WO2001042205A2 - Traitement de maladies enteriques inflammatoires avec des composes de la vitamine d - Google Patents

Traitement de maladies enteriques inflammatoires avec des composes de la vitamine d Download PDF

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WO2001042205A2
WO2001042205A2 PCT/US2000/042393 US0042393W WO0142205A2 WO 2001042205 A2 WO2001042205 A2 WO 2001042205A2 US 0042393 W US0042393 W US 0042393W WO 0142205 A2 WO0142205 A2 WO 0142205A2
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vitamin
compound
hydroxy
group
hydrogen
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PCT/US2000/042393
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WO2001042205A3 (fr
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Margherita T. Cantorna
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The Penn State Research Foundation
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Priority to JP2001543506A priority patent/JP2003516386A/ja
Priority to AU45100/01A priority patent/AU4510001A/en
Publication of WO2001042205A2 publication Critical patent/WO2001042205A2/fr
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    • 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
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • 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
    • A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This invention relates to vitamin D compounds, and more particularly to the use of vitamin D compounds to treat inflammatory bowel disease.
  • the natural hormone, l ⁇ ,25-dihydroxyvitamin D3 and its analog l ⁇ ,25- dihydroxyvitamin D2 are known to be highly potent regulators of calcium homeostasis in animals and humans, and their activity in cellular differentiation has also been established, Ostrem et al., Proc. Natl. Acad. Sci. USA, 84, 2610 (1987). Many structural analogs of these metabolites have been prepared and tested, including l ⁇ -hydroxyvitamin D3, l ⁇ - hydroxyvitamin D2, various side chain homologated vitamins and fluorinated analogs.
  • Some of these compounds exhibit an interesting separation of activities in cell differentiation and calcium regulation. This difference in activity may be useful in the treatment of a variety of diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, and certain malignancies.
  • IBD Inflammatory bowel diseases
  • GI gastrointestinal
  • IBD ulcerative colitis
  • Crohn's disease chronic recurring illnesses most commonly involving inflammation of the terminal ileum and colon, although these diseases can also affect many sites throughout the alimentary tract.
  • genetic factors predispose individuals to development of IBD (Podolosky 1991).
  • the environment contributes to IBD development, and there is reason to believe that vitamin D may be an environmental factor which affects IBD. Vitamin D from sunlight exposure is less in areas where IBD occurs most often, as IBD is most prevalent in northern climates such as North America and Northern Europe (Podolosky 1991, Sonnenberg et al.
  • vitamin D A major source of vitamin D results from its manufacture via a photolysis reaction in the skin, and vitamin D available from sunlight exposure is significantly less in northern climates, and especially low during the winter (Clemens et al. 1982, DeLuca 1993). Dietary intake of vitamin D is problematic since there are few foods which are naturally rich in vitamin D. Weight loss occurs in 65-75% of patients diagnosed with Crohn's disease and 18-62% of patients with ulcerative colitis (Fleming 1995, Geerling et al. 1998). Vitamin deficiencies in general and vitamin D deficiency in particular have been shown to occur in IBD patients (Andreassen et al. 1998, Kuroki et al. 1993). To date the possible association between vitamin D status and the incidence and severity of IBD in humans or animals has not been studied. The anecdotal information suggests that vitamin D status could be an environmental factor affecting the prevalence rate for IBD and that the correlation warrants investigation.
  • the CD4+ Th cells have vitamin D receptors and are therefore targets for vitamin D (Veldman et al. 2000).
  • Hormonally active vitamin D (1,25-dihydroxycholecalciferol) suppressed the development of at least two experimental autoimmune diseases (Cantorna et al. 1996, Cantorna et al. 1998a).
  • 1,25-dihydroxycholecalciferol inhibited T cell proliferation and decreased the production of interleukin (IL)-2, interferon (IFN)- ⁇ , and tumor necrosis factor (TNF)- ⁇ (Lemire 1992a).
  • IL interleukin
  • IFN interferon
  • TNF tumor necrosis factor
  • Vitamin D is a potent regulator of the immune system in general and T cells specifically.
  • T cells which preferentially produce the Thl cytokines (IL-2, IFN- ⁇ , and TNF- ⁇ ), have been shown to transfer Crohn's- like symptoms to naive mice (Aranda et al. 1997, Bregenholt and Claesson 1998) and the production of Thl cytokines is associated with IBD in humans as well (Niessner and Volk 1995).
  • 1,25- dihydroxycholecalciferol treatment has been shown to suppress the development of other T cell mediated experimental autoimmune diseases (multiple sclerosis, and arthritis; Cantorna et al. 1996, Cantorna et al.
  • vitamin D (1,25- dihydroxycholecalciferol) is known to increase bone mineralization when given to experimental animals (Cantora et al. 1998b) and people (Ongphiphadhanakul et al. 2000).
  • a further benefit of vitamin D and or 1,25-dihydroxycholecalciferol supplementation may be the maintenance of bone mineral density.
  • the present invention is a method of preventing inflammatory bowel diseases (IBD) in susceptible individuals and treating patients with IBD by administering an amount of a vitamin D compound, preferably l,25(OH) 2 D 3 or analogs thereof, effective to prevent IBD development or to diminish IBD symptoms, respectively.
