EP1781302A1 - Nouvelle utilisation - Google Patents
Nouvelle utilisationInfo
- Publication number
- EP1781302A1 EP1781302A1 EP05766728A EP05766728A EP1781302A1 EP 1781302 A1 EP1781302 A1 EP 1781302A1 EP 05766728 A EP05766728 A EP 05766728A EP 05766728 A EP05766728 A EP 05766728A EP 1781302 A1 EP1781302 A1 EP 1781302A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- vitamin
- use according
- compound
- medicament
- treatment
- 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.)
- Withdrawn
Links
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
- A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the present invention relates to the use of a vitamin D compound, which is able to specifically and directly up-regulate hCAP18, for the manufacturing of a medicament with antimicrobial effect for treatment of conditions deficient in LL-37, such as chronical ulcers, and atopic dermatitis.
- Epithelia constitute the primary barrier between host and the potentially harmful environment, and therefore the protection of this interface is vital.
- a wound represents a broken barrier and immediately sets in motion a series of tightly orchestrated events with the purpose to promptly reinstate the integrity of the barrier.
- Urgent wound closure has evolved in higher organisms, diverging from the time-consuming process of complete regeneration of tissue seen in lower species. Impaired wound healing represents a major challenge in clinical medicine ranging from the relative delay in "normal" healing seen with increasing age to pathologic non-healing ulcers.
- Antimicrobial peptides are effector molecules of the innate immune system, which serve to protect the host against potentially harmful microorganisms. They are conserved through evolution and are widespread in nature. In human, only a handful has been identified so far; among which the defensins and the human cathelicidin antimicrobial peptide hCAPl ⁇ have been implicated in epithelial defence (Selsted et al., J Biol Chem 258:14485-14489, 1983) .
- WO 96/08508 relates to the human polypeptide FALL- 39, as well as to pharmaceutical compositions containing said peptide and having an antimicrobial activity against bacteria.
- the peptide was named FALL-39 after the first four amino acid residues and consisted of the 39 amino acid C- terminal part of a proprotein concomitantly identified by three separate groups (Cowland et al. r FEBS 1 1995; Agerberth et al. r Proc Natl Acad Sci USA 1995; Larrick et al. , FEBS Letters 1996) .
- the peptide was shown to have potent anti ⁇ microbial activity against both gram-positive and gram- negative bacteria.
- the proprotein was named hCAPl ⁇ , human cationic anti-microbial protein, and is a member of the cathelicidin family of proteins consisting of cathelin, which has been conserved through evolution and a C-terminal part, variable in different species.
- hCAPl ⁇ is the only member of this protein family, whereas in other species, such as mouse and pig, there are several members.
- LL-37 is an endogenous peptide, which is released by proteolytic cleavage of hCAP18; the C-terminus is LL-37. LL-37 is thought to func ⁇ tion extracellularly and there is no evidence for intra ⁇ cellular cleavage of the pro-protein.
- hCAP18/LL-37 is present in leukocytes and in barrier organs such as skin, mucous membranes, respiratory epithelium and reproductive organs.
- barrier organs such as skin, mucous membranes, respiratory epithelium and reproductive organs.
- the localization of hCAPl8/LL-37 to barrier epithelia seems to be consistent with a protective role for the peptide in preventing local infection and systemic microbial invasion.
- hCAP18/LL-37 In association with inflammation hCAP18/LL-37 is upregulated in skin epithelium (Frohm et al. f J Biol Chem 272:15258-15263, 1997) and mucous membranes (Frohm Nilsson et al., Infect Immun 67:2561-2566, 1999) .
- dermatitis and eczema encompass a variety of distinct conditions with different etiological background, such as allergic and non-allergic contact dermatitis, nummular eczema, sebborhoic eczema and atopic eczema.
- Atopic eczema or in other words atopic dermatitis is a chronic, itchy inflammatory skin disease affecting approximately 20 % of children in Western societies. The etiology is unknown but a combination of genetic and environmental factors are considered to interplay to mani ⁇ fest the disease.
- Atopic eczema lesions are characterized by a defect in skin barrier and the patients are prone to skin infections.
