihydroxyvitamin D2 |
US6541670B2 (en) * | 1999-12-06 | 2003-04-01 | Leo Pharmaceutical Products Ltd. A/S | Aminobenzophenones as inhibitors of IL 1β and TNF-α |
US6552009B2 (en) * | 1998-07-16 | 2003-04-22 | Gentrix Llc | Compositions and methods of treating abnormal cell proliferation |
US6555710B1 (en) * | 1999-07-16 | 2003-04-29 | Leo Pharmaceutical Products Ltd A/S Lovens Kemiske Fabrik Produktionsaktieselskab | Aminobenzophenones as inhibitors of IL-1 β and TNF-α |
US6566554B1 (en) * | 1999-07-16 | 2003-05-20 | Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) | Aminobenzophenones as inhibitors of IL-1β and TNF-α |
US6566353B2 (en) * | 1996-12-30 | 2003-05-20 | Bone Care International, Inc. | Method of treating malignancy associated hypercalcemia using active vitamin D analogues |
US6573256B2 (en) * | 1996-12-30 | 2003-06-03 | Bone Care International, Inc. | Method of inhibiting angiogenesis using active vitamin D analogues |
US20030109506A1 (en) * | 1999-12-21 | 2003-06-12 | Northern Lights Pharmaceuticals, Llc | Treating vitamin D responsive diseases |
US6582710B2 (en) * | 1997-05-27 | 2003-06-24 | Sembiosys Genetics Inc. | Products for topical applications comprising oil bodies |
US6599513B2 (en) * | 1997-05-27 | 2003-07-29 | Sembiosys Genetics Inc. | Products for topical applications comprising oil bodies |
US20030149006A1 (en) * | 1999-07-23 | 2003-08-07 | Andreas Steinmeyer | New vitamin D derivatives with cyclic substructures in the side chains, process and intermediate products for their production, and the use for the production of pharmaceutical agents |
US20030149005A1 (en) * | 2001-08-22 | 2003-08-07 | Posner Gary H. | 24-sulfur-substituted analogs of 1alpha, 25-dihydroxy vitamin D3 |
US20040019023A1 (en) * | 2000-06-15 | 2004-01-29 | Kazumi Morikawa | Vitamin d derivatives |
Family Cites Families (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3697559A (en) | 1971-02-25 | 1972-10-10 | Wisconsin Alumni Res Found | 1,25-dihydroxycholecalciferol |
US3907843A (en) | 1974-06-14 | 1975-09-23 | Wisconsin Alumni Res Found | 1{60 -Hydroxyergocalciferol and processes for preparing same |
US4225596A (en) | 1978-10-13 | 1980-09-30 | Wisconsin Alumni Research Foundation | Method for treating calcium imbalance and improving calcium absorption in mammals |
US4234495A (en) | 1979-09-10 | 1980-11-18 | Wisconsin Alumni Research Foundation | Process for preparing 1α-hydroxyvitamin D compounds from 1α-hydroxy-3,5-cyclovitamin D compounds |
US4362710A (en) | 1980-07-04 | 1982-12-07 | Nissan Gosei Kogyo Co., Ltd. | Feeds for baby pigs, process for preparing the same and method of breeding baby pigs |
NL193245C (en) | 1983-05-09 | 1999-04-02 | Wisconsin Alumni Res Found | A 1,25-dihydroxyvitamin D2 related compound and pharmaceutical composition having a calcium metabolism-regulating action containing such a compound. |
US4555364A (en) | 1984-11-01 | 1985-11-26 | Wisconsin Alumni Research Foundation | Method for preparing 1-hydroxyvitamin D compounds |
US4554106A (en) | 1984-11-01 | 1985-11-19 | Wisconsin Alumni Research Foundation | Method for preparing 1α-hydroxyvitamin D compounds |
IL78342A (en) | 1985-04-04 | 1991-06-10 | Gen Hospital Corp | Pharmaceutical composition for treatment of osteoporosis in humans comprising a parathyroid hormone or a fragment thereof |
