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WO2002030430A1 - Utilisation de composes de vitamine d2 pour l'alopecie - Google Patents

Utilisation de composes de vitamine d2 pour l'alopecie Download PDF

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Publication number
WO2002030430A1
WO2002030430A1 PCT/US2001/029980 US0129980W WO0230430A1 WO 2002030430 A1 WO2002030430 A1 WO 2002030430A1 US 0129980 W US0129980 W US 0129980W WO 0230430 A1 WO0230430 A1 WO 0230430A1
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WO
WIPO (PCT)
Prior art keywords
volume
vitamin
compound
alopecia
rats
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Application number
PCT/US2001/029980
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English (en)
Inventor
Melanie A. Blanchard
Patricia L. Mershimer
Honorate Stelmach
Scott E. Toner
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Abbott Laboratories
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Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to AU2001291239A priority Critical patent/AU2001291239A1/en
Publication of WO2002030430A1 publication Critical patent/WO2002030430A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia

Definitions

  • the invention relates to a method for preventing and treating the condition of hair loss, known as alopecia
  • the invention more particularly relates to preventing and treating alopecia induced by the administration of chemotherapeutic agents
  • Active agents for use in the method of the invention are vitamin D 2 compounds, analogs, derivatives, or active metabolites thereof
  • the condition of hair loss or baldness occurs as a side effect of the chemical therapy often necessary to treat various kinds of cancer
  • This side effect commonly referred to as chemotherapy- induced alopecia
  • chemotherapy- induced alopecia can have a devastating effect on the appearance of the patient
  • alopecia is that the condition has an insignificant effect on the successful prognosis of cancer patients Nonetheless, patients receiving chemotherapy often regard alopecia as a more important side-effect than other adverse reactions, including even vomiting Tierney, A , et al "Hair Loss due to Cytotoxic Chemotherapy A Prospective Descriptive Study," Br J Cancer, 62 527-528 (1990)
  • chemotherapeutic agents have potent alopecia-inducing effect
  • adnamycin ADM
  • CX cytoxan
  • VP-16 etoposide
  • paclitaxel adnamycin
  • C AF CTX 4- ADM + 5-fluorourac ⁇ l (5-FU)
  • C AF is typically administered to patients for treatment of metastatic breast cancer
  • Patients treated under the CAF regimen typically lose 50% of their hair within 4-5 weeks after the first cycle of treatment After a second cycle of treatment, more than 90% of patients become totally alopecic
  • a mechanical apparatus called a scalp tourniquet
  • a scalp tourniquet is applied to the patient's head just before chemotherapy to reduce blood flow to the blood vessels in the scalp
  • the reduced blood flow is intended to limit the amount of drug reaching the hair follicle
  • One limitation is that the scalp tourniquet technique is inconsistently applied, which produces variability in the therapeutic results
  • a complication of the technique is that the tourniquet can cause headache and nerve compression
  • a preferred method will involve a compound demonstrating less calcemic effect while maintaining the beneficial quality of preventing and treating hair loss attributed to chemotherapy
  • the invention provides a method of preventing or treating chemotherapy- induced alopecia
  • a vitamin D 2 compound is administered to a patient affected with an alopecic condition caused by a chemotherapeutic agent
  • the compounds suitable for the method exhibit less calcemic effect than vitamin D 3 derivatives
  • Compounds for use in the method have demonstrated in vivo protection against alopecia induced by the administration of a chemotherapeutic agent or a combination of chemotherapeutic agents
