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WO1997011702A1 - Methode de prevention de l'alopecie androgenetique par des inhibiteurs de la 5-alpha reductase - Google Patents

Methode de prevention de l'alopecie androgenetique par des inhibiteurs de la 5-alpha reductase Download PDF

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Publication number
WO1997011702A1
WO1997011702A1 PCT/US1996/015164 US9615164W WO9711702A1 WO 1997011702 A1 WO1997011702 A1 WO 1997011702A1 US 9615164 W US9615164 W US 9615164W WO 9711702 A1 WO9711702 A1 WO 9711702A1
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Prior art keywords
day
androst
aza
dosage amount
reductase
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PCT/US1996/015164
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English (en)
Inventor
Glenn J. Gormley
Keith D. Kaufman
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Merck and Co Inc
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Merck and Co Inc
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Priority claimed from GBGB9602834.5A external-priority patent/GB9602834D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Priority to JP9513521A priority Critical patent/JPH11513380A/ja
Priority to EP96931671A priority patent/EP0859617A1/fr
Priority to AU70782/96A priority patent/AU7078296A/en
Publication of WO1997011702A1 publication Critical patent/WO1997011702A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens

Definitions

  • the present invention is concerned with the prevention of androgenetic alopecia, including male pattem baldness, with compounds that are 5-alpha reductase isozyme 2 inhibitors.
  • Certain undesirable physiological manifestations such as acne vulgaris, seborrhea, female hirsutism, androgenetic alopecia (also called androgenic alopecia) which includes female and male pattem baldness, and benign prostatic hyperplasia, are the result of hyperandrogenic stimulation caused by an excessive accumulation of testosterone ("T") or similar androgenic hormones in the metabolic system.
  • T testosterone
  • chemotherapeutic agent to counter the undesirable results of hyperandrogenicity resulted in the discovery of several steroidal antiandrogens having undesirable hormonal activities of their own.
  • the estrogens for example, not only counteract the effect of the androgens but have a feminizing effect as well.
  • Non ⁇ steroidal antiandrogens have also been developed, for example, 4'-nitro- 3'-trifluoromethyl-isobutyranilide. See Neri, et al., Endocrinol. 1972, 91 (2). However, these products, though devoid of hormonal effects, compete with all natural androgens for receptor sites, and hence have a tendency to feminize a male host or the male fetus of a female host and/or initiate feed-back effects which would cause hyperstimulation of the testes.
  • the principal mediator of androgenic activity in some target organs is 5 ⁇ -dihydrotestosterone ("DHT"), formed locally in the target organ by the action of testosterone-5 ⁇ - reductase.
  • DHT 5 ⁇ -dihydrotestosterone
  • Inhibitors of testosterone-5 ⁇ -reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation in these organs. See especially United States Patent No. 4,377,584 assigned to Merck & Co., Inc., issued March 22, 1983.
  • a second 5 - reductase isozyme exists, which interacts with skin tissues, especially in - 2 - scalp tissues. See, e.g., G. Harris, et al., Proc. Natl. Acad. Sci. USA.
  • the isozyme that principally interacts in skin tissues is conventionally designated as 5 -reductase 1 (or 5 ⁇ -reductase type 1 ), while the isozyme that principally interacts within the prostatic tissues is designated as 5cc-reductase 2 (or 5 ⁇ - reductase type 2).
  • Finasteride 17 ⁇ -(N-tert-buty lcarbamoy l)-4-aza-5oc- androst-l -ene-3-one
  • PROSCAR® is an inhibitor of 5 ⁇ -reductase 2 and is known to be useful for the treatment of hyperandrogenic conditions. See e.g., U.S. Patent No. 4,760,071. Finasteride is currently marketed in the United States and worldwide for the treatment of benign prostatic hyperplasia.
  • Finasteride's utility in the treatment of androgenetic alopecia and prostatic carcinoma is also disclosed in the following documents: EP 0 285,382, published 5 October 1988; EP 0 285 383, published 5 October 1988; Canadian Patent no. 1 ,302,277; and Canadian Patent no. 1 ,302,276.
  • the specific dosages exemplified in the above- noted disclosures varied from 5 to 2000 mg per patient per day.