  • the method comprises selecting an IBD patient and administering a sufficient amount of the vitamin D analog to the patient such that the IBD symptoms are abated.
  • R can represent a saturated or unsaturated hydrocarbon radical of 1 to 35 carbons, that may be straight-chain, branched or cyclic and that may contain one or more additional substituents, such as hydroxy- or protected-hydroxy groups, fluoro, carbonyl, ester, epoxy, amino or other heteroatomic groups.
  • Preferred side chains of this type are represented by the structure below
  • stereochemical center (corresponding to C-20 in steroid numbering) may have the R or S configuration, (i.e. either the natural configuration about carbon 20 or the 20-epi configuration), and where Z is selected from Y, -OY, -CH 2 OY, -C ⁇ CY and -CH-CHY, where the double bond may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, -COR- and a radical of the structure:
  • m and n independently, represent the integers from 0 to 5, where R is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and C ⁇ -alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected- hydroxy substituent, and where each of R , R3, and R , independently, is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and C ⁇ _ ⁇ alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy or protected-hydroxy substituent, and where R* and R2, taken together, represent an oxo group, or an alkylidene group,
  • R ⁇ represents hydrogen, hydroxy, protected hydroxy, or C 1 .5 alkyl and wherein any of the CH-groups at positions 20, 22, or 23 in the side chain may be replaced by a nitrogen atom, or where any of the groups -CH(CH3)-, -CH(R ⁇ )-, or -CH(R ⁇ )- at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.
  • side chains with natural 20R-configuration are the structures represented by formulas (a), b), (c), (d) and (e) below, i.e. the side chain as it occurs in 25-hydroxyvitamin D3 (a); vitamin D3 (b); 25 -hydroxy vitamin D2 (c); vitamin
  • Vitamin D analogs such as but not limited to the following are particularly preferred: l,25-dihydroxyvitamin D 3 ; l ⁇ -hydroxyvitamin D 3 ; l,25-dihydroxyvitamin D 2 ; 19-nor- 1 ,25-dihydroxyvitamin D 2 ; 26,27-hexafluoro- 1 ,25-dihydroxyvitamin D 2 ; 1 ,25- dihydroxy-24(E)-dehydro-24-homo-vitamin D 3 ; 19-nor-l,25-dihydroxy-21-epi-vitamin D 3 ; l ⁇ ,25 dihydroxyvitamin D 3 triacetate; and 25-acetyl-l ⁇ ,25 dihydroxyvitamin D 3 .
  • the compound is l,25(OH) 2 D 3 .
  • the above compounds may be present in a composition to treat IBD in an amount from about O.Ol ⁇ g/gm to about lOO ⁇ g/gm of the composition, and may be administered topically, transdermally, orally or parenterally in dosages of from about O.Ol ⁇ g/day to about lOO ⁇ g/day.
  • a preferred dose of vitamin D compound for the present invention is the maximum that a patient can tolerate and not develop serious hypercalcemia. If the vitamin D compound is not a l ⁇ -hydroxy compound, a particularly advantageous daily dose of vitamin D compound is between 5.0 and 50 ⁇ g per day per 160 pound patient. If the vitamin D compound is a l ⁇ -hydroxy compound, the preferred dose is between 0.5 and lO ⁇ g per day per 160 pound patient. If the patient has calcium intakes of above 800 mg/day, doses of l,25(OH) 2 D 3 over 0.75 ⁇ g per day per 160 pound patient are not preferred. If the patient is on a low calcium diet and/or takes the dose late at night, higher doses of l,25(OH) 2 D 3 would be possible and would be preferred.
  • the amount of l,25(OH) 2 D 3 administered could be as high as 1.5 ⁇ g per day per 160 pound patient.
  • a preferred dose of l,25(OH) 2 D 3 would be 0.5-1.O ⁇ g per day per 160 pound patient.
  • Figure 1 is a graph illustrating the mortality rate of interleukin-10 knockout mice (IL-10 KO) either maintained deficient of l,25(OH) 2 D 3 (-D) or supplemented with l,25(OH) 2 D 3 (+D) as compared to interleukin -10 wildtype mice (IL-lOWt) deficient of l,25(OH) 2 D 3 ; and
  • Figure 2 is a graph illustrating growth curves for IL-10 KO mice either maintained deficient of l,25(OH) 2 D 3 (-D) or supplemented with l,25(OH) 2 D 3 (+D) as compared to IL- 10 Wt mice deficient of 1 ,25(OH) 2 D 3 .
  • hydroxy-protecting group signifies any group commonly used for the temporary protection of hydroxy functions, such as for example, alkoxycarbonyl, acyl, alkylsilyl or alkylarylsilyl groups (hereinafter referred to simply as “silyl” groups), and alkoxyalkyl groups.
  • Alkoxycarbonyl protecting groups are alkyl-O-CO- groupings such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl or allyloxycarbonyl.
  • acyl signifies an alkanoyl group of 1 to 6 carbons, in all of its isomeric forms, or a carboxyalkanoyl group of 1 to 6 carbons, such as an oxalyl, malonyl, succinyl, glutaryl group, or an aromatic acyl group such as benzoyl, or a halo, nitro or alkyl substituted benzoyl group.
  • alkyl as used in the description or the claims, denotes a straight-chain or branched alkyl radical of 1 to 10 carbons, in all its isomeric forms.
  • Alkoxyalkyl protecting groups are groupings such as methoxymethyl, ethoxymethyl, methoxyethoxymethyl, or tetrahydrofuranyl and tetrahydropyranyl.
  • Preferred silyl-protecting groups are trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, dibutylmethylsilyl, diphenylmethylsilyl, phenyldimethylsilyl, diphenyl-t-butylsilyl and analogous alkylated silyl radicals.
  • aryl specifies a phenyl-, or an alkyl-, nitro- or halo-substituted phenyl group.
  • a “protected hydroxy” group is a hydroxy group derivatised or protected by any of the above groups commonly used for the temporary or permanent protection of hydroxy functions, e.g. the silyl, alkoxyalkyl, acyl or alkoxycarbonyl groups, as previously defined.
  • hydroxyalkyl deuteroalkyl
  • fluoroalkyl refer to an alkyl radical substituted by one or more hydroxy, deuterium or fluoro groups respectively.