KR940010767B1 (en) | 1985-08-02 | 1994-11-11 | 레오 파마슈티칼스 프로덕츠 리미티드 에이/에스(레벤스 케미스케 파브리크 프로덕션 사크티에셀스카브) | Novel vitamin-d analogues |
JP2550391B2 (en) | 1988-06-30 | 1996-11-06 | 日清製粉株式会社 | Method for producing 1β-hydroxyvitamin D 2 below and D 3 below |
CA1333616C (en) | 1989-03-09 | 1994-12-20 | Hector F. Deluca | 19-nor-vitamin d compounds |
US5372996A (en) | 1989-03-10 | 1994-12-13 | Endorecherche, Inc. | Method of treatment of androgen-related diseases |
JP2645130B2 (en) | 1989-03-31 | 1997-08-25 | 日清製粉株式会社 | Steroid derivatives |
GB2229921B (en) | 1989-04-05 | 1992-12-16 | Chugai Pharmaceutical Co Ltd | Treatment for hyperparathyroidism with use of vitamin d derivatives |
US5801164A (en) | 1990-09-21 | 1998-09-01 | Bone Care International, Inc. | Methods of treating osteoporosis prophylactically or therapeutically |
US6166000A (en) | 1991-01-08 | 2000-12-26 | Bone Care International, Inc. | Methods for preparation and use of 1α,24(S)-Dihydroxy vitamin . D.sub2 |
WO1992021355A1 (en) | 1991-05-28 | 1992-12-10 | The Procter & Gamble Company | Calcium, trace mineral, vitamin d and drug therapy combinations |
DE69125836T2 (en) | 1991-11-14 | 1997-12-18 | Quantum Corp | Spindle and hub equipment |
AU682817B2 (en) | 1992-01-29 | 1997-10-23 | Bone Care International, Inc. | 1alpha-hydroxy-24-(epi)-vitamin D4 |
EP0562497A1 (en) | 1992-03-27 | 1993-09-29 | Nisshin Flour Milling Co., Ltd. | 1 alpha-hydroxy vitamins D7 and D4' processes for the preparation thereof and pharmaceutical compositions |
CA2121689C (en) | 1992-08-28 | 2008-03-18 | Ronald L. Horst | 1.alpha.,24(s)-dihydroxy vitamin d2, its formation and use |
US5350745A (en) | 1993-01-29 | 1994-09-27 | Lunar Corporation | Treatment of myocardial failure |
ES2120122T3 (en) | 1994-01-20 | 1998-10-16 | Duphar Int Res | VITAMIN D COMPOUNDS AND METHOD OF PREPARING THESE COMPOUNDS. |
DE19549243A1 (en) | 1995-12-21 | 1997-06-26 | Schering Ag | Pharmaceutical preparations containing clathrates of cyclodextrins and unnatural vitamin D analogues |
US6034074A (en) | 1996-09-13 | 2000-03-07 | New Life Pharmaceuticals Inc. | Prevention of ovarian cancer by administration of a Vitamin D compound |
AUPO727097A0 (en) | 1997-06-10 | 1997-07-03 | Unisearch Limited | Method of treatment of hepatoma and pharmaceutical compositions for use therein |
JP2002507415A (en) | 1998-03-25 | 2002-03-12 | キュタノジェン, インコーポレイテッド | Methods for prevention and treatment of cancer |
DK1220676T3 (en) | 1999-09-29 | 2005-09-05 | Colotech As | Prevention of colorectal cancer |
DK1276482T3 (en) | 2000-03-02 | 2008-05-26 | Univ Pittsburgh | combination chemotherapy |
-
2001
- 2001-06-26 US US09/891,763 patent/US6566353B2/en not_active Expired - Fee Related
-
2002
- 2002-06-26 KR KR10-2003-7017015A patent/KR20040015301A/en not_active Application Discontinuation
- 2002-06-26 CN CNA028128710A patent/CN1520301A/en active Pending
- 2002-06-26 EP EP02747979A patent/EP1416939A2/en not_active Withdrawn
- 2002-06-26 CA CA002451037A patent/CA2451037A1/en not_active Abandoned
- 2002-06-26 MX MXPA03011305A patent/MXPA03011305A/en unknown
- 2002-06-26 WO PCT/US2002/020320 patent/WO2003002060A2/en not_active Application Discontinuation
- 2002-06-26 JP JP2003508302A patent/JP2004535439A/en active Pending
- 2002-06-26 IL IL15906902A patent/IL159069A0/en unknown