  • FIG 1 is a photograph of 6 rats from Experiment III All rats received 1 5 mg/kg of etoposide for 3 consecutive days The 3 rats on the left received placebo lotion administered topically on day 5 after birth and continuing through day 10 The 3 rats on right received l ⁇ ,25- d ⁇ hydroxy-19-nor- vitamin D 2 applied topically (0 1 mL per square centimeter of surface area treated) beginning on day 5 after birth and continuing through day 10
  • FIG 2 is a photograph of 6 rats from Experiment IV All rats received 35 mg/kg of cytoxan for 1 day The 3 rats on the left received placebo lotion administered topically on day 5 after birth and continuing through day 10 The 3 rats on the right received l ⁇ ,25-d ⁇ hydroxy-19- nor-vitamin D 2 applied topically (0 25 mL per square centimeter of surface area treated) beginning on day 5 after birth and continuing through day 10
  • FIG 3 is a photograph of 6 rats from Experiment V All rats received 35 mg/kg of cytoxan for 1 day followed by 2 5 mg/kg for 3 days The 3 rats on the left received placebo lotion administered topically on day 5 after birth and continuing through day 10 The 3 rats on the right received l ⁇ ,25-d ⁇ hydroxy-19-nor-v ⁇ tam ⁇ n D 2 applied topically (0 25 mL per square centimeter of surface area treated) beginning on day 5 after birth and continuing through day 10
  • FIG 4 shows the cross-section for a skin biopsy taken from the control rats used for obtaining blood serum All control rats received placebo lotion administered topically on day 5 after birth and continuing through day 10
  • the lotion was applied daily over the head, neck and back After application of the lotion, the rats were kept individually separated for a period of 3 hours The area having lotion was carefully washed at the end of three hours Skin biopsies were taken from the rats and placed in formaldehyde The biopsies were processed and stained with H&E A cross-section of a skin biopsy from a control rat is shown
  • FIG 5 shows the cross-section for a skin biopsy taken from the treated rats used for obtaining blood serum All treated rats received l ⁇ ,25-d ⁇ hydroxy-l 9-nor-v ⁇ tam ⁇ n D 2 administered topically as a lotion on day 5 after birth and continuing through day 10
  • the lotion was applied daily over the head, neck and back After treatment with the lotion, the rats were kept individually separated for a period of 3 hours The treated area was carefully washed at the end of three
  • vitamin D 2 compound as used throughout the specification and claims shall refer to any vitamin D 2 compound, an analog, derivative, or active metabolite thereof.
  • the method of inhibiting chemotherapy-induced alopecia comprises administering to a host, treated with at least one chemotherapeutic agent, an effective amount of a vitamin D 2 compound.
  • the compounds useful for the claimed invention have the structural formula:
  • R 1 represents hydrogen or a methylene group
  • R 2 is hydrogen or hydroxy
  • R 3 represents an unsaturated, aliphatic alkyl group optionally substituted with methyl or hydroxy, provided that R 1 and R 2 are not both hydrogen.
  • the preferred substituents for R 1 and R 2 are methylene and hydroxy, respectively.
  • the group defined as R 3 represents a side chain common to vitamin D 2 compounds, Examples of suitable side chains for the compounds include, but are not limited to:
  • side chain is a group represented by (a) or (c) above.
  • Compounds contemplated as part of the invention include, but are not limited to:
  • pancalcitol 1 ⁇ ,25-d ⁇ hydroxy-l 9-nor-v ⁇ tamm 2
  • the preferred compound for the method of the invention is 1 ⁇ ,25-d ⁇ hydroxy- 19-nor- vitamin D 2 , also referred to herein as pancalcitol or 19-nor D 2
  • a preparation of pancalcitol is commercially available as ZEMPLAR ® from Abbott Laboratories (Abbott Park, IL U S A ) or can be prepared by methods previously described in the literature
  • the preparation of vitamin D2 compounds useful in the invention, the reagents, conditions, and procedures suitable for the preparation of vitamin D2 compounds has been described in the literature in at least U S Patent Nos 4,195,027, 4,260,549, 4,448,721, 4,769,181, 5,030,772, 5,237,110, 5,321,018, 5,342,975, and by Paaren et al in J Org Chem 48, 3819 (1983), which are incorporated by reference
  • Vitamin D 2 compounds exhibit unexpected activity in reducing, preventing or treating the condition of hair loss induced by a chemotherapeutic agent