  • a 5 ⁇ -reductase 2 inhibitor is particularly useful in the prevention of androgenetic alopecia in individuals predisposed to androgenetic alopecia. These individuals include men with normal androgen levels who have a genetic predisposition to develop androgenetic alopecia. These men may be identified as those with a family history of early and aggressive onset of baldness in a sibling, parent or grandparent.
  • the instant invention involves a method of preventing androgenetic alopecia and promoting hair growth, which comprises administering to a patient in need of such treatment a 5 ⁇ -reductase 2 inhibitor.
  • prevention includes reducing the risk of developing androgenetic alopecia, particularly in individuals predisposed to androgenetic alopecia. These individuals include men with normal androgen levels who have a genetic predisposition to develop androgenetic alopecia. These men may be identified as those with a family history of early and aggressive onset of baldness in a sibling, parent or grandparent.
  • the "prevention" of androgenetic alopecia is further defined in a patient in a clinical setting when a patient does not lose hair below the baseline amount of hair the patient had when the 5 ⁇ -reductase 2 inhibitor is first administered, as determined by any of the following techniques: hair count, investigator assessment, or global photography, or a combination of these techniques.
  • the method of the present invention may also be employed to prevent further hair loss.
  • androgenetic alopecia includes both male pattem baldness, and female pattem baldness, the latter of which is characterized by a more diffuse balding pattem.
  • the 5 ⁇ - reductase 2 inhibitor is administered in a dosage amount of from 0.01 to 100 mg/day. In one class of this embodiment, the 5 ⁇ -reductase 2 inhibitor is administered in a dosage amount of from 0.05 to 10 mg/day, and in a sub-class of this embodiment, the 5 ⁇ -reductase 2 inhibitor is administered in dosage amounts of about 0.2 to 5 mg/day. Illustrating this subclass are dosage amounts of about 0.2, 1.0, and 5.0 mg/day.
  • Compounds which are inhibitors of 5 ⁇ -reductase 2 can be determined by employing the assay described below in Example 3.
  • the method of preventing androgenetic alopecia comprises administration of 5 ⁇ - reductase 2 inhibitor compounds which have the structural formula I
  • Rl is selected from hydrogen, methyl and ethyl
  • R2 is a hydrocarbon radical selected from straight and branched chain alkyl of from 1-12 carbons or monocyclic aryl optionally containing one to three substituents selected from: lower alkyl of from 1-2 carbon atoms; halogen-substituted Cl -2 alkyl, and halogen;
  • R' is hydrogen or methyl
  • R" is hydrogen or ⁇ -methyl
  • R'" is hydrogen, oc-methyl or ⁇ -methyl.
  • alkyl substituent of two or fewer carbons must be straight chain, but that an alkyl substituent of three or greater carbon atoms may be either straight or branched chain.
  • Aryl is selected from phenyl, naphthyl, thiophene, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, pyrrole, benzofuran, furan, indole, purine, and the like, but is preferably monocyclic aryl, and most preferably phenyl.
  • the 5oc-reductase 2 inhibitor compounds have the structural formula II
  • R l is hydrogen, or methyl; and R3 is branched chain alkyl of from 4-8 carbons.
  • Representative compounds that may be employed in the present invention include the following: 17 ⁇ -(N-tert-butylcarbamoyl)-4-aza-5- ⁇ -androst- 1 -en-3-one, 17 ⁇ -(N-isobuty lcarbamoy l)-4-aza-5- -androst- 1 -en-3-one, 17 ⁇ -(N-tert-octylcarbamoyl)-4-aza-5 ⁇ -androst-l -en-3-one, 17 ⁇ -(N-octylcarbamoyl)-4-aza-5 -androst- 1 -en-3-one, 17 ⁇ -(N- 1 , 1 -diethylbutylcarbamoy l)-4-aza-5- ⁇ -androst- 1 -en-3-one, 17 ⁇ -(N-neopentylcarbamoy])-4-aza-5 ⁇ -androst- 1 -en-3-one, 17 ⁇ -(N
  • the method of preventing androgenetic alopecia comprises administration of 5 ⁇ - reductase 2 inhibitor compounds which have the structural formula III: ⁇ 13
  • the A ring has up to 2 double bonds
  • the B, C, and D rings have optional double bonds where indicated by the broken lines, provided that the A-B rings and B-C rings do not have adjacent double bonds and the D ring does not have a Ci6- C 17 double bond when R 13 represents two substituents or a divalent substituent; M is O or S; Z is CH2 or, when part of a double bond, CH; X is H, Cl, F, Br, I, CF3, or Ci-6 alkyl; Y is H, CF3, F, or Cl, CH3 provided that Y is H when there is no C5-C6 double bond; Rl l is H or Cl-8alkyl; Rl2 i s absent or present as H or CH3 provided Rl 2 is absent when the carbon to which it is attached is double bonded; R20 is absent when there is a C4-C5, C5-C6, or C5-C10, double bond, or present as an alpha hydrogen, and R l3 is: (1 ) cc-hydrogen, ⁇ -hydroxyl