- the skin of patients with atopic eczema is frequently colonized with bacteria such as Staphylococcus aureus and the patients often require treatments with antibiotics. Effective topical antibacterial treatment is lacking. This is in contrast to psoriasis, another inflamma ⁇ tory skin disease, where the skin seems to be rather protected against infections.
- Vitamin D refers to a number of vital fat-soluble steroid hormones, such as cholecalciferol (vitamin D 3 ) and ergocalciferol (vitamin D 2 ) • Cholecalciferol is obtained from animal food, and ergocalciferol is produced in plants and yeast. Said two forms of vitamin D are metabolised in the same way, first hydroxylated into 25-OH-D, which compound is then 1-hydroxylated into 1, 25- (OH) 2 ⁇ D, the biologically most active metabolite.
- the chemical formulas of vitamin D 2 and vitamin D 3 are given in Fig. 1. Vitamin D has for long been known for its important role in regulating body levels of calcium and phosphorus, and in mineralization of bone.
- vitamin D As a transcriptional regulator, of bone matrix proteins, vitamin D induces the expression of osteocalcin and suppresses synthesis of type I collagen. In cell cultures, vitamin D stimulates differentiation of osteo- clasts.
- vitamin D defic"* ⁇ . ,y ⁇ V mutations in the vitamin D receptor suggest that these effects are perhaps not of major physiologic importance, and that the crucial effect of vitamin D on bone is to provide the proper balance of calcium and phosphorus to support mineralization-.
- Vitamin D defici ⁇ ency The classical manifestations of vitamin D defici ⁇ ency are rickets, which is seen in children and results in bony deformities including bowed long bones. Deficiency in adults leads to the disease osteomalacia. Both rickets and osteomalacia reflect impaired mineralization of newly synthesized bone matrix, and usually result from a combina ⁇ tion of inadequate exposure to sunlight and decreased dietary intake of vitamin D. Vitamin D 3 has also been reported to be involved in insulin secretion (C. Cade et al, Endocrinology ⁇ 120, 1490 (1987), prolactin synthesis (J.D. Wark et al, J. Biol. Chem. , ' 258, 270 (1983), epidermal cell differentiation (J. Hasami et al, Endocrinology, 113,1950 (1983) and in cancer (K. Chida et al, Cancer Res. , 45, 5426 (1985) .
- compositions contain- ing 1-alpha-hydroxycholecalciferol or l ⁇ , 25-dihydroxy- cholecalciferol for the topical treatment of skin disorders such as dermatitis and psoriasis.
- the used dosages were between 0.03-1.0 ⁇ g/g of composition to avoid side effects.
- the results in Table I show that no effect on dermatitis could be obtained with ergocalciferol, cholecalciferol or
- WO 9105537 discloses methods for enhancing wound healing including gastric ulcer healing by administration of high doses of a vitamin D compound. Both topical and other ⁇ administration forms are claimed. A large number of compounds such as vitamin D 2 , vitamin D 3 , 5,6-epoxy deriva ⁇ tives of vitamin.D and fluoro derivatives are listed but data are only available for 1, 25-dihydroxy-cholecalciferol on puncture, that is acute, wounds in rats using dosages up to 54 ⁇ g/g oil.
- 25-hydroxy vitamin D 3 25-OH-D 3
- 1, 25-dihydroxy vitamin D 3 (1,25-(OH) 2 -D 3 ) surprisingly, specifically and directly, stimulate the upregulation of hCAPl ⁇ and the biosynthesis of the antimicrobial peptide LL-37.
- Fig. 1 shows the chemical formulas of vitamin D 2 and D 3 , respectively.
- Fig. 2 is a staple diagram showing the expression of hCAPl ⁇ RNA in human primary keratinocytes after treatment with vitamin D 3 and analogues.
- Fig. 3 shows a Western blot analysis of protein extracts from keratinocytes treated with 1 ⁇ M 1,25-(OH) 2 -D 3 .
- Fig. 4 is a staple diagram showing the concentration dependence of hCAPl ⁇ stimulation by vitamin D 3 .
- Fig. 5 is a staple diagram showing that there is no significant effect of 7-dehydrocholesterol on hCAPl ⁇ expression.
- Fig. 6 is a staple diagram showing that the expression of hCAP18/LL37 is up-regulated by vitamin D 3 in - human skin in vivo.