-
2003
- 2003-05-20 US US10/441,731 patent/US20030207810A1/en not_active Abandoned
Patent Citations (99)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2383446A (en) * | 1941-06-04 | 1945-08-28 | Du Pont | Antirachitic materials and processes for their production |
US3741996A (en) * | 1971-12-02 | 1973-06-26 | Wisconsin Alumni Res Found | 1{60 -hydroxycholecalciferol |
US4670190A (en) * | 1973-01-10 | 1987-06-02 | Hesse Robert H | 1-α-hydroxy vitamin D compounds and process for preparing same |
US4202829A (en) * | 1978-01-05 | 1980-05-13 | Wisconsin Alumni Research Foundation | Process for preparing 1α-hydroxylated compounds |
US4195027A (en) * | 1978-01-16 | 1980-03-25 | Wisconsin Alumni Research Foundation | Process for preparing 1α-hydroxylated compounds |
US4160803A (en) * | 1978-03-23 | 1979-07-10 | Corning Glass Works | Self packaged test kit |
US4260549A (en) * | 1979-05-21 | 1981-04-07 | Wisconsin Alumni Research Foundation | Process for preparing 1α-hydroxylated compounds |
US4391802A (en) * | 1981-03-13 | 1983-07-05 | Chugai Seiyaku Kabushiki Kaisha | Method of treating leukemia or leukemoid diseases |
US4508651A (en) * | 1983-03-21 | 1985-04-02 | Hoffmann-La Roche Inc. | Synthesis of 1α,25-dihydroxyergocalciferol |
US4689180A (en) * | 1984-01-30 | 1987-08-25 | Wisconsin Alumni Research Foundation | 1α,25-dihydroxy-22Z-dehydroxyvitamin D compound |
US4588716A (en) * | 1984-05-04 | 1986-05-13 | Wisconsin Alumni Research Foundation | Method for treating metabolic bone disease in mammals |
US4728643A (en) * | 1984-11-02 | 1988-03-01 | The General Hospital Corporation | Method of treating psoriasis |
US5037816A (en) * | 1984-11-02 | 1991-08-06 | The General Hospital Corporation | Method of treating psoriasis |
US4661294A (en) * | 1985-03-18 | 1987-04-28 | The General Hospital Corporation | Biologically active 1-thio derivatives of vitamin D |
US4686104A (en) * | 1985-04-30 | 1987-08-11 | Sloan-Kettering Institute For Cancer Research | Methods of treating bone disorders |
US4717721A (en) * | 1985-05-30 | 1988-01-05 | Howard W. Bremer | Sidechain homo-vitamin D compounds with preferential anti-cancer activity |
US5527524A (en) * | 1986-08-18 | 1996-06-18 | The Dow Chemical Company | Dense star polymer conjugates |
US5338532A (en) * | 1986-08-18 | 1994-08-16 | The Dow Chemical Company | Starburst conjugates |
US4833125A (en) * | 1986-12-05 | 1989-05-23 | The General Hospital Corporation | Method of increasing bone mass |
US4902481A (en) * | 1987-12-11 | 1990-02-20 | Millipore Corporation | Multi-well filtration test apparatus |
US5087619A (en) * | 1988-01-20 | 1992-02-11 | Hoffman-La Roche Inc. | Vitamin D3 analogs |
US5232836A (en) * | 1988-05-04 | 1993-08-03 | Ire-Medgenix S.A. | Vitamin D derivatives: therapeutic applications and applications to assays of metabolites of vitamin D |
US5104864A (en) * | 1988-08-02 | 1992-04-14 | Bone Care International, Inc. | Method for treating and preventing loss of bone mass |
US5602116A (en) * | 1988-08-02 | 1997-02-11 | Bone Care International, Inc. | Method for treating and preventing secondary hyperparathyroidism |
US5403831A (en) * | 1988-08-02 | 1995-04-04 | Bone Care International, Inc. | Method of treating and preventing loss of bone mass using 1α-hydroxy-vitamin D2 |