  • vitamin D compound refers to the compounds defined by general formula I. It should be noted in this description that the term “24-homo” refers to the addition of one methylene group and the term “24-dihomo” refers to the addition of two methylene groups at the carbon 24 position in the side chain. Likewise, the term “trihomo” refers to the addition of three methylene groups. Also, the term “26,27-dimethyl” refers to the addition of a methyl group at the carbon 26 and 27 positions so that for example R ⁇ and R4 are ethyl groups. Likewise, the term “26,27-diethyl” refers to the addition of an ethyl group at the 26 and 27 positions so that R ⁇ and R ⁇ are propyl groups.
  • alkylidene or alkyl substituent if an alkylidene or alkyl substituent is attached at the carbon 2 position then the particular alkylidene or alkyl substituent should be added to the nomenclature. For example, if a methylene group is the alkylidene substituent, the term “2-methylene” should proceed each of the named compounds. If an ethylene group is the alkylidene substituent, the term “2-ethylene” should proceed each of the named compounds, and so on. Likewise, if a methyl or ethyl group is the alkyl substituent, then the term “2-methyl” or "2-ethyl” respectively should proceed each of the named compounds, and so on.
  • the term "19-nor” should proceed each of the named compounds.
  • the term "20(S)” or “20-epi” should be included in each of the following named compounds.
  • the named compounds could also be of the vitamin D2 and/or D 4 type if desired.
  • vitamin D compounds of structure I when the side chain is unsaturated are: l ⁇ -hydroxy-22-dehydrovitamin D 3 ; 1 ,25-dihydroxy-22-dehydrovitamin D 3 ; l,24-dihydroxy-22-dehydrovitamin D 3 ; 24-homo- 1 ,25-dihydroxy-22-dehydrovitamin D3 ; 24-dihomo- 1 ,25-dihydroxy-22-dehydrovitamin D3 ;
  • vitamin D compounds of structure I when the side chain is saturated are: l ⁇ -hydroxyvitamin D 3 ; 1,25 -dihydroxyvitamin D 3 ; l,24-dihydroxyvitamin D 3 ;
  • vitamin D compounds having the basic structure I can be accomplished by a common general method, i.e. the condensation of a bicyclic Windaus- Grundmann type ketone II with the allylic phosphine oxide III to the corresponding vitamin D analogs IV followed by deprotection, if desired, at C-1 and C-3 in the latter compounds:
  • X 1? and X 2 , Y1 and Y2, Z h and Z 2 , and R represent groups defined above; Y1 and Y2 are preferably hydroxy-protecting groups, it being also understood that any functionalities in R that might be sensitive, or that interfere with the condensation reaction, be suitably protected as is well-known in the art.
  • the process shown above represents an application of the convergent synthesis concept, which has been applied effectively for the preparation of vitamin D compounds [e.g. Lythgoe et al., J.
  • Hydrindanones of the general structure II are known, or can be prepared by known methods. Specific important examples of such known bicyclic ketones are the structures with the side chains (a), (b), (c) and (d) described above, i.e. 25-hydroxy Grundmarm's ketone (f) [Baggiolini et al., J. Org. Chem, 51, 3098 (1986)]; Grundmarm's ketone (g) [Inhoffen et al., Chem. Ber. 90, 664 (1957)]; 25-hydroxy Windaus ketone (h) [Baggiolini et al., J. Org. Chem., 51, 3098 (1986)] and Windaus ketone (i) [Windaus et al., Ann., 524, 297 (1936)]:
  • This invention is further described by the following illustrative example.
  • This example demonstrates that vitamin D deficiency exacerbates symptoms of IBD in IL-10 KO mice. Vitamin D deficiency also exacerbated the symptoms of enterocolitis in the animal model. These data predict that both forms of IBD (ulcerative colitis and Chron's disease) are amenable to treatment with l,25(OH) 2 D 3 and other vitamin D analogs.
  • IL-10 knockout mice (Kuhn et al. 1993, Mac Donald 1994).
  • the IL-10 KO mice develop enterocolitis within 5-8 weeks of life (Kuhn et al. 1993).
  • Approximately 30% of the IL-10 KO mice die following the development of severe anemia and weight loss (Kuhn et al. 1993).
  • the enterocolitis which develops in IL-10 KO mice is due to an uncontrolled immune response to conventional microflora since germfree IL-10 KO mice do not develop disease.
  • mice raised in specific pathogen free facilities develop milder disease which doesn't result in the death of the mice (Kuhn et al. 1993).
  • DIETS DIETS. From a single pool of breeding females fed commercial mouse diet (#5105 Ralston Purina Co.), females in the second week of gestation were selected and randomly distributed into two groups. Starting pregnant dams on vitamin D deficient diet ensured that by 5 weeks of age the weanlings were vitamin D deficient (Cantorna et al. 1996). All mice were fed synthetic diets made in the laboratory (Yang et al. 1993; modification of Smith et al. 1987). The mice were vitamin D deficient, vitamin D sufficient or 1,25-dihydroxycholecalciferol supplemented. Mice were housed under yellow light to prevent the synthesis of vitamin D in skin. All of the mice were vitamin D deficient until weaning.
  • mice The 3 week old vitamin D deficient mice were randomly assigned to various treatment groups as described below. Because l,25(OH) 2 D 3 treatment of other experimental autoimmune diseases was most effective when dietary calcium was high (lg calcium/ lOOg diet), all mice were fed high calcium diets (Cantorna et al. 1999). Experimental diets were prepared fresh and replaced every 2-3 days during the experiment. To ensure that 1,25-dihydroxycholecalciferol (l,25(OH) 2 D 3 ) treated mice ate all of the l,25(OH) 2 D 3 provided, food cups containing 8 g of diet were replaced every other day (completely eaten) for the duration of each experiment (Cantorna et al. 1996, Cantorna et al. 1998a).