- Fig. 7 is . a staple diagram showing that hCAPl ⁇ mRNA is up-regulated by vitamin D in acute wounds.
- Fig. 8 shows a Western blot analysis of hCAPl ⁇ and LL-37 protein extracts from acute wounds treated with calcipotriol
- the ' present invention refers to the use of a vitamin D compound active in up-regulating the expression and production of hCAPl ⁇ in humans for the manufacture of a medicament for treatment of conditions deficient in or benefiting from LL-37.
- Vitamin D compounds which can be used in accord ⁇ ance with the invention, are vitamin D compounds which up- regulate the expression and production of hCAPl ⁇ in the assays as described in Example 1.
- Examples of said compounds can be selected from the group consisting of cholecalciferol (D 3 ), 25-hydroxy-cholecalciferol (25-OH-D 3 ), 1, 25-dihydroxy- cholecalciferol (1,25- (OH)2-D3) , 1,25-dihydroxyergocalciferol (1,25-(OH) 2 -Da), as well as other vitamin D active metabo ⁇ lites, and vitamin D active synthetic analogues.
- vitamin D active metabolites are, in addition to 25-OH-D 3 and 1,25-(OH) 2 -D 3 , 24,25-(OH) 2 -D 3 and 1,24,25-(OH) 3 -D 3 ., and also 25-OH-D 2 and 1,25-(OH) 2 -D 2 , 24,25- (OH) 2 -D 2 and 1,24,25-(OH) 3 -D 2 .
- Vitamin D active synthetic vitamin D analogues are for instance calcipotriol, calcitriol, tacalcitol, ⁇ maxacalcitol and others, for instance as described in WO 02/34235.
- the active vitamin D compounds also activate the VDRs, vitamin D receptors.
- Vitamin D has a direct effect by binding the VDRE, vitamin D responsive element, in the hCAPl ⁇ promotor. We have shown that the crucial VDRE is located at -494/-4 ⁇ O in the promotor (Weber et al., J. Invest Dermatol 124(5) : 1080-2) .
- a preferred vitamin D compound is 25-hydroxy-chole- calciferol (25-(OH)-D 3 ), or 1,25-dihydroxy-cholecalciferol (1,25-(OH) 2 -D 3 ) .
- vitamin D compound to enhance the endogenous production of LL-37 is a safe way of providing the antimicrobial peptide LL-37 to a site in need of said peptide.
- the up-regulation of hCAP18 by vitamin D compound in skin epithelial cells is potentiated by the preaddition to the cells .of a calcium salt.
- the invention therefore also refers to the use of a vitamin D 3 compound in combination with a calcium salt for treatment of conditions deficient in LL-37.
- the invention refers to the use of a vitamin D active compound in a sufficient amount for stimulating the endogenous production of the antimicrobial peptide LL-37 in human cells, especially epithelial cells.
- the up-regulation of hCAPl8 by the vitamin D compound and the biosynthesis of the antimicrobial peptide LL-37 is obtained using a rela- tively low concentration, such as 10 nM - 1 ⁇ M of a vitamin D compound.
- the vitamin D compound is preferably locally administered. In systemic administration there is always a risk of hypercalcemia.
- the vitamin D compound is preferably applied to the skin or membrane in 'an amount " of 0.05-10 ⁇ g/cm 2 , preferably in an amount of 0.1- 0.5 ⁇ g/cm 2 .
- the invention especially refers to the use of a vitamin D compound for the manufacture of ' a medicament having an antimicrobial effect.
- the invention also refers to the use of a vitamin D compound for the manufacture of a medicament providing a sustained and enhanced antimicrobial protection in injured tissue.
- the invention also refers to the use of a vitamin D compound for the manufacture of a medicament for the prophylactic and curative treatment of infections in connection with atopic dermatitis.
- the invention also refers to the use of a vitamin D compound for the manufacture of a medicament for healing of wounds, especially chronic ulcers, such as ulcers due to venous insufficiency, ulcers due to arteriosclerotic deficiency, ulcers due to diabetes, and burns.
- the invention also refers to the use of a vitamin D compound for the manufacture of a medicament for improving microvasculature through stimulation of angiogenesis.
- a pharmaceutical composition comprising a vitamin D compound, as mentioned above, in combination with a pharma- ceutically acceptable carrier can be used to facilitate administration of the compound, systemically or locally.