US5098899A (en) * | 1989-03-06 | 1992-03-24 | Trustees Of Boston University | Method for therapeutically treating psoriatic arthritis using vitamin D analogues and metabolites |
US5321018A (en) * | 1989-03-09 | 1994-06-14 | Wisconsin Alumni Research Foundation | Use of 1α-hydroxylated-19-nor-vitamin D compounds to treat psoriasis |
US4948789A (en) * | 1989-03-28 | 1990-08-14 | Chugai Seiyaku Kabushiki Kaisha | Suppression of parathyroid hormone synthesis and secretion |
US5219528A (en) * | 1989-07-28 | 1993-06-15 | Pierce Chemical Company | Apparatus for rapid immunoassays |
US5194248A (en) * | 1990-06-21 | 1993-03-16 | Trustees Of Boston University | Compositions comprising vitamin D analog precursors and the use thereof |
US5141719A (en) * | 1990-07-18 | 1992-08-25 | Bio-Rad Laboratories, Inc. | Multi-sample filtration plate assembly |
US6025346A (en) * | 1990-09-21 | 2000-02-15 | Bone Care International, Inc. | 1α-hydroxy vitamin D4 and novel intermediates and analogues |
US5798345A (en) * | 1990-09-21 | 1998-08-25 | Bone Care International, Inc. | Method of inhibiting the hyperproliferation of malignant cells |
US5488120A (en) * | 1990-09-21 | 1996-01-30 | Lunar Corporation | 1α-hydroxy vitamin D4 and novel intermediates and analogues |
US5763428A (en) * | 1990-09-21 | 1998-06-09 | Bone Care International, Inc. | Methods of treating skin disorders with novel 1a-hydroxy vitamin D4 compounds and derivatives thereof |
US6538037B2 (en) * | 1991-01-08 | 2003-03-25 | Bone Care International, Inc. | Methods for preparation and use of 1α,24(S)-dihydroxyvitamin D2 |
US6211168B1 (en) * | 1991-01-08 | 2001-04-03 | Bone Care International, Inc | Methods for preparation and use of 1α,24 (S)-dihydroxy vitamin D2 |
US5786348A (en) * | 1991-01-08 | 1998-07-28 | Bone Care International, Inc. | Methods for preparation and use of 1α,24(S)-dihydroxy vitamin D2 |
US5334740A (en) * | 1991-03-13 | 1994-08-02 | Kurary Co., Ltd. | Cyclohexanetriol derivatives |
US5417923A (en) * | 1991-04-24 | 1995-05-23 | Pfizer Inc. | Assay tray assembly |
US5486636A (en) * | 1991-05-28 | 1996-01-23 | Wisconsin Alumni Research Foundation | Synthesis of 19-nor vitamin D compounds |
US5637742A (en) * | 1991-07-05 | 1997-06-10 | Duphar International Research B.V. | Vitamin D compound, method of preparing this compound and intermediate therefor |
US5300687A (en) * | 1991-07-18 | 1994-04-05 | Ortho Pharmaceutical Corporation | Trifluoromethylbenzylphosphonates useful in treating osteoporosis |
US5205989A (en) * | 1991-09-18 | 1993-04-27 | Minnesota Mining And Manufacturing Company | Multi-well filtration apparatus |
US5661025A (en) * | 1992-04-03 | 1997-08-26 | Univ California | Self-assembling polynucleotide delivery system comprising dendrimer polycations |
US5529991A (en) * | 1992-06-22 | 1996-06-25 | Lunar Corporation | Oral 1α-hydroxyprevitamin D |
US5795882A (en) * | 1992-06-22 | 1998-08-18 | Bone Care International, Inc. | Method of treating prostatic diseases using delayed and/or sustained release vitamin D formulations |
US5753638A (en) * | 1992-10-07 | 1998-05-19 | Hoffmann-La Roche Inc. | Method of treating hyperproliferative skin disease with Vitamin D3 fluorinated analogs |
US5512554A (en) * | 1992-10-07 | 1996-04-30 | Hoffmann-La Roche Inc. | Method of treating hyperproliferative skin diseases with fluorinated vitamin D3 analogs |