  • the compounds have demonstrated activity by inhibiting patterns of chemotherapy- induced hair loss in vivo in a newborn rat model
  • the pattern of hair growth in the newborn rats is comparable with the growth pattern of the hair follicles in the human head, 1 e approximately 90% of the scalp hairs are in the active growing phase, anagen, and the remaining 10% are in the resting or shedding phase, teiogen
  • the model is effective for predicting the prevention or treatment of alopecia in vivo in a patient undergoing treatment with chemotherapeutic agents See, for example, Jimenez, J J et al FASEB J 1992b 6 911-13, Jimenez, J J , et al Cancer Research 1992c, 52 413-15, and Jimenez, J J et al Am J
  • the compounds can be administered to a host, or patient, treated with at least one chemotherapeutic agent that induces alopecia
  • the host or patient is a mammal, including humans and animals
  • the host or patient is the recipient of therapeutic treatment with either a chemotherapeutic agent or a combination of chemotherapeutic agents
  • a suitable combination therapy will have two or three chemotherapeutic agents
  • the chemotherapeutic agents can be either cell cycle specific or non-cell cycle specific
  • the compounds have demonstrated preventative effect in newborn rat host treated with cytoxan, a combination of adnamycin and cytoxan, and etoposide
  • the compounds can have effect in reducing, preventing or treating alopecia induced by other chemotherapeutic agents as well, including adnamycin alone, cytosine arabinoside, doxorubicin, 5-fluorourac ⁇ l, and paclitaxel
  • a suitable dosage amount of the vitamin D 2 compound is from about 0 05 microgram to about 0 2 microgram of compound per square centimeter of surface area treated
  • the dosage amount is about 0 125 micrograms of compound per square centimeter of surface area treated
  • the compounds can be formulated as solutions in innocuous solvents, or as emulsions, suspensions or dispersions in a pharmaceutically acceptable solvent or carrier
  • the compounds can be formulated into solutions, lotions, creams, ointments, gel, emulsions or other similar vehicles for topical application
  • the compound can be formulated into other dosage forms, including oral, lntrape ⁇ toneal, or subcutaneous dosage forms, for example a tablet, capsule, emulsion, micro emulsion, suspension or injectable solution
  • Any such formulation may also contain a combination of one or more solvents or carriers
  • the combination can optionally contain other pharmaceutically acceptable and non-toxic excipients, such as stabilizers, anti-oxidants, binders, coloring agents or emulsifying agents
  • the topical dosage forms can also include olfactory-enhancing agents
  • Oral dosage forms can optionally incorporate taste-modifying agents to consciously improve the overall desirability of the product
  • a preferred topical formulation comprises the vitamin D2 compound in a pharmaceutically acceptable aqueous medium or pharmaceutically acceptable hydroalcoho c preparation
  • an aqueous medium means a water-based solution without organic solvent
  • a hydroalcohohc preparation means a water-based solution comprising one or more alcohols
  • the vitamin D 2 compound can be dissolved in an organic solvent, preferably alcohol
  • the alcohol and one or more pharmaceutically acceptable adjuvants are blended to provide a homogenous formulation
  • Suitable alcohols for the invention include methanol, ethanol, isopropyl alcohol, and the like
  • the preferred alcohol is isopropyl alcohol
  • the adjuvant that can be used in the formulation of the invention is preferably a cosolvent, for example propylene glycol, low molecular weight polyethylene glycol, and the like, alone or in combination with water It is more preferred that the cosolvent is propylene glycol, more preferably in combination with water Additional non-therapeutic ingredients can also be incorporated into the formulation
  • a preferred hydroalcohohc preparation comprises from about 2 micrograms per milliliter to about 40 micrograms per milliliter of a vitamin D2 compound, from about 25% to about 75% volume/volume of alcohol, and about 75% to about 25% volume/volume of a pharmaceutically acceptable adjuvant in water