  • mice were treated for 2 weeks and the 9 week old mice were sacrificed. FOOD RESTRICTION. Because of the dramatic weight loss and death of vitamin D deficient IL-10 KO mice a series of controlled feeding experiments were done. These experiments used 3 groups of mice. All of the mice for these experiments were maintained vitamin D deficient for the first 5 weeks of life (the earliest signs of weight loss). At 5 weeks the vitamin D deficient IL-10 KO mice were split into 2 groups. Half of the mice were maintained vitamin D deficient and the other half were switched to a vitamin D sufficient diet, which contained 5.0 ⁇ g/d cholecalciferol. In addition a group of vitamin D deficient WT mice were also switched to a diet which contained 5.0 ⁇ g cholecalciferol/d diet. The food eaten by vitamin D deficient IL-10 KO mice was weighed daily and the vitamin D sufficient IL-10 KO and WT mice were fed a restricted diet which contained the amount of food eaten by vitamin D deficient IL-10 KO mice in the previous 24 hours.
  • SERUM MEASUREMENTS Mice were bled at 5 weeks of age and at the end of the experiments to measure hemoglobin, calcium, and red blood cell numbers. Serum was collected every 2 weeks and serum calcium measured (normal for mice is 2.00-2.75 mmol/L). Vitamin D deficiency was also monitored by serum calcium analysis (serum calcium less then 1.75 mmol/L). Calcium (587-A) and hemoglobin ( 525-A) colorometric kits were from Sigma Chemical Co. (St. Louis, MO). Red blood cells were counted using a hemocytometer.
  • IBD SEVERITY Mortality associated with the development of diarrhea was recorded in IL-10 KO and WT mice.
  • SI small intestines
  • the jejunum of the IL-10 KO mice is visibly inflamed and has been used by others to monitor symptoms of IBD in mice (Kuhns et al. 1993).
  • the jejunum of the SI was saved in lOOg/L formalin in phosphate buffered saline solution and sent to the Perm State Diagnostic Laboratory for sectioning and staining with hematoxyalin and eosin.
  • Four or more paraffin sections (4 microns) from each mouse were scored using the exact procedure described by Kuhns et. al (1993).
  • the sections were scored blindly on a scale of 0 to 5 for inflammation. 0-was no inflammation, 1-was a few inflammatory cells, 2- was mild inflammation, 3- was abscess formation, 4- was abscess formation with many inflammatory cells throughout, and 5-was massive inflammation throughout the section.
  • FIGURE 1 Vitamin D deficiency induces the mortality of IL-10 KO mice.
  • FIGURE 2 Growth curves for vitamin D deficient and sufficient IL-10 KO mice and vitamin D deficient WT mice.
  • vitamin D deficient WT mice The growth of vitamin D deficient WT mice was retarded but constant over the 12 week period (+D WT mice weighed significantly less then +D IL- 10 KO mice from 7 to 11 weeks of age, PO.05) and by 12 weeks the vitamin D deficient WT mice matched the vitamin D sufficient mice in weight.
  • the vitamin D deficient IL-10 KO mice were growth retarded compared to vitamin D sufficient IL-10 KO and vitamin D deficient WT mice (Fig. 2).
  • the vitamin D deficient WT mice grew slower than the vitamin D sufficient IL-10 KO mice but by 12 weeks of age the vitamin D sufficient IL-10 KO and vitamin D deficient WT mice were the same size.
  • the vitamin D deficient IL-10 KO mice had stopped growing and were significantly smaller than the vitamin D deficient WT mice (Fig. 2).
  • vitamin D deficient IL-10 KO mice began to eat less and rapidly lost additional weight over the next 3 weeks. Subsequent experiments were terminated at 9 weeks to prevent unnecessary pain and suffering of the IL-10 KO mice.
  • the vitamin D deficient IL-10 KO mice died following a wasting disease which was preceded by diarrhea.
  • Vitamin D deficient WT and IL-10 KO mice weighed less than their l,25(OH) 2 D 3 supplemented counte ⁇ arts at 9 weeks of age (Table 1). The weights of the vitamin D deficient IL-10 KO mice were lower than in previous experiments (Fig. 2); although in this case consistent with the accelerated weight loss observed previously in vitamin D deficient IL-10 KO mice. As expected the serum calcium values in l,25(OH) 2 D 3 supplemented mice were significantly (P ⁇ 0.05) higher than the vitamin D deficient mice (Table 1). Hemoglobin levels and erythrocyte numbers were normal and not different in vitamin D deficient, vitamin D sufficient, and l,25(OH) 2 D 3 supplemented IL-10 KO and WT mice (data not shown).
  • Vitamin D deficient IL-10 KO mice had significantly more inflammation in the SI than their l,25(OH) 2 D 3 supplemented or vitamin D sufficient counterparts (P ⁇ 0.05, Table 1 and data not shown). Although the vitamin D deficient IL-10 KO mice were the smallest in size, necropsy showed that they had extremely large SI.
  • mice were vitamin D deficient (-D) for the first 5 weeks of life.
  • mice were divided into 2 groups: half were supplemented with 0.005 ⁇ g/day l,25(OH) 2 D 3 for 4 weeks. Values are means ⁇ SEM.
  • IL interleukin
  • KO knockout: -D
  • vitamin D deficient l,25(OH) 2 D 3
  • 1,25-dihydroxycholecalciferol WT, wildtype.
  • mice were vitamin D deficient (-D) for the first 7 weeks of life. At 7 weeks of age, the vitamin D-deficient IL-10 KO mice begin to show symptoms of enterocolities (diarrhea and weight loss).
  • the 7-week-old IL-10 KO and WT mice were divided into two group; half were supplemented with 0.2 ⁇ g/d l,25(OH) 2 D 3 for 2 weeks. Values are means ⁇ SEM.
  • IL interleukin
  • KO knockout: -D
  • vitamin D deficient l,25(OH) 2 D 3
  • 1,25-dihydroxycholecalciferol WT, wildtype.
  • IL interleukin
  • KO knockout: -D
  • vitamin D deficient +D
  • l,25(OH) 2 D 3 sufficient: WT, wildtype.
  • Vitamin D deficiency exacerbates the symptoms of enterocolitis in IL-10 KO mice, and 1,25-dihydroxycholecalciferol treatment for as little as 2 weeks ameliorated IBD symptoms in these mice.
  • vitamin D is a regulator of CD4+ T cells, which cause autoimmune disease (Cantorna et al. 1996, Cantorna et al. 1998c).