- Suitable routes for administration may include topical, rectal, transdermal, vaginal, intestinal, transmucosal and oral administration, parenteral delivery, including intramuscular, subcutaneous, and intracutaneous injections.
- Pharmaceutically acceptable carriers enable the formulation of tablets, pills, capsules, powders, liquids, gels, syrups, slurries, suspensions or creams, ointments, solutions, patches or any other suitable type of formulation.
- the amount ' of the vitamin D compound can be 1-100 ⁇ g/g of the composition, and preferably 5-50 ⁇ g/g.
- a pharmaceutical composition can be formulated with carriers comprising in addition to the active substance a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in- carrying or transporting the vitamin D compound from the application area to the cells or site of treatment.
- the carrier must be compatible with the other ingredients of the composition and not injurious to the patient.
- materials which can be used in a pharmaceutically acceptable carrier are: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc- cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; membrane lipids, such as phospho ⁇ lipids and galactolipids; glycols, such as propylene glycol; polyols, such as glycerine, sorbitol, mannitol and poly ⁇ ethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid;
- the invention also refers to the use of UVB irradiation for treatment of conditions deficient in or benefiting from LL-37, such as acute and chronic wounds, burn wounds, skin infections and atopic dermatitis. It has recently been demonstrated that irradiation with a single dose of UVB, 280-320 ran, but not of UVA, 340-400 nm, significantly up-regulated the expression of hCAP18 and vitamin D receptor (DR) in the skin of healthy volunteers.
- DR vitamin D receptor
- the invention also refers to a method of enhancing the expansion of human autologous cells in vitro, wherein cells are isolated from an excised piece of healthy tissue, said isolated cells are cultivated in vitro in a growth medium, and the cultivated cells are subsequently harvested and used for tissue repair, which is characterised in that a vitamin D compound active in up-regulating the expression and production of hCAP18 in humans is added to the growth medium.
- Vitamin D up-regulates the expression of hCAPl ⁇ mRNA and protein in human keratinocytes
- Fig. 2 shows the expression of hCAP18 mRNA in human primary keratinocytes after treatment with 1, 25-dihydroxy- D 3 , 25-hydroxy-U 3 and MC 903. Keratinocytes were grown as above and treated with said compounds for 24 h. RNA was extracted with the RNeasy kit (Qiagen) and reverse trans ⁇ cribed with, a first strand synthesis kit (Amersham- Pharmacia) . RNA was quantified by Real-Time PCR on an ABI Prism 7700 (Applied Biosystems) using 5 ng of cDNA according to standard protocols. The samples were evaluated in triplicates.
- Sequences were 5' -GTCACCAGAGGATTGTGACTTCAA-3' and 5'- TTGAGGGTCACTGTCCCCATA-3' • for the primers, and 5'- CCGCTTCACCAGCCCGTCCTT-3' for the fluorigenic probe.
- the samples were normalized by quantification of 18S-RNA (Assay on Demand, Applied Biosystems) .
- the induction of differentiation by calcium increased the expression by about 1.5 fold.
- the vitamin D compounds assayed here up-regulated hCAPl ⁇ by about one magnitude.
- the transcription of. hCAP18 was already up- regulated after 6 h treatment, indicating an event of early regulation.
- Fig. 3 shows a Western blot analysis of protein extracts from keratinocytes treated with 1 ⁇ M 1, 25- (OH) 2 -D 3 . Cells were grown and treated with 1,25-(OH) 2 -Ds as described above, and extracted in SDS-containing sample buffer according to standard protocols.
- the extracts were separated on a 15 % Tris-Glycine gel. To confirm that equal amounts of protein in each sample were blotted, the filters were reversibly stained with a 3 % Ponceau S (Sigma) solution in 3 % TCA, before incubating with the primary antibody. Affinity purified anti-LL37 antiserum (Heilborn et al., supra) was used at a 1:1000 dilution.
- Vitamin D compounds stimulate the expression of hCAP18 at physiological concentrations.
- a dosage form of a vitamin D compound for topical administration includes for instance about 1-100, preferably 5-50 ⁇ g vitamin D compound per gram composition.
- Example 3 Specificity of vitamin D compounds
- 7-DHC 7- dehydrocholesterol
- Fig. 5 shows that there is no significant effect of 7-dehydrocholesterol on hCAPl ⁇ expression.