  • An example of a preferred formulation suitable for the method of the invention comprises 20 micrograms of 1 ⁇ ,25-d ⁇ hydroxy- 19-nor- vitamin D2 per milliliter of solution, wherein the solution comprises from about 51% volume/volume of isopropyl alcohol, about 4% volume/volume of propylene glycol, about 1% weight /volume hydroxypropylcellulose, and sufficient water to yield the desired volume
  • the preferred formulation is prepared by combining the isopropanol, propylene glycol and approximately forty percent of the final volume of distilled water in a suitably sized container or flask
  • the hydroxypropylcellulose is added to the above solution and stirred for a sufficient period of time to completely disperse the hydroxyproplycellulose Pancalcitol is added and stirred until dissolved
  • the resulting mixture is adjusted to final volume with distilled water
  • the preferred dosing regimen is carried out in a manner to assure the delivery the compound to the affected area, for example, the hair follicles Particularly in the case of chemotherapy- induced alopecia, the affected area more specifically refers to the hair follicles in the scalp
  • the l ⁇ ,25-dihydroxy- 19-nor- vitamin D 2 formulation used in the following experiments was prepared from the commercially available ZEMPLAR ® solution.
  • concentration of paricalcitol in ZEMPLAR was increased from 2 micrograms per milliliter to 8 micrograms per milliliter.
  • Sprague Dawley rats were purchased from Charles River Laboratories (Wilmington, Massachusetts, U.S.A.). Rats were fed and housed according to NIH guidelines. Daily weight gains were individually recorded. Cytoxan and adriamyc ⁇ n were obtained from Adria Laboratories (Columbus, Ohio, U.S.A.). Etoposide was obtained from Bristol Laboratories (Princeton, New Jersey, U.S.A.).
  • a solution of 19-nor-D 2 and a placebo were applied to newborn rats daily starting on day 5 after birth and continuing through day 10 after birth. The solution was applied topically over the head, neck and back. .After treatment with solution, animals were then kept individually separated for a period of 3 hours, following which the treated area was carefully washed. Daily weights were recorded to determine systemic toxicity.
  • Chemotherapy was given intraperitoneally (I.P.) and began at 1 1 days of age. Cytoxan (CTX, 35 mg/kg) was given for one day only. A combination of cytoxan and adriamycin (CTX + ADM) was administered as follows: CTX (25 mg/kg) for 1 day and adriamycin (ADM, 2.5 mg/kg) for 3 days. Etoposide (VP-16, 1.5 mg/kg) was given for 3 consecutive days.
  • the first three sets of experiments were conducted to screen for protection and to determine the minimal effective dose of 19-nor-D 2 .
  • the chemotherapy used was etoposide.
  • six, 5-day-old rats were randomized in two groups of three each.
  • Group 1 received 19-nor-D 2 .
  • Group 2 received placebo and served as control.
  • Group 1 received 0 1 mL of 19-nor-D 2 and group 2 received placebo solution In group 1, there was significant evidence of protection One rat was completely protected from developing alopecia, scale 0, one rat ranked as a 1 on the scale, and the other as a 2 All the rats in group 2 became totally alopecic, scale 3 There was no evidence of skin irritation, or of systemic toxicity, as indicated by the change in body weight, Table 1
  • the 19-nor-D 2 was applied at a volume of 0.25 mL.
  • Group 1 Six 5-day-old rats were randomized into two groups of 3 each. Group 1, received 0.25 mL of 19-nor-D 2 topically starting on day 5 after birth and continued through day 10 after birth. Group 2 received placebo similarly.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne l'utilisation de composés de vitamine D2, notamment 1 α,25-dihydroxy-19-nor-vitamine D2, dans le cadre de la prévention ou du traitement de l'alopécie induite par chimiothérapie.
PCT/US2001/029980 2000-10-06 2001-09-26 Utilisation de composes de vitamine d2 pour l'alopecie WO2002030430A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001291239A AU2001291239A1 (en) 2000-10-06 2001-09-26 Use of vitamin d2 compounds for alopecia