  • One possible mechanism of vitamin D action is in the negative regulation of CD4+ T cells, which cause IBD.
  • Vitamin D has been shown to directly inhibit the effector functions of CD4+ T cells both in vitro and in vivo (Cippitelli and Santoni 1998, Lemire 1992).
  • the other possibility is that vitamin D is a positive regulator of T cells or other cells which inhibit the induction or function of IBD causing T cells.
  • Two possible vitamin D targets are transforming growth factor (TGF)- ⁇ l and IL-4 secreting cells (Cantorna et al. 1998c).
  • TGF- ⁇ l and IL-4 Increased production of TGF- ⁇ l and IL-4 have been shown to occur in mice treated with 1,25-dihydroxycholecalciferol in vivo (Cantorna et al. 1998c). Furthermore, the production of TGF- ⁇ l and IL-4 is associated with the inhibition of T cell effector function and suppression of many autoimmune diseases (Groux et al. 1997). Vitamin D regulation of the immune system is probably complex and includes multiple targets, which together explain the mechanism by which 1,25-dihydroxycholecalciferol suppresses the development of IBD.
  • Standard treatments of patients with IBD include short-term high dose and long term low dose prednisone use (Andreassen et al. 1998, Podolosky 1991).
  • Prednisone and other corticosteroid therapies result in a decreased bone mineral density and many times result in higher risks for vertebral fracture (Andreassen et al. 1997, Andreassen et al. 1998).
  • Vitamin D supplementation of patients on corticosteroids has been shown to prevent steroid induced bone loss (Buckley et al. 1996).
  • the hormonally active form of vitamin D (1,25-dihydroxycholecalciferol) is known to increase bone mineralization when given to experimental animals (Cantorna et al. 1998b) and people (Ongphiphadhanakul et al. 2000).
  • vitamin D and or 1,25- dihydroxycholecalciferol supplementation may be the maintenance of bone mineral density.
  • 1,25-dihydroxycholecalciferol and its analogs are novel and effective treatments for IBD patients.
  • a possible limitation of 1,25- dihydroxycholecalciferol treatment is the hypercalcemia, which can result.
  • the greatest promise thus may be for vitamin D analogs used in combination with the standard treatments.
  • the standard treatments often work well but have many side effects; like bone loss which vitamin D analogs could reverse or block entirely.
  • Vitamin D analogs in combination with corticosteroids, or sulfasalazine drugs could reduce the effective dose of these drugs, limit side effects and prove to be novel and effective treatments for human IBD.
  • novel compounds of this invention defined by formula I may be formulated for pharmaceutical applications as a solution in innocuous solvents, or as an emulsion, suspension or dispersion in suitable solvents or carriers, or as pills, tablets or capsules, together with solid carriers, according to conventional methods known in the art. Any such formulations may also contain other pharmaceutically-acceptable and non- toxic excipients such as stabilizers, anti-oxidants, binders, coloring agents or emulsifying or taste-modifying agents.
  • the compounds may be administered orally, topically, parenterally or transdermally.
  • the compounds are advantageously administered by injection or by intravenous infusion or suitable sterile solutions, or in the form of liquid or solid doses via the alimentary canal, or in the form of creams, ointments, patches, or similar vehicles suitable for transdermal applications.
  • Doses of from O.Ol ⁇ g to lOO ⁇ g per day of the compounds are appropriate for treatment pu ⁇ oses, such doses being adjusted according to the activity of the particular compound being used, the disease to be treated, its severity and the response of the subject as is well understood in the art.
  • Each compound may be suitably administered alone, or together with graded doses of another active vitamin D compound — e.g. l ⁇ -hydroxyvitamin D2 and/or D3, in combination with l ⁇ ,25 -dihydroxyvitamin D3 ⁇ in situations where different degrees of bone mineral mobilization and calcium transport stimulation is found to be advantageous.
  • compositions for use in the above-mentioned treatment of IBD comprise an effective amount of one or more vitamin D compound as defined by the above formula I as the active ingredient, and a suitable carrier.
  • An effective amount of such compounds for use in accordance with this invention is from about O.Ol ⁇ g to about lOO ⁇ g per gm of composition, and may be administered topically, transdermally, orally or parenterally in dosages of from about O.Ol ⁇ g/day to about lOO ⁇ g/day.
  • the compounds may be formulated as creams, lotions, ointments, topical patches, pills, capsules or tablets, or in liquid form as solutions, emulsions, dispersions, or suspensions in pharmaceutically innocuous and acceptable solvent or oils, and such preparations may contain in addition other pharmaceutically innocuous or beneficial components, such as stabilizers, antioxidants, emulsifiers, coloring agents, binders or taste- modifying agents.
  • the formulations of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredients.
  • the carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof.
  • Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion.
  • Formulations for rectal administration may be in the form of a suppository inco ⁇ orating the active ingredient and carrier such as cocoa butter, or in the form of an enema.
  • Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations such as liniments, lotions, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops; or as sprays.
  • dosage unit a unitary, i.e. a single dose which is capable of being administered to a patient as a physically and chemically stable unit dose comprising either the active ingredient as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers.