- Assays were performed and measured as above. The effect of 1,25- (OH) 2 -D 3 is shown for comparison. 1,25-(OH) 2 -D 2 was also tested and was found to have an activity comparable to 1,25-(OH)-D 3 .
- Example 4 25- (OH) 2-D3 up-regulates the expression of hCAP!8 and the production of the mature antimicrobial peptide LL-37 in human skin in vivo.
- a stock solution of 4 mM 1,25-dihydroxyvitamin D 3 In isopropanol was diluted in ethanol:propylene glycol [70:30] to a final vitamin D concentration of 0.002 %.
- BHT butylated hydroxy toluene
- the vitamin D and-the control were locally applied to the skin (the right and left upper arm respectively) of three healthy volunteers.
- the test area of 2 x 2.5 cm on each arm was cleaned with saline solution (NaCl 0.9) before application. Evaporation time for the solutions of vitamin D and the vehicle varied between 8 and 15 minutes.
- Fig. 6 shows that the expression of hCAP18/ll-37 is up-regulated by vitamin D 3 in human skin in vivo.
- Left panel Real-Time PCR expression analysis on cDNA from skin biopsies of three probands. The biopsies were cut in 50 ⁇ m sections, placed in RNA Later solution and extracted for RNA as described above.
- Protein concentrations were measured by Protein Assay Kit (Bio-Rad Laboratories, Hercules CA) based on the Bradford method (Bradford, 1976) and samples were diluted to a final protein concentration of 1 mg per ml. The Western blot analysis was performed as described above.
- Vitamin D enhances the up-regulation of the protein hCAP18/LL-37 during wounding in human skin in vivo
- the topical treatment with vitamin D was applied on one side and the control treatment on the contra lateral side.
- __ To each of the wounds on one side, 25 ⁇ g calcipotriol in 0.5 g ointment (Daivonex, LEO Pharma, Malm ⁇ , Sweden) was applied to a total test area of 2 x 2.25 cm, including one wo.und with surrounding intact skin.
- the control wounds in the opposite inguinal region were treated with vaseline (ACO, Sweden) . All wounds were covered with inert dressing (Melolin, Smith and Nephew, Hull, UK; Mefix, Molnlycke AB, Gothenburg, Sweden; Tegaderm, 3M Health Care, St. Paul, USA) .
- the dressing was changed and the treatment was repeated.
- the bandage was removed at 24 hours and the wounds were excised with a 6 mm biopsy punch and snap frozen.
- biopsies were obtained from intact skin at 0 hours in addition to the wounds excised at 24 hours. These five individuals were treated with vitamin D and control for totally 24 hours as described above.
- the bandage was then removed, the test area was cleaned with saline solution and the remaining wounds were covered with inert dressing and subsequently excised 48 hours post-wounding. Expression of hCAP18 mRNA was quantified by Real-
- hCAPl ⁇ protein For the detection of hCAPl ⁇ protein, the extracts were separated on a 18 % Tris-Tricine gel (Schagger and von Jagow 1987) . The total protein amount in each sample was corrected to 5 ⁇ g. Affinity purified anti-LL-37 antiserum (Heilborn et al, 2003) was used at a 1:1000 dilution.
- Fig. 7 shows Real-Time RT-PCR expression analysis of the nine probands (no. 1-9) at 24 hours, showing that topical vitamin D treatment enhances the up-regulation of hCAPl ⁇ mRNA in acute wounds.
- RNA was extracted from excision biopsies of acute wounds locally treated with calcipotriol or vaseline (control) for 24 h.
- the stimulation of hCAPl ⁇ gene expression after treatment is shown in arbitrary units and standardized to 18S RNA expression. For each individual, values are presented relative to the expression of hCAPl ⁇ mRNA of the respective control wound, which is set as 1 (not shown) .
- Fig. 8 shows that vitamin D treatment enhances the up-regulation of hCAPl8 and the processed peptide LL-37 in acute wounds.
- three of the five individ- uals investigated demonstrated stronger immunoreactive bands, corresponding to the intact non-processed 18 kDa holoprotein, for the calcipotriol treated wounds, compared with the bands of the control wounds.