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US68457400A 2000-10-06 2000-10-06
US09/684,574 2000-10-06

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003028674A3 (fr) * 2001-10-02 2003-12-11 Cedars Sinai Medical Center Procede pour stimuler la repousse des cheveux par l'administration des analogues de la vitamine d
JP2013501790A (ja) * 2009-08-14 2013-01-17 バーグ バイオシステムズ，エルエルシー 脱毛症を治療するためのビタミンｄ３およびその類似体
WO2017220998A1 (fr) * 2016-06-22 2017-12-28 Paxman Coolers Ltd Traitement de l'alopécie secondaire à la chimiothérapie.

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2139627A (en) * 1983-05-09 1984-11-14 Wisconsin Alumni Res Found 1 alpha ,25-Dihydroxylated vitamin D2 compounds and intermediates in the preparation thereof
WO1993000079A1 (fr) * 1991-06-28 1993-01-07 University Of Miami Procede de prevention et de traitement de l'alopecie induite par chimiotherapie
WO1999016451A1 (fr) * 1997-08-29 1999-04-08 University Of Pittsburgh Of The Commonwealth System Of Higher Education Utilisation de derives de vitamine d en vue d'accroitre l'efficacite d'agents cytotoxiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2139627A (en) * 1983-05-09 1984-11-14 Wisconsin Alumni Res Found 1 alpha ,25-Dihydroxylated vitamin D2 compounds and intermediates in the preparation thereof
WO1993000079A1 (fr) * 1991-06-28 1993-01-07 University Of Miami Procede de prevention et de traitement de l'alopecie induite par chimiotherapie
WO1999016451A1 (fr) * 1997-08-29 1999-04-08 University Of Pittsburgh Of The Commonwealth System Of Higher Education Utilisation de derives de vitamine d en vue d'accroitre l'efficacite d'agents cytotoxiques

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
COTA J G ET AL: "JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 26, no. 53, 1988, pages 6094, XP002077584, ISSN: 0022-3263 *
JIMENEZ JOAQUIN J ET AL: "Novel approaches to the prevention of chemotherapy-induced alopecia.", EXPERIMENTAL BIOLOGY AND MEDICINE;NUTRIENTS IN CANCER PREVENTION AND, 1995, 1995 Humana Press Inc. Suite 808, 999 Riverview Drive, Totowa, New Jersey 07512, USA, pages 333 - 345, XP001038605, ISBN: 0-89603-318-X *
JOAQUIN J JIMENEZ ET AL: "Protection from chemotherapy-induced alopecia by 1,25-dihydroxyvitamin D3", CANCER RESEARCH, AMERICAN ASSOCIATION FOR CANCER RESEARCH, BALTIMORE, MD, US, vol. 52, no. 18, 15 September 1992 (1992-09-15), pages 5123 - 5125, XP002095914, ISSN: 0008-5472 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003028674A3 (fr) * 2001-10-02 2003-12-11 Cedars Sinai Medical Center Procede pour stimuler la repousse des cheveux par l'administration des analogues de la vitamine d
TWI595877B (zh) * 2009-08-14 2017-08-21 博格有限責任公司 用於治療禿髮症之維他命ｄ３及其類似物
EP2464357A4 (fr) * 2009-08-14 2013-08-14 Berg Pharma Llc Vitamine d3 et ses analogues pour le traitement de l'alopécie
AU2010282731B2 (en) * 2009-08-14 2015-08-13 Berg Llc Vitamin D3 and analogs thereof for treating alopecia
AU2010282731C1 (en) * 2009-08-14 2016-04-21 Berg Llc Vitamin D3 and analogs thereof for treating alopecia
JP2017008064A (ja) * 2009-08-14 2017-01-12 バーグ エルエルシー 脱毛症を治療するためのビタミンｄ３およびその類似体
JP2013501790A (ja) * 2009-08-14 2013-01-17 バーグ バイオシステムズ，エルエルシー 脱毛症を治療するためのビタミンｄ３およびその類似体
AU2015238850B2 (en) * 2009-08-14 2017-08-24 Berg Llc Vitamin D3 and analogs thereof for treating alopecia
KR101791828B1 (ko) * 2009-08-14 2017-10-31 베르그 엘엘씨 탈모증 치료용 비타민 ｄ3 및 이의 유사체들
KR20170121323A (ko) * 2009-08-14 2017-11-01 베르그 엘엘씨 탈모증 치료용 비타민 ｄ3 및 이의 유사체들
US9901637B2 (en) 2009-08-14 2018-02-27 Berg Llc Vitamin D3 and analogs thereof for treating alopecia
KR101880032B1 (ko) * 2009-08-14 2018-07-20 베르그 엘엘씨 탈모증 치료용 비타민 ｄ3 및 이의 유사체들
US11305016B2 (en) 2009-08-14 2022-04-19 Berg Llc Vitamin D3 and analogs thereof for treating alopecia
WO2017220998A1 (fr) * 2016-06-22 2017-12-28 Paxman Coolers Ltd Traitement de l'alopécie secondaire à la chimiothérapie.

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