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  • Health & Medical Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
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  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

L'invention concerne une méthode de traitement de maladies entériques inflammatoires, en particulier la colite ulcéreuse et la maladie de Crohn. La méthode consiste à administrer un composé de la vitamine D en quantité suffisante pour traiter la maladie. L'administration d'un composé de la vitamine D prévient également le développement ou retarde l'apparition de maladies entériques inflammatoires chez les personnes y étant sensibles.
PCT/US2000/042393 1999-12-02 2000-11-30 Traitement de maladies enteriques inflammatoires avec des composes de la vitamine d WO2001042205A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP00992552A EP1233942A2 (fr) 1999-12-02 2000-11-30 Traitement de maladies enteriques inflammatoires avec des composes de la vitamine d
CA002390859A CA2390859A1 (fr) 1999-12-02 2000-11-30 Traitement de maladies enteriques inflammatoires avec des composes de la vitamine d
JP2001543506A JP2003516386A (ja) 1999-12-02 2000-11-30 ビタミンｄ化合物での炎症性腸疾患の治療
AU45100/01A AU4510001A (en) 1999-12-02 2000-11-30 Treatment of inflammatory bowel disease with vitamin d compounds

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US16850199P 1999-12-02 1999-12-02
US60/168,501 1999-12-02
US19782700P 2000-04-14 2000-04-14
US60/197,827 2000-04-14
US20863200P 2000-06-01 2000-06-01
US60/208,632 2000-06-01
US23190600P 2000-09-11 2000-09-11
US60/231,906 2000-09-11

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US10/969,394 Continuation US20050070513A1 (en) 1999-12-02 2004-10-20 Treatment of inflammatory bowel disease with vitamin D compounds

Publications (2)

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WO2001042205A2 true WO2001042205A2 (fr) 2001-06-14
WO2001042205A3 WO2001042205A3 (fr) 2002-03-21

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EP (1) EP1233942A2 (fr)
JP (1) JP2003516386A (fr)
AU (1) AU4510001A (fr)
CA (1) CA2390859A1 (fr)
WO (1) WO2001042205A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1240136A1 (fr) * 1999-12-21 2002-09-18 Northern Lights Pharmaceuticals, LLC Utilisation de composes de vitamine d biologiquement actifs pour prevenir et traiter la maladie intestinale inflammatoire
WO2003106629A2 (fr) * 2002-06-13 2003-12-24 Wisconsin Alumni Research Foundation Traitement des maladies influencees par la vitamine d
CN115515435A (zh) * 2020-02-11 2022-12-23 沃尔夫森医疗中心 有效治疗溃疡性结肠炎的方法

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6114292B2 (ja) * 2011-10-21 2017-04-12 ウイスコンシン アラムニ リサーチ ファンデーション ２−メチレン−ビタミンｄ類似体およびそれらの使用
JP6397695B2 (ja) * 2014-08-25 2018-09-26 学校法人自治医科大学 抗ピロリ菌剤
US9688596B2 (en) * 2015-08-05 2017-06-27 Wisconsin Alumni Research Foundation Synthesis and biological activity of 2-methylene analogs of calcitriol and related compounds

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DE4405545A1 (de) * 1994-02-22 1995-08-31 Dietl Hans Fettlösliche Vitamine enthaltende Zubereitung zur oralen Applikation
WO1996030326A1 (fr) * 1995-03-30 1996-10-03 The Trustees Of The University Of Pennsylvania Agents de differenciation utilises pour le traitement des maladies intestinales inflammatoires
US5583125A (en) * 1992-10-06 1996-12-10 Schering Aktiengesellschaft 25-Carboxylic acid derivatives in the vitamin D series, process for their production, intermediate products for these processes, pharmaceutical preparations containing these derivatives as well as their use for the production of pharmaceutical agents
US5663157A (en) * 1992-06-30 1997-09-02 Schering Aktiengesellschaft 22-en-25-oxa derivatives in the vitamin D series, process for their production, pharmaceutical preparations containing these derivatives as well as their use as pharmaceutical agents
WO1998051664A1 (fr) * 1997-05-16 1998-11-19 Women & Infants Hospital Composes de 3-epi-vitamine d2 et utilisations desdits composes
WO1998051678A1 (fr) * 1997-05-16 1998-11-19 Women & Infants Hospital COMPOSES DE VITAMINE D3 A ETHER CYCLIQUE ET COMPOSES DE 1α(OH)3-EPI-VITAMINE D3, ET UTILISATION DESDITS COMPOSES
WO1999003828A1 (fr) * 1997-07-17 1999-01-28 F.Hoffmann-La Roche Ag Dihomo-seco-cholestanes comportant deux liaisons insaturees dans la chaine laterale

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JP2543627B2 (ja) * 1990-02-09 1996-10-16 帝人株式会社 活性型ビタミンｄ含有治療剤
US6358939B1 (en) * 1999-12-21 2002-03-19 Northern Lights Pharmaceuticals, Llc Use of biologically active vitamin D compounds for the prevention and treatment of inflammatory bowel disease

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US5663157A (en) * 1992-06-30 1997-09-02 Schering Aktiengesellschaft 22-en-25-oxa derivatives in the vitamin D series, process for their production, pharmaceutical preparations containing these derivatives as well as their use as pharmaceutical agents
US5583125A (en) * 1992-10-06 1996-12-10 Schering Aktiengesellschaft 25-Carboxylic acid derivatives in the vitamin D series, process for their production, intermediate products for these processes, pharmaceutical preparations containing these derivatives as well as their use for the production of pharmaceutical agents
DE4405545A1 (de) * 1994-02-22 1995-08-31 Dietl Hans Fettlösliche Vitamine enthaltende Zubereitung zur oralen Applikation
WO1996030326A1 (fr) * 1995-03-30 1996-10-03 The Trustees Of The University Of Pennsylvania Agents de differenciation utilises pour le traitement des maladies intestinales inflammatoires
WO1998051664A1 (fr) * 1997-05-16 1998-11-19 Women & Infants Hospital Composes de 3-epi-vitamine d2 et utilisations desdits composes
WO1998051678A1 (fr) * 1997-05-16 1998-11-19 Women & Infants Hospital COMPOSES DE VITAMINE D3 A ETHER CYCLIQUE ET COMPOSES DE 1α(OH)3-EPI-VITAMINE D3, ET UTILISATION DESDITS COMPOSES
WO1999003828A1 (fr) * 1997-07-17 1999-01-28 F.Hoffmann-La Roche Ag Dihomo-seco-cholestanes comportant deux liaisons insaturees dans la chaine laterale

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PATENT ABSTRACTS OF JAPAN vol. 018, no. 093, 16 February 1994 (1994-02-16) -& JP 05 294834 A (TEIJIN LTD) -& DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; STN, CAPLUS accession no. 1994:153715, XP002167821 *
See also references of EP1233942A2 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1240136A1 (fr) * 1999-12-21 2002-09-18 Northern Lights Pharmaceuticals, LLC Utilisation de composes de vitamine d biologiquement actifs pour prevenir et traiter la maladie intestinale inflammatoire
EP1240136A4 (fr) * 1999-12-21 2004-05-26 Wisconsin Alumni Res Found Utilisation de composes de vitamine d biologiquement actifs pour prevenir et traiter la maladie intestinale inflammatoire
US6858595B2 (en) 1999-12-21 2005-02-22 Wisconsin Alumni Research Association Use of biologically active vitamin D compounds for the prevention and treatment of inflammatory bowel disease
US6989377B2 (en) 1999-12-21 2006-01-24 Wisconsin Alumni Research Foundation Treating vitamin D responsive diseases
WO2003106629A2 (fr) * 2002-06-13 2003-12-24 Wisconsin Alumni Research Foundation Traitement des maladies influencees par la vitamine d
WO2003106629A3 (fr) * 2002-06-13 2004-09-30 Wisconsin Alumni Res Found Traitement des maladies influencees par la vitamine d
CN115515435A (zh) * 2020-02-11 2022-12-23 沃尔夫森医疗中心 有效治疗溃疡性结肠炎的方法

Also Published As

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WO2001042205A3 (fr) 2002-03-21
EP1233942A2 (fr) 2002-08-28
AU4510001A (en) 2001-06-18
CA2390859A1 (fr) 2001-06-14
JP2003516386A (ja) 2003-05-13

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