- Overall the strongest bands for hCAPl ⁇ were detected at 24 hours, but by 48 hours the difference between the wounds treated with calcipotriol and the control wounds was even more pronounced.
- vitamin D ointment significantly increases the level of hCAP18/LL-37 protein in acute wounds thereby providing a • sustained antimicrobial activity.
- Calcipotriol 25 ⁇ g in 0.5 g ointment (Daivonex, LEO Pharma, Malmo, Sweden) was applied to a test area of 2 x 2.25 cm localized in the wound margin of the chronic ulcers, including 50 % of the epithelialized area.
- Vaseline ACO, Sweden, served as control.
- results are expressed as arbitrary units comparing the expression of hCAP18 mRNA in untreated and treated biopsies from the same patient.
- results are presented as average of triplicates and standard deviations in the following Table 1.
- a stock solution of 4 mM 1,25- (OH)2-D3 in isopro- panol was diluted in ethanol:propylene glycol (70:30) to a final concentration of 0.002 %.
- the procedure was performed in a room with dim light.
- the 1,25- (OH) 2 -D 3 were locally applied on lesional and non-lesional skin area of patients.
- the skin surface was cleaned with saline solution (NaCl 0.9) before application.
- the treated skin area was measured to 2 * 2.25 cm. Evapora- tion time for the solutions of 1,25-(OH) 2 -D 3 varied between 8 and 15 minutes.
- the skin area was then covered with plastic film and band-aid (Quickpack: Mull und Hygiene GmbH, Renningen, Germany; Melolin: Smith and Nephew, Hull, UK; Mefix: Molnlycke AB, Gothenburg, Sweden) .
- band-aid and the plastic film were removed and the skin areas were rapidly cleaned with 40 % ethanol.
- Punch biopsies (4 mm) were obtained from the treated skin areas (after infiltration anesthesia with 2-3 ml Xylocain with epine- phrin) and frozen instantly.
- control biopsies were also obtained from non-treated lesional and non-lesional skin and the tissues were snap-frozen as described.
- Tests are planned for investigation of the effect of vitamin D treatment on the microflora, especially on Staphylococcus aureus, in atopic eczema patients.
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Abstract
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US59161504P | 2004-07-28 | 2004-07-28 | |
SE0401943A SE0401943D0 (sv) | 2004-07-28 | 2004-07-28 | New use |
PCT/SE2005/001184 WO2006011849A1 (fr) | 2004-07-28 | 2005-07-26 | Nouvelle utilisation |
Publications (2)
Publication Number | Publication Date |
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EP1781302A1 true EP1781302A1 (fr) | 2007-05-09 |
EP1781302A4 EP1781302A4 (fr) | 2010-02-17 |
Family
ID=35786492
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP05766728A Withdrawn EP1781302A4 (fr) | 2004-07-28 | 2005-07-26 | Nouvelle utilisation |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1781302A4 (fr) |
AU (1) | AU2005267629A1 (fr) |
CA (1) | CA2581693A1 (fr) |
WO (1) | WO2006011849A1 (fr) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010009032A1 (fr) | 2008-07-14 | 2010-01-21 | Medtronic, Inc. | Procédé de gestion d'horloge pour dispositif médical implantable |
RU2011136576A (ru) * | 2009-02-26 | 2013-04-10 | Джи-СЕНС ЛТД. | Устройство с резервуарами, находящимися под давлением, для хранения и дозирования жидкостей |
JPWO2016035804A1 (ja) * | 2014-09-02 | 2017-07-20 | 東レ株式会社 | 掻痒性皮膚疾患の治療又は予防剤 |
WO2017209934A1 (fr) * | 2016-05-13 | 2017-12-07 | Case Western Reserve University | Activateurs de l'autophagie pour le traitement ou la prévention de lésions cutanées |