  • W is a bond or Cl -I 2alkyl
  • Rl4 j s: (i) hydrogen, (ii) hydroxyl, (iii) Cl -8aikyl, (iv) hydroxy Cl -8alkyl, (v) Cl-8alkoxy,
  • Rl5 and Rl6 are each independently selected from hydrogen, Ci - 8alkyl, C3-6 cycloalkyl, phenyl; or R 5 and
  • Rl6 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen, or
  • R 1 9 is C l - 12alky 1 or ⁇ -NRl5R l6 where R l5 and R l6 have the same meaning as above,
  • the A ring has a C3-C4 double bond, the B ring has a C5-C6 double bond, Rl 1 is methyl and Rl 3 is keto;
  • the A ring has a C3-C4 double bond, the B ring has a C5-C6 double bond, Rl 1 is methyl and R 13 is COOCH3; and
  • the B ring has a C5-C6 double bond, Rl 1 is methyl and Rl3 is
  • the method of preventing androgenetic alopecia comprises administration of a 5 ⁇ - reductase 2 inhibitor compound which has the structural formula IV:
  • R21 is hydrogen, a C ⁇ _6alkyl group, a benzyl group, a p- methoxybenzyl group, or a benzoyl group;
  • Y 1 is oxygen or sulphur;
  • W 1 is a group
  • each of R22 and R 3 is independently selected from the group consisting of hydrogen, Cl _6alkyl,
  • C5_6cycloalkyl, C6-9cycloalkylalkyl and phenyl wherein each of the groups alkyl, cycloalkyl, cycloalkylalkyi, and phenyl may be unsubstituted or substituted with a substituent -OR24 where R24 j s hydrogen or Cl -4alkyl;
  • a l is hydrogen, Cl -6alkyl, C5-6cycloalkyl, or C6-
  • R25 and R2 i independently selected from the group consisting of hydrogen, C] . 6alkyl, C5-6cycloalkyl, and phenyl, or R 2 5 and R 2 , taken together with the nitrogen atom to which they are linked, are
  • the compounds of formula I and II described above can be synthesized according to procedures well known in the art, and which are described, for example, in U.S. Patent No. 4,760,071 , EP 0 285,382 and EP 0 285 383.
  • the compound finasteride is currently available as a prescription pharmaceutical from Merck & Co. Inc.
  • the synthesis of finasteride is described in US Patent 4,760,071.
  • a further synthesis of finasteride is described in Synthetic Communications. 30 (17), p. 2683- 2690 ( 1990).
  • the compounds of formula III described above can be synthesized according to procedures well known in the art, and which are described, for example, in U.S. Patent 5,017,568.
  • the compound of formula IV described above can be synthesized according to procedures well known in the art, and which are described, for example, in U.S. Patents 5, 155,107 and 5,342,948.
  • the present invention has the objective of providing methods of preventing the hyperandrogenic conditions of androgenetic alopecia, including male pattem baldness and female pattem baldness, by systemic, including oral, parenteral and topical administration of a 5 ⁇ -reductase 2 inhibitor in a dosage amount 0.01 to 100 mg/day, and particularly, from about 0.05 to 10 mg/day, and more particularly 0.2 to 5 mg/day.
  • a 5 ⁇ -reductase 2 inhibitor e.g.
  • finasteride can be used in combination with a potassium channel opener, such as minoxidil or a pharmaceutically acceptable salt thereof, for the treatment of androgenetic alopecia, including male pattem baldness
  • a potassium channel opener such as minoxidil or a pharmaceutically acceptable salt thereof
  • the 5 ⁇ -reductase 2 inhibitor and the potassium channel opener may both be applied topically, or each agent can be given via different administration routes; for example, the 5 ⁇ -reductase 2 inhibitor may be administered orally while the potassium channel opener may be administered topically.
  • the present invention also has the objective of providing suitable systemic, including oral, parenteral and topical pharmaceutical formulations for use in the novel methods of treatment of the present invention.
  • suitable systemic, including oral, parenteral and topical pharmaceutical formulations for use in the novel methods of treatment of the present invention.
  • the compositions containing 5 ⁇ -reductase 2 inhibitor compounds as the active ingredient for use in the treatment of the above-noted hyperandrogenic conditions can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration.
  • the compounds can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, symps and emulsions.