US5547947A (en) * | 1993-03-11 | 1996-08-20 | Hoffmann-La Roche Inc. | Methods of treatment |
US5612327A (en) * | 1993-09-01 | 1997-03-18 | Teijin Limited | 1α,24-(OH)2 -cholecalciferol emulsion composition and method for treating psoriasis |
US6048845A (en) * | 1993-09-03 | 2000-04-11 | Supergen, Inc. | Pharmaceutical formulation |
US20040023934A1 (en) * | 1993-09-10 | 2004-02-05 | Bone Care International, Inc. | Method of treating prostatic diseases using active vitamin D analogues |
US6537982B1 (en) * | 1993-09-10 | 2003-03-25 | Bone Care International, Inc. | Method of treating prostatic diseases using active vitamin D analogues |
US5763429A (en) * | 1993-09-10 | 1998-06-09 | Bone Care International, Inc. | Method of treating prostatic diseases using active vitamin D analogues |
US6103709A (en) * | 1993-12-23 | 2000-08-15 | The Regents Of The University Of California | Therapeutically effective 1α,25-dihydroxyvitamin D3 analogs and methods for treatment of vitamin D diseases |
US5739271A (en) * | 1995-06-07 | 1998-04-14 | Gen-Probe Incorporated | Thiocationic lipids |
US6221911B1 (en) * | 1995-06-07 | 2001-04-24 | Karo Bio Ab | Uses for thyroid hormone compounds or thyroid hormone-like compounds |
US5789399A (en) * | 1995-10-10 | 1998-08-04 | Strube; Marilyn E. | Treatment of pruritus with vitamin D and analogs thereof |
US5905074A (en) * | 1995-10-30 | 1999-05-18 | Hoffmann-La Roche Inc. | Vitamin D derivative |
US5786397A (en) * | 1996-02-14 | 1998-07-28 | Hoechst Aktinegesellschaft | Foamable molding compositions |
US5902806A (en) * | 1996-02-28 | 1999-05-11 | Sumitomo Pharmaceuticals Company, Limited | Crystalline vitamin D derivative |
US20020049344A1 (en) * | 1996-04-30 | 2002-04-25 | Andreas Steinmeyer | New vitamin d derivatives with carbo-or heterocyclic substituents at c-25, a process for their production, intermediate products and their use for producing medicaments |
US6566353B2 (en) * | 1996-12-30 | 2003-05-20 | Bone Care International, Inc. | Method of treating malignancy associated hypercalcemia using active vitamin D analogues |
US6503893B2 (en) * | 1996-12-30 | 2003-01-07 | Bone Care International, Inc. | Method of treating hyperproliferative diseases using active vitamin D analogues |
US6680309B2 (en) * | 1996-12-30 | 2004-01-20 | Bone Care International, Inc. | Method of treating hyperproliferative diseases using active vitamin D analogues |
US6573256B2 (en) * | 1996-12-30 | 2003-06-03 | Bone Care International, Inc. | Method of inhibiting angiogenesis using active vitamin D analogues |
US6599513B2 (en) * | 1997-05-27 | 2003-07-29 | Sembiosys Genetics Inc. | Products for topical applications comprising oil bodies |
US6582710B2 (en) * | 1997-05-27 | 2003-06-24 | Sembiosys Genetics Inc. | Products for topical applications comprising oil bodies |
US6087350A (en) * | 1997-08-29 | 2000-07-11 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Use of pretreatment chemicals to enhance efficacy of cytotoxic agents |
US6559139B1 (en) * | 1997-08-29 | 2003-05-06 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Combination chemotherapy |
US6521608B1 (en) * | 1998-03-27 | 2003-02-18 | Oregon Health & Science University | Vitamin D and its analogs in the treatment of tumors and other hyperproliferative disorders |