IT202000009388A1 (it) * | 2020-04-29 | 2021-10-29 | Steve Jones S R L | Composizione per applicazione topica con attività antiinfiammatoria, antimicrobica e riparatrice |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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US4335120A (en) * | 1979-03-21 | 1982-06-15 | Hoffmann-La Roche Inc. | Administration of biologically active vitamin D3 and vitamin D2 materials |
US20010049365A1 (en) * | 1998-07-16 | 2001-12-06 | Achkar Charles C. | Compositions and methods of treating abnormal cell proliferation |
WO2002044403A2 (fr) * | 2000-11-29 | 2002-06-06 | Mcgill University | Marqueurs destines au test d'analogues de la vitamine d et applications therapeutiques associees |
WO2003018545A1 (fr) * | 2001-08-22 | 2003-03-06 | Johns Hopkins University | Analogues substitues par le soufre 24 de la 1$g(a),25 dihydroxy-vitamine d¿3? |
WO2005115403A2 (fr) * | 2004-05-26 | 2005-12-08 | Cedars-Sinai Medical Center | Induction de l'immunite innee par la vitamine d3 et ses analogues |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1991005537A1 (fr) * | 1989-10-04 | 1991-05-02 | Trustees Of Boston University | Procede d'acceleration de la cicatrisation de plaies et d'ulceres, et de traitement de maladie periodontique |
US5610978A (en) * | 1994-12-30 | 1997-03-11 | Mitel Corporation | Ring discriminator |
JP2000143515A (ja) * | 1998-11-16 | 2000-05-23 | Sumitomo Pharmaceut Co Ltd | 湿疹・皮膚炎群治療剤 |
CA2423930C (fr) * | 2000-10-27 | 2009-11-24 | Leo Pharma A/S | Composition topique contenant au moins une vitamine d ou un analogue de vitamine d et au moins un corticosteroide |
DE10161729A1 (de) * | 2001-12-15 | 2003-06-18 | Mira Ursic | Medizinische bzw. pharmazeutische Salbenzubereitung |
JP2004115451A (ja) * | 2002-09-27 | 2004-04-15 | Noevir Co Ltd | 表皮トランスグルタミナーゼ生合成促進剤及び活性促進剤 |
-
2005
- 2005-07-26 AU AU2005267629A patent/AU2005267629A1/en not_active Abandoned
- 2005-07-26 EP EP05766728A patent/EP1781302A4/fr not_active Withdrawn
- 2005-07-26 WO PCT/SE2005/001184 patent/WO2006011849A1/fr active Application Filing
- 2005-07-26 CA CA002581693A patent/CA2581693A1/fr not_active Abandoned
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US20010049365A1 (en) * | 1998-07-16 | 2001-12-06 | Achkar Charles C. | Compositions and methods of treating abnormal cell proliferation |
WO2002044403A2 (fr) * | 2000-11-29 | 2002-06-06 | Mcgill University | Marqueurs destines au test d'analogues de la vitamine d et applications therapeutiques associees |
WO2003018545A1 (fr) * | 2001-08-22 | 2003-03-06 | Johns Hopkins University | Analogues substitues par le soufre 24 de la 1$g(a),25 dihydroxy-vitamine d¿3? |
WO2005115403A2 (fr) * | 2004-05-26 | 2005-12-08 | Cedars-Sinai Medical Center | Induction de l'immunite innee par la vitamine d3 et ses analogues |
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DATABASE WPI Week 200045 Thomson Scientific, London, GB; AN 2000-500665 XP002558645 & JP 2000 143515 A (SUMITOMO SEIYAKU KK) 23 May 2000 (2000-05-23) * |
DATABASE WPI Week 200429 Thomson Scientific, London, GB; AN 2004-310753 XP002558646 & JP 2004 115451 A (NOEVIR KK) 15 April 2004 (2004-04-15) * |
LANSDOWN ALAN B G: "Calcium: A potential central regulator in wound healing in the skin." WOUND REPAIR AND REGENERATION, vol. 10, no. 5, September 2002 (2002-09), pages 271-285, XP002558644 ISSN: 1067-1927 * |
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TIAN X Q ET AL: "1,25-Dihydroxyvitamin D3: A novel agent for enhancing wound healing" JOURNAL OF CELLULAR BIOCHEMISTRY, WILEY-LISS INC, US, vol. 59, 1 January 1995 (1995-01-01), pages 53-56, XP002459131 ISSN: 0730-2312 * |
Also Published As
Publication number | Publication date |
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WO2006011849A1 (fr) | 2006-02-02 |
CA2581693A1 (fr) | 2006-02-02 |
AU2005267629A1 (en) | 2006-02-02 |
EP1781302A4 (fr) | 2010-02-17 |
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