  • they may also be administered in intravenous
  • compositions can be provided in the form of scored or unscored tablets containing 0.01 , 0.05, 0.1 , 0.2, 1.0. and 5.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the 5 ⁇ -reductase 2 inhibitor compounds may be administered in a pharmaceutical composition comprising the active compound in combination with a pharmaceutically acceptable carrier adapted for topical administration.
  • Topical pharmaceutical compositions may be, e.g., in the form of a solution, cream, ointment, gel, lotion, shampoo or aerosol formulation adapted for application to the skin.
  • Topical pharmaceutical compositions useful in the method of treatment of the present invention may include about 0.001 % to 0.1 % of the active compound in admixture with a pharmaceutically acceptable carrier.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed.
  • a physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the dmg required to prevent, counter, arrest or reverse the progress of the condition.
  • Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
  • the 5 ⁇ -reductase 2 inhibitor compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, symps and the like, and consistent with conventional pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • the active dmg component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Capsules containing the product of this invention can be prepared by mixing an active compound of the present invention with lactose and magnesium stearate, calcium stearate, starch, talc, or other carriers, and placing the mixture in gelatin capsule. Tablets may be prepared by mixing the active ingredient with conventional tableting ingredients such as calcium phosphate, lactose, com starch or magnesium stearate.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be inco ⁇ orated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta- lactose, co sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • Other dispersing agents which may be employed include glycerin and the like.
  • glycerin for parenteral administration, sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • Topical preparations containing the active dmg component can be admixed with a variety of carrier materials well known in the art, such as, e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG2 myristyl propionate, and the like, to form, e.g., alcoholic solutions, topical cleansers, cleansing creams, skin gels, skin lotions, and shampoos in cream or gel formulations. See, e.g., EP 0 285 382.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable dmg carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxy- ethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a dmg, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a class of biodegradable polymers useful in achieving controlled release of a dmg, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • Finasteride is known to occur in two distinct polymo ⁇ hic crystal forms, termed “form 1 " and “form II”.
  • Form I is the marketed form of finasteride as a 5 mg tablet (PROSCAR®).
  • Finasteride Form I can be prepared by dissolving finasteride in glacial acetic acid (ca. 100 mg/mL) and adding water with stirring until the weight % of water equals or exceeds 84%. The resulting solid phase is collected by filtration and dried under vacuum and at about 50°C.
  • the resulting Form I is characterized by a differential scanning calorimetry (DSC) curve, at heating rate of 20°C/min and in a closed cup, exhibiting a minor endotherm with a peak temperature of about 232°C, an extrapolated onset temperature of about 223°C with an associated heat of about 1 1 joules/gm and by a major melting endotherm with a peak temperature of about of 261 °C, an extrapolated onset temperature of about 258°C with an associated heat of about 89 J/gm.
  • the x- ray powder diffraction pattem is characterized by d-spacings of 6.44, 5.69, 5.36, 4.89, 4.55, 4.31 , 3.85, 3.59 and 3.14 .
  • Form I of finasteride can be prepared by recrystallization from dry (H2 ⁇
  • Form II of finasteride can be prepared by dissolving finasteride in glacial acetic acid (ca. 100 mg/mL) and adding water with stirring until the weight % of water equals about 75% but not in excess of 80%.
  • the resulting solid phase is collected by filtration and dried under vacuum and at about 100°C.