US20030119795A1 (en) * | 1998-03-27 | 2003-06-26 | Oregon Health & Science University | Vitamin D and its analogs in the treatment of tumors and other hyperproliferative disorders |
US6506912B2 (en) * | 1998-05-21 | 2003-01-14 | Wisconsin Alumni Research Foundation | Method of locking 1α-OH of vitamin D compounds in axial orientation |
US20020068723A1 (en) * | 1998-05-21 | 2002-06-06 | Wisconsin Alumni Research Foundation | Method of locking 1alpha-OH of vitamin D compounds in axial orientation |
US6369099B1 (en) * | 1998-05-21 | 2002-04-09 | Wisconsin Alumni Research Foundation | Method of locking 1 α-OH of vitamin D compounds in axial orientation |
US20030040508A1 (en) * | 1998-05-21 | 2003-02-27 | Wisconsin Alumni Research Foundation | Method of locking 1alpha-OH of vitatmin D compounds in axial orientation |
US20020006917A1 (en) * | 1998-05-21 | 2002-01-17 | Wisconsin Alumni Research Foundation | Method of locking 1alpha-OH of vitamin D compounds in axial orientation |
US6552009B2 (en) * | 1998-07-16 | 2003-04-22 | Gentrix Llc | Compositions and methods of treating abnormal cell proliferation |
US6242435B1 (en) * | 1998-07-16 | 2001-06-05 | Gentrix Llc | Compositions and methods of treating abnormal cell proliferation |
US20010002396A1 (en) * | 1998-07-16 | 2001-05-31 | Charles Achkar | Compositions and methods of treating skin conditions |
US6218430B1 (en) * | 1998-08-24 | 2001-04-17 | Ligand Pharmaceuticals Incorporated | Vitamin D3 mimics |
US20020091109A1 (en) * | 1998-10-23 | 2002-07-11 | Teijin Limited | Vitamin D3 derivative and treating agent for inflammatory respiratory disease using same |
US6531460B1 (en) * | 1998-10-23 | 2003-03-11 | Teijin Limited | Vitamin D, derivatives and remedies for inflammatory respiratory diseases containing the same |
US6548489B2 (en) * | 1998-10-23 | 2003-04-15 | Teijin Limited | Vitamin D3 derivative and treating agent for inflammatory respiratory disease using same |
US20020103173A1 (en) * | 1998-10-23 | 2002-08-01 | Teijin Limited | Vitamin D3 derivative and treating agent for inflammatory respiratory disease using same |
US20020099039A1 (en) * | 1998-10-23 | 2002-07-25 | Teijin Limited | Vitamin D3 derivative and treating agent for inflammatory respiratory disease using same |
US6524594B1 (en) * | 1999-06-23 | 2003-02-25 | Johnson & Johnson Consumer Companies, Inc. | Foaming oil gel compositions |
US6555710B1 (en) * | 1999-07-16 | 2003-04-29 | Leo Pharmaceutical Products Ltd A/S Lovens Kemiske Fabrik Produktionsaktieselskab | Aminobenzophenones as inhibitors of IL-1 β and TNF-α |
US6566554B1 (en) * | 1999-07-16 | 2003-05-20 | Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) | Aminobenzophenones as inhibitors of IL-1β and TNF-α |
US20030149006A1 (en) * | 1999-07-23 | 2003-08-07 | Andreas Steinmeyer | New vitamin D derivatives with cyclic substructures in the side chains, process and intermediate products for their production, and the use for the production of pharmaceutical agents |
US6521222B1 (en) * | 1999-09-28 | 2003-02-18 | Societe L'oreal S.A. | Inorganic/organic complexes for reducing skin irritation |
US6369098B1 (en) * | 1999-10-05 | 2002-04-09 | Bethesda Pharmaceuticals, Inc. | Dithiolane derivatives |
US6541670B2 (en) * | 1999-12-06 | 2003-04-01 | Leo Pharmaceutical Products Ltd. A/S | Aminobenzophenones as inhibitors of IL 1β and TNF-α |