  • the resulting Form II is characterized by a DSC curve, at heating rate of 20°C/min and in a closed cup, exhibiting a single melting endotherm with a peak temperature of about of 261 °C, an extrapolated onset temperature of about 258°C with an associated heat of about 89 J/gm.
  • the x- ray powder diffraction pattem is characterized by d-spacings of 14.09, 10.36, 7.92, 7.18, 6.40, 5.93, 5.66, 5.31 , 4.68, 3.90, 3.60 and 3.25.
  • the FT-IR spectrum shows bands at 3441 , 3215, 1678, 1654, 1597, 1476 and 752 cm-1.
  • the solubilities in water and cyclohexane at 25°C are 0.16+0.02 and 0.42+0.05 mg/gm respectively.
  • Form II of finasteride can be prepared by recrystallization from ethyl acetate containing between 2 to 30 mg/mL of water and isopropyl acetate containing between 2 to 15 mg/mL of water.
  • Form II can also be prepared by heating Form I up to about 150°C, holding for about one hour and cooling back to room temperature.
  • the Form II prepared in this manner has the same physical characterization data as given above.
  • Samples of human tissue were pulverized using a freezer mill and homogenized in 40 mM potassium phosphate, pH 6.5, 5 mM magnesium sulfate, 25 mM potassium chloride, 1 mM phenylmethyl ⁇ sulfonyl fluoride, 1 mM dithiothreitol (DTT) containing 0.25 M sucrose using a Potter-Elvehjem homogenizer.
  • a cmde nuclear pellet was prepared by centrifugation of the homogenate at l ,500xg for 15 min. The cmde nuclear pellet was washed two times and resuspended in two volumes of buffer. Glycerol was added to the resuspended pellet to a final concentration of 20%.
  • the enzyme suspension was frozen in aliquots at -80°C.
  • the prostatic reductases were stable for at least 4 months when stored under these conditions.
  • the reaction mixture for the type 2 5 ⁇ -reductase contained 40 mM sodium citrate, pH 5.5, 0.3 ⁇ M [7- 3 H]-testosterone, 1 mM dithiothreitol and 500 ⁇ M NADPH in a final volume of 100 ⁇ l.
  • the assay was initiated by the addition of 50-100 ⁇ g prostatic homogenate and incubated at 37°C. After 10-50 min the reaction was quenched by extraction with 250 ⁇ l of a mixture of 70% cyclohexane: 30% ethyl acetate containing 10 ⁇ g each DHT and T. The aqueous and organic layers were separated by centrifugation at 14,000 ⁇ m in an Eppendorf microfuge.
  • the organic layer was subjected to normal phase HPLC ( 10 cm Whatman partisil 5 silica column equilibrated in 1 mL/min 70% cyclohexane: 30% ethyl acetate; retention times: DHT, 6.8-7.2 min; androstanediol, 7.6-8.0 min; T, 9.1 -9.7 min).
  • HPLC system consisted of a Waters Model 680 Gradient System equipped with a Hitachi Model 655A autosampler, Applied Biosystems Model 757 variable UV detector, and a Radiomatic Model A 120 radioactivity analyzer.
  • the conversion of T to DHT was monitored using the radioactivity flow detector by mixing the HPLC effluent with one volume of Flo Scint 1 (Radiomatic). Under the conditions described, the production of DHT was linear for at least 25 min.
  • the only steroids observed with the human prostate preparation were T, DHT and androstanediol.
  • IC50 values represent the concentration of inhibitor required to decrease enzyme activity to 50% of the control. IC50 values were determined using a 6 point titration where the concentration of the inhibitor was varied from 0.1 to 1000 nM.
  • the haircount area on the patient is prepared as follows: A small ( ⁇ lmm) dot tattoo is placed at the beginning of the study at the leading edge of the bald area directly anterior to the center of the vertex bald spot, using a commercial tattooing machine or manually (needle and ink). An area approximately one square inch in size, centered at the tattoo at the leading edge of the balding area, is clipped short ( ⁇ 2mm). Cut hairs are removed from the area to be photographed, using tape. Compressed air and/or ethanol wipes may also be used to facilitate removal of cut hairs.
  • Each lens supplied has a fixed reproduction ratio of 1 : 1.2.
  • a trained technician places a transparency over the photographic print and, using a felt tip pen, places a black dot over each visible hair.
  • the dot map transparency is then counted using image analysis with computer assistance.
  • Photographs are coded with a random number corresponding to study site, visit number and patient allocation number to insure blinding to time.
  • baseline and Month 6 photographs are counted and data analyzed for interim analysis.
  • Month 12, baseline, Month 6 and Month 12 photographs are counted and data analyzed for the primary endpoint.

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Abstract

La présente invention couvre un procédé destiné à prévenir l'alopécie androgénétique, à encourager la pousse des cheveux et consistant à administrer aux patients, notamment aux individus prédisposés à l'alopécie androgénétique, y compris aux hommes présentant des niveaux d'androgènes normaux mais qui ont une prédisposition génétique à développer une alopécie androgénétique, une dose, propre à maintenir la quantité de cheveux, d'un inhibiteur de la 5α-réductase 2, du type finastéride.
PCT/US1996/015164 1995-09-27 1996-09-23 Methode de prevention de l'alopecie androgenetique par des inhibiteurs de la 5-alpha reductase Ceased WO1997011702A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP9513521A JPH11513380A (ja) 1995-09-27 1996-09-23 ５−αレダクターゼ阻害剤によるアンドロゲン性脱毛症の予防方法
EP96931671A EP0859617A1 (fr) 1995-09-27 1996-09-23 Methode de prevention de l'alopecie androgenetique par des inhibiteurs de la 5-alpha reductase
AU70782/96A AU7078296A (en) 1995-09-27 1996-09-23 Method of preventing androgenetic alopecia with 5-alpha reductase inhibitors

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US442195P 1995-09-27 1995-09-27
US60/004,421 1995-09-27
GBGB9602834.5A GB9602834D0 (en) 1996-02-13 1996-02-13 Method of preventing androgenetic alopecia with 5-alpha reductase inhibitors
GB9602834.5 1996-02-13

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WO1999008684A3 (fr) * 1997-08-19 1999-06-10 Glaxo Group Ltd Solutions contenant des azasteroïdes
WO1999062464A1 (fr) * 1998-06-04 1999-12-09 Ben Gurion University Of The Negev Research And Development Authority Composition topique destinee au traitement de la calvitie
US6380179B1 (en) 1997-07-29 2002-04-30 Sankyo Company, Limited Method for treatment of alopecia
US6645974B2 (en) 2001-07-31 2003-11-11 Merck & Co., Inc. Androgen receptor modulators and methods for use thereof
EP1154783A4 (fr) * 1999-07-06 2005-01-19 Raziel Lurie Medicaments comprenant de la relaxine et leur utilisation
USRE39056E1 (en) 1995-09-15 2006-04-04 Merck & Co, Inc. 4-Azasteroids for treatment of hyperandrogenic conditions
WO2012110768A1 (fr) 2011-02-18 2012-08-23 The University Of Birmingham Utilisations thérapeutiques des diarylalcanes tels que le mitotane

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE39056E1 (en) 1995-09-15 2006-04-04 Merck & Co, Inc. 4-Azasteroids for treatment of hyperandrogenic conditions
US6380179B1 (en) 1997-07-29 2002-04-30 Sankyo Company, Limited Method for treatment of alopecia
WO1999008684A3 (fr) * 1997-08-19 1999-06-10 Glaxo Group Ltd Solutions contenant des azasteroïdes
WO1999062464A1 (fr) * 1998-06-04 1999-12-09 Ben Gurion University Of The Negev Research And Development Authority Composition topique destinee au traitement de la calvitie
EP1154783A4 (fr) * 1999-07-06 2005-01-19 Raziel Lurie Medicaments comprenant de la relaxine et leur utilisation
US6645974B2 (en) 2001-07-31 2003-11-11 Merck & Co., Inc. Androgen receptor modulators and methods for use thereof
WO2012110768A1 (fr) 2011-02-18 2012-08-23 The University Of Birmingham Utilisations thérapeutiques des diarylalcanes tels que le mitotane

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EP0859617A1 (fr) 1998-08-26
AU7078296A (en) 1997-04-17
JPH11513380A (ja) 1999-11-16
CA2231434A1 (fr) 1997-04-03

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