US20030109506A1 (en) * | 1999-12-21 | 2003-06-12 | Northern Lights Pharmaceuticals, Llc | Treating vitamin D responsive diseases |
US6432962B2 (en) * | 2000-05-22 | 2002-08-13 | Leo Pharmaceutical Products Ltd. A/S | Benzophenones as inhibitors of IL-1β and TNF-α |
US6395784B1 (en) * | 2000-06-07 | 2002-05-28 | Bristol-Myers Squibb Company | Benzamide ligands for the thyroid receptor |
US20040019023A1 (en) * | 2000-06-15 | 2004-01-29 | Kazumi Morikawa | Vitamin d derivatives |
US20030149005A1 (en) * | 2001-08-22 | 2003-08-07 | Posner Gary H. | 24-sulfur-substituted analogs of 1alpha, 25-dihydroxy vitamin D3 |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020128240A1 (en) * | 1996-12-30 | 2002-09-12 | Bone Care International, Inc. | Treatment of hyperproliferative diseases using active vitamin D analogues |
US20030191093A1 (en) * | 2001-12-03 | 2003-10-09 | Novacea, Inc. | Pharmaceutical compositions comprising active vitamin D compounds |
US20050222190A1 (en) * | 2004-03-30 | 2005-10-06 | Curd John G | 1,4-bis-N-oxide azaanthracenediones and the use thereof |
WO2005101022A2 (en) * | 2004-04-15 | 2005-10-27 | Bayer Healthcare Ag | Diagnostics and therapeutics for diseases associated with vitamin d (1,25-dihydroxyvitamin d3) receptor 1 (vdr1) |
WO2005101022A3 (en) * | 2004-04-15 | 2006-02-09 | Bayer Healthcare Ag | Diagnostics and therapeutics for diseases associated with vitamin d (1,25-dihydroxyvitamin d3) receptor 1 (vdr1) |
Also Published As
Publication number | Publication date |
---|---|
JP2004535439A (en) | 2004-11-25 |
KR20040015301A (en) | 2004-02-18 |
US20020010165A1 (en) | 2002-01-24 |
US6566353B2 (en) | 2003-05-20 |
CA2451037A1 (en) | 2003-01-09 |
CN1520301A (en) | 2004-08-11 |
WO2003002060A3 (en) | 2004-03-11 |
MXPA03011305A (en) | 2004-03-19 |
WO2003002060A2 (en) | 2003-01-09 |
IL159069A0 (en) | 2004-05-12 |
EP1416939A2 (en) | 2004-05-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6680309B2 (en) | Method of treating hyperproliferative diseases using active vitamin D analogues | |
US6573256B2 (en) | Method of inhibiting angiogenesis using active vitamin D analogues | |
US20070043005A1 (en) | Treatment of hyperproliferative diseases using high doses of active vitamin d | |
AU2002322346A1 (en) | Method of treating hyperproliferative diseases using active vitamin D analogues | |
US6537982B1 (en) | Method of treating prostatic diseases using active vitamin D analogues | |
US6566353B2 (en) | Method of treating malignancy associated hypercalcemia using active vitamin D analogues | |
WO2006004917A2 (en) | Method of treating breast cancer using a combination of 1alpha, 24-dihydroxyvitamin d2 and a further chemotherapeutic agent | |
WO2006004918A2 (en) | Method of treating prostatic diseases using a combination of vitamin d analogues and other agents | |
US20020032179A1 (en) | Methods for preparation and use of 1alpha,24(S)-dihydroxyvitamin D2 | |
US20040009958A1 (en) | Methods for preparation and use of 1alpha,24(S)-dihydroxyvitamin D2 | |
AU2002318421A1 (en) | Method of treating malignancy associated hypercalcemia using active vitamin D analogues | |
MXPA99006989A (en) | Method of treating prostatic diseases using active vitamin d analogues |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |