EP1292610A1 - Procedes de traitement et de prevention de l'alopecie - Google Patents

Procedes de traitement et de prevention de l'alopecie

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Publication number
EP1292610A1
EP1292610A1 EP00980808A EP00980808A EP1292610A1 EP 1292610 A1 EP1292610 A1 EP 1292610A1 EP 00980808 A EP00980808 A EP 00980808A EP 00980808 A EP00980808 A EP 00980808A EP 1292610 A1 EP1292610 A1 EP 1292610A1
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EP
European Patent Office
Prior art keywords
seq
sequence
alopecia
group
active agent
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EP00980808A
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German (de)
English (en)
Inventor
Kathleen E. Roders
Gere S. Dizerega
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University of Southern California USC
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University of Southern California USC
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Publication of EP1292610A1 publication Critical patent/EP1292610A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/14—Angiotensins: Related peptides
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1808—Epidermal growth factor [EGF] urogastrone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1825—Fibroblast growth factor [FGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2006—IL-1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 present invention relates to methods and pharmaceutical compositions for treating and preventing alopecia in a a patient in need thereof.
  • Hair growth is not continuous, but comprises alternating periods of growth (“anagen”), regression (“categen”) and rest (“telogen”).
  • anagen periods of growth
  • categen categories
  • telogen rest
  • the growth of scalp hair is not synchronous, and the rate of growth is about 0.4 mm per day.
  • About 90 percent of the more than 100,000 scalp hairs are growing (anagen), so that 50 to 100 hairs are shed daily as they are pushed out at the onset of a new hair cycle.
  • the hair follicle is an epidermal appendage, the lower part of which undergoes cycles of growth and degeneration.
  • U.S. Patent No. 5,556,783, incorporated by reference herein in its entirety matrix keratinocytes located in the bulb region grow vigorously, generating cells that differentiate into several distinct hair components including the medulla, cortex and inner root sheath.
  • keratinocytes of the lower follicle below the bulge region degenerate and the dermal papilla cells (DP; a group of specialized mesenchymal cells) aggregate and become encapsulated by a connective tissue sheath.
  • DP dermal papilla cells
  • the DP aggregate ascends and becomes attached to the bottom of the upper (permanent) portion of the follicle (telogen or the resting phase).
  • a new epithelial growth originates from the bottom of the bulge area; this downgrowth pushes the DP away and reforms a growing bulb.
  • Alopecia hair loss
  • adrenergic alopecia common baldness
  • alopecia common baldness
  • Telogen effluvium is a transient, reversible, diffuse shedding of hair in which a high percentage of hair follicles enter the telogen phase prematurely as a result of physical or mental illness.
  • a high percentage of hair follicles enter the telogen phase prematurely as a result of physical or mental illness.
  • Among the most important factors incriminated are childbirth, high fever, hemorrhage, sudden starvation, accidental or surgical trauma, severe emotional stress, and certain drugs.
  • Alopecia areata is an immunologic alopecia characterized by the abrupt onset of sharply defined areas of hair loss. In the most severe cases, the scalp will develop total hair loss (alopecia totalis) or the hair loss will involve the whole body surface (alopecia universalis). Most of the patients will run an unpredictable and relapsing course with multiple episodes of hair loss and regrowth. Only about 20 to 30 percent will have a single reversible episode. Regrowth of hair is common within several months, but in many instances is not complete, and relapses are common. Alopecia areata may be associated with autoimmune diseases such as vitiligo, pernicious anemia, collagen disease, and endocrinopathies.
  • Traumatic alopecia is induced by physical trauma, of which the two most important groups, from the therapeutic standpoint are trichotillomania and alopecia resulting from cosmetic procedures or improper hair care.
  • Trichotillomania is a compulsive habit in which the individual repeatedly pulls or breaks off his or her own hair in a partially conscious state similar to thumb sucking or nail biting. Traumatic alopecia from cosmetic procedures is done consciously in ill- advised individuals and is almost exclusively seen among females. Sometimes this type of alopecia is associated with folliculitis induced by the occlusive effect of the oily cosmetics used in the procedure.
  • Anagen effluvium is a temporary alopecia caused by the inhibition of mitosis in the hair papilla by certain cytotoxic drugs, leading to constriction of the hair shaft or to complete failure of hair formation.
  • alopecia frequently occurs in cancer patients who are treated with chemotherapeutic drugs such as cyclophospharnide (CY) and/or irradiation.
  • chemotherapeutic drugs such as cyclophospharnide (CY) and/or irradiation.
  • CY cyclophospharnide
  • US 5,962,523 Such agents damage hair follicles which contain mitotically active hair-producing cells. Such damage may cause abnormally slow growth of the hair or may lead to frank loss.
  • Alopecia may also result from nutritional deficiencies and metabolic defects. Caloric deprivation must be very severe to produce hair loss. Increased shedding sometimes occurs after marked weight loss for obesity. Anemia, diabetes, hyper- and hypovitaminosis, and zinc deficiency may also lead to alopecia.
  • Treatments for androgenetic alopecia have been ineffective in inducing regrowth.
  • the use of cyclic estrogen therapy in females with an estrogen-dominant contraceptive or topical estrogen has been advocated to reduce the rate of hair loss, but results are not impressive.
  • the claim that topical testosterone induces the growth of terminal hairs in bald scalp of males has not been confirmed.
  • minoxidil ROGAINE®., Upjohn
  • a potent vasodilator has been effective in causing scalp hair regrowth in patients with androgenetic alopecia, but the results have been mixed.
  • U.S. Patent 5,962,523 discloses the use of butyric acid or butyric acid derivatives to protect against hair damage or loss in a mammal as described herein.
  • the present invention provides methods and kits for treating or preventing alopecia by contacting the cells with angiotensinogen, angiotensin I (Al), Al analogues, Al fragments and analogues thereof, angiotensin II (All), All analogues, AU fragments or analogues thereof, ACE inhibitors, or All AT 2 type 2 receptor agonists, either alone or in combination with other alopecia-inhibiting compounds.
  • Figure 1 Effect of angiotensin peptides AII(l-7) and 9GD on hair regrowth after cyclophospharnide treatment.
  • angiotensin converting enzyme inhibitors or "ACE inhibitors” includes any compound that inhibits the conversion of the decapeptide angiotensin I to angiotensin II, and include but are not limited to alacepril, alatriopril, altiopril calcium, ancovenin, benazepril, benazepril hydrochloride, benazeprilat, benzazepril, benzoylcaptopril, captopril, captopril-cysteine, captopril-glutathione, ceranapril, ceranopril, ceronapril, cilazapril, cilazaprilat, converstatin, delapril, delapril-diacid, enalapril, enalaprilat, enalkiren, enapril, epicaptopril, foroxymithine, fosfenopril, fosen
  • active agents refers to the group of compounds comprising angiotensinogen, angiotensin I (Al), Al analogues, Al fragments and analogues thereof, ATI, angiotensin II (AH) analogues, AH fragments or analogues thereof, ACE inhibitors, or All AT type 2 receptor agonists, either alone, combined, or in further combination with other compounds, for treating or preventing alopecia, such as minoxidol, keratinocyte growth factor (KGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), butyric acid and its derivatives, ammonium trichloro(dioxy ethylene-0,0') tellurate (AS101), interleukin 1, prostaglandin E2, cyclosporine A, corticosteroids such as dexamethasone, ImuvertTM (immunomodulatory preparation of membrane and ribosomes from Serratia marcescens
  • alopecia refers to hair loss associated with conditions including, but not limited to, adrenergic alopecia, telogen effluvium, alopecia areata, traumatic alopecia, anagen effluvium, and hair loss associated with nutritional deficiencies, metabolic defects, marked weight loss, diabetes, hyper- and hypovitaminosis, and zinc deficiency, alopecia vulgaris, alopecia pustulosa, alopecia erythrodermica, alopecia arthropathica, paraalopecia, pahnoplantar pustulosis, all forms of ichthyoses, e.g.
  • ichthyosis vulgaris and congenital ichthyoses keratodermias of all types, e.g., palmoplantar keratodermia, other genodermatoses with pathological cornification disorders, e.g. Darier's disease, further lichen ruber planus and pityriasis rubra pilaris.
  • treating or preventing alopecia is meant the ability to cure, reduce or prevent one or more clinical symptoms of alopecia, including, but not limited to, hair loss, cornification, scaling, uneven thickness, persistent itch, inflammation, and rapid epithelial cell turnover in the skin.
  • U.S. Patent No. 5,015,629 to DiZerega describes a method for increasing the rate of healing of wound tissue, comprising the application to such tissue of angiotensin H (AH) in an amount which is sufficient for said increase.
  • AH angiotensin H
  • the application of All to wound tissue significantly increases the rate of wound healing, leading to a more rapid re-epithelialization and tissue repair.
  • AH refers to an octapeptide present in humans and other species having the sequence Asp-Arg-Nal-Tyr-Ile- His-Pro-Phe [SEQ ID ⁇ O:l].
  • angiotensin The biological formation of angiotensin is initiated by the action of renin on the plasma substrate angiotensinogen (Circulation Research 60:786-790 (1987); Clouston et al., Genomics 2:240-248 (1988); Kageyama et al., Biochemistry 23:3603-3609; Ohkubo et al., Proc. Natl. Acad. Sci. 80:2196-2200 (1983)); all references hereby incorporated in their entirety).
  • angiotensin I (Al) which is converted to AH by the converting enzyme angiotensinase which removes the C-terminal His- Leu residues from Al, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu [SEQ ID NO:37].
  • An is a known pressor agent and is commercially available. Studies have shown that AH increases mitogenesis and chemotaxis in cultured cells that are involved in wound repair, and also increases their release of growth factors and extracellular matrices (diZerega, U.S. Patent No. 5,015,629; Dzau et. al., J. Mol. Cell. Cardiol.
  • AH was shown to be angiogenic in rabbit corneal eye and chick chorioallantoic membrane models (Fernandez, et al., J Lab. Clin. Med. 105:141 (1985); LeNoble, et al, Eur. J. Pharmacol. 195:305-6 (1991)).
  • angiotensinogen angiotensin I (Al), Al analogues, Al fragments and analogues thereof, AH, AH analogues, AH fragments or analogues thereof; AH AT type 2 receptor agonists are effective in accelerating wound healing and the proliferation of certain cell types, including keratinocytes. See, for example, co-pending U.S. Patent Application Serial Nos.
  • AH receptor subtype expression is a dynamic process that changes during development, at least in some cell types.
  • AH activity is typically modulated by either or both the ATI and AT2 AH receptors.
  • angiotensinogen angiotensin I (Al)
  • Al Al analogues
  • Al fragments and analogues thereof AH
  • AH analogues AH fragments or analogues thereof
  • ACE inhibitors or AH AT 2 type 2 receptor agonists
  • a peptide agonist selective for the AT2 receptor has 100 times higher affinity for
  • AT2 than ATI is p-aminophenylalanine6-AII ["(p-NH 2 -Phe)6-AH)"], Asp-Arg-Val-Tyr-Ile- Xaa-Pro-Phe [SEQ ID NO.36] wherein Xaa is p-NH 2 -Phe (Speth and Kim, BBRC 169:997-1006 (1990).
  • This peptide gave binding characteristics comparable to AT2 antagonists in the experimental models tested (Catalioto, et al., Eur. J. Pharmacol. 256:93-97 (1994); Bryson, et al., Eur. J. Pharmacol. 225:119-127 (1992).
  • AH and All receptor antagonists have been examined in two experimental models of vascular injury and repair which suggest that both AH receptor subtypes (ATI and AT2) play a role in wound healing (Janiak et al., Hypertension 20:737-45 (1992); Prescott, et al., Am. J. Pathol. 139:1291-1296 (1991); Kauffman, et al., Life Sci. 49:223-228 (1991); Niswanathan, et al., Peptides 13:783-786 (1992); Kimura, et al., BBRC 187:1083-1090 (1992)).
  • a preferred class of AT2 agonists for use in accordance with the present invention comprises AH analogues or active fragments thereof having p- ⁇ H-Phe in a position corresponding to a position 6 of AIL
  • various nonpeptidic agents e.g., peptidomimetics
  • having the requisite AT2 agonist activity are further contemplated for use in accordance with the present invention.
  • the active agents of particular interest in accordance with the present invention comprise a sequence of at least three contiguous arnino acids of groups R ⁇ R 8 in the sequence of general formula I R 1 -R 2 -R 3 -R -R 5 -R 6 -R 7 ⁇ . 8
  • R 1 is selected from H, Asp, Glu, Asn, Acpc (1-aminocyclopentane carboxylic acid), Ala, Me 2 Gly, Pro, Bet, Glu(NH 2 ), Gly, Asp(NH 2 ) and Sue,
  • R 2 is selected from Arg, Lys, Ala, Citron, Orn, Ser(Ac), Sar, D-Arg and D-Lys
  • R 3 is selected from the group consisting of Nal, Ala, Leu, norLeu, He, Gly, Lys,
  • R 4 is selected from the group consisting of Tyr, Tyr(PO 3 ) , Thr, Ser, homoSer, azaTyr, and Ala;
  • R 5 is selected from the group consisting of He, Ala, Leu, norLeu, Val and Gly;
  • R 6 is selected from the group consisting of His, Arg or 6- ⁇ H 2 -Phe;
  • R 7 is selected from the group consisting of Pro or Ala; and R 8 is selected from the group consisting of Phe, Phe(Br), He and Tyr, excluding sequences including R 4 as a terminal Tyr group.
  • the active agents comprise a sequence of at least four, five, six, or seven contiguous amino acids of groups R ! -R 8 in the sequence of general formula I.
  • the active agents consist essentially of a sequence of at least four, five, six, or seven contiguous amino acids of groups R ⁇ R 8 in the sequence of general formula I.
  • AT2 agonists useful in the practice of the invention include the AH analogues set forth above subject to the restriction that R is p ⁇ NH 2 - Phe.
  • R 1 and R 2 are Asp-Arg, Asp-Lys, Glu-Arg and Glu-Lys.
  • Particularly preferred embodiments of this class comprise the following sequences: All [SEQ ID NO:l], AIII or AII(2-8), Arg-Val-Tyr-Ile-His-Pro-Phe [SEQ ID NO:2]; AH(3-8), also known as desl-AHI or AIV, Val-Tyr-Ile-His-Pro-Phe [SEQ ID NO:3]; AII(l-7), Asp-Arg- Nal-Tyr-Ile-His-Pro [SEQ ID NO:4]; AII(2-7).
  • Arg-norLeu-Tyr-Ile-His-Pro-Phe [SEQ ID NO: 12] and Arg-Val-Tyr-norLeu-His-Pro-Phe [SEQ ID NO:13].
  • Still another preferred embodiment encompassed within the scope of the invention is a peptide having the sequence Asp-Arg-Pro- Tyr-Ile-His-Pro-Phe [SEQ ID NO:31].
  • AII(6-8), His-Pro-Phe [SEQ ID NO:14] and AH(4-8), Tyr-Ile-His-Pro-Phe [SEQ ID NO: 15] were also tested and found not to be effective.
  • Another class of compounds of particular interest in accordance with the present invention comprise an amino acid sequence of the general formula II
  • R 2 is selected from the group consisting of H, Arg, Lys, Ala, Orn, Citron, Ser(Ac), Sar, D-Arg and D-Lys;
  • R 3 is selected from the group consisting of Nal, Ala, Leu, norLeu, He, Gly, Pro, Aib, Acpc and Tyr;
  • R 4 is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer, azaTyr, and Ala;
  • R 5 is selected from the group consisting of He, Ala, Leu, norLeu, Nal and Gly;
  • R 6 is selected from the group consisting of His, Arg or 6- ⁇ H 2 -Phe;
  • R 7 is selected from the group consisting of Pro or Ala
  • R 8 is selected from the group consisting of Phe, Phe(Br), lie and Tyr.
  • a particularly preferred subclass of the compounds of general formula II has the formula
  • R 2 , R 3 and R 5 are as previously defined.
  • Particularly preferred is angiotensin III of the fo ⁇ nula Arg-Nal-Tyr-Ile-His-Pro-Phe [SEQ ID NO:2].
  • Other preferred compounds include peptides having the structures Arg-Nal-Tyr-Gly-His-Pro-Phe [SEQ JD NO: 17] and Arg-
  • AH and its analogues adopt either a gamma or a beta turn (Regoli, et al., Pharmacological Reviews 26:69 (1974).
  • neutral side chains in position R 3 , R 5 and R 7 may be involved in maintaining the appropriate distance between active groups in positions R 4 , R 6 and R 8 primarily responsible for binding to receptors and/or intrinsic activity.
  • Hydrophobic side chains in positions R 3 , R 5 and R 8 may also play an important role in the whole conformation of the peptide and/or contribute to the formation of a hypothetical hydrophobic pocket.
  • R 2 Appropriate side chains on the amino acid in position R 2 may contribute to affinity of the compounds for target receptors and/or play an important role in the conformation of the peptide. For this reason, Arg and Lys are particularly preferred as R 2 .
  • R 2 may be H, Ala, Orn, Citron, Ser(Ac), Sar, D-Arg, or D-Lys.
  • R 3 may be involved in the formation of linear or nonlinear hydrogen bonds with R 5 (in the gamma turn model) or R 6 (in the beta turn model). R 3 would also participate in the first turn in a beta antiparallel structure (which has also been proposed as a possible structure).
  • R 3 may suitably be selected from Lys, Nal, Ala, Leu, norLeu, He, Gly, Pro, Aib, Acpc and Tyr.
  • R 4 is preferably selected from Tyr, Thr, Tyr (PO 3 ) 2 , homoSer, Ser and azaTyr.
  • Tyr is particularly preferred as it may form a hydrogen bond with the receptor site capable of accepting a hydrogen from the phenolic hydroxyl (Regoli, et al. (1974), supra). It has also been found that R 4 can be Ala.
  • R 5 an amino acid with a ⁇ aliphatic or alicyclic chain is particularly desirable.
  • Gly is suitable in position R 5 , it is preferred that the amino acid in this position be selected from He, Ala, Leu, norLeu, and Nal.
  • R 6 is His, Arg or 6- ⁇ H 2 -Phe.
  • the unique properties of the imidazole ring of histidine e.g., ionization at physiological pH, ability to act as proton donor or acceptor, aromatic character) are believed to contribute to its particular utility as R 6 .
  • conformational models suggest that His may participate in hydrogen bond formation (in the beta model) or in the second turn of the antiparallel structure by influencing the orientation of R .
  • R 7 should be Pro or Ala in order to provide the most desirable orientation of R 8 .
  • R 8 both a hydrophobic ring and an anionic carboxyl terminal appear to be particularly useful in binding of the analogues of interest to receptors; therefore, Tyr, He, Phe(Br), and especially Phe are preferred for purposes of the present invention.
  • Analogues of particular interest include the following: TABLE 2
  • polypeptides of the instant invention may be synthesized by any conventional method, including, but not limited to, those set forth in J. M. Stewart and J. D. Young, Solid Phase Peptide Synthesis, 2nd ed., Pierce Chemical Co., Rockford, 111. (1984) and J. Meienhofer, Hormonal Proteins and Peptides, Vol. 2, Academic Press, New York, (1973) for solid phase synthesis and E. Schroder and K. Lubke, Ebe Peptides, Vol. 1, Academic Press, New York, (1965) for solution synthesis.
  • the disclosures of the foregoing treatises are incorporated by reference herein.
  • these methods involve the sequential addition of protected amino acids to a growing peptide chain (U.S. Patent No. 5,693,616, herein incorporated by reference in its entirety). Normally, either the amino or carboxyl group of the first amino acid and any reactive side chain group are protected. This protected amino acid is then either attached to an inert solid support, or utilized in solution, and the next amino acid in the sequence, also suitably protected, is added under conditions amenable to formation of the amide linkage. After all the desired amino acids have been linked in the proper sequence, protecting groups and any solid support are removed to afford the crude polypeptide. The polypeptide is desalted and purified, preferably chromatographically, to yield the final product.
  • peptides are synthesized according to standard solid-phase methodologies, such as may be performed on an Applied Biosystems Model 430A peptide synthesizer (Applied Biosystems, Foster City, Calif), according to manufacturer's instructions. Other methods of synthesizing peptides or peptidomimetics, either by solid phase methodologies or in liquid phase, are well known to those skilled in the art. Alternatively, the peptides can be produced by standard molecular biological techniques.
  • a method of treating or preventing alopecia by administering to a patient in need thereof an amount effective to treat or prevent alopecia of angiotensinogen, Al, Al analogues, and/or Al fragments and analogues thereof, AH, AH analogues, AH fragments and analogues thereof, ACE inhibitors, or AH AT 2 type 2 receptor agonists, ("active agents"), is disclosed, either alone, combined, or in further combination with other compounds or treatments effective for treating or preventing alopecia, including but not limited to minoxidol, keratinocyte growth factor (KGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), butyric acid and its derivatives, ammonium trichloro(dioxy ethylene-0,0') tellurate (AS101), interleukin 1, prostaglandin E2, cyclosporine A, corticosteroids such as dexamethasone, ImuvertTM (imm
  • the active agents may be made up in a solid form (including granules, powders or suppositories) or in a liquid form (e.g., solutions, suspensions, or emulsions), and may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as stabilizers, wetting agents, emulsifiers, preservatives, cosolvents, suspending agents, viscosity enhancing agents, ionic strength and osmolality adjusters and other excipients in addition to buffering agents.
  • conventional adjuvants such as stabilizers, wetting agents, emulsifiers, preservatives, cosolvents, suspending agents, viscosity enhancing agents, ionic strength and osmolality adjusters and other excipients in addition to buffering agents.
  • Suitable water soluble preservatives which may be employed in the drug delivery vehicle include sodium bisulfite, sodium thiosulfate, ascorbate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric borate, parabens, benzyl alcohol, phenylethanol or antioxidants such as Nit-unin E and tocopherol and chelators such as EDTA and EGTA. These agents may be present, generally, in amounts of about 0.001% to about 5% by weight and, preferably, in the amount of about 0.01 to about 2% by weight.
  • the active agents are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration.
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration.
  • the compounds of tins invention may be dissolved in saline, water, polyethylene glycol, propylene glycol, carboxymethyl cellulose colloidal solutions, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.
  • the carrier or diluent may include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
  • the active agents may be administered by any suitable route, including local delivery, parentally, transdermally, or topically in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles.
  • parenteral as used herein includes, subcutaneous, intravenous, intramuscular, intrasternal, intratendinous, intraspinal, intracranial, intrathoracic, infusion techniques or intraperitoneally.
  • the active agents may be formulated as is known in the art for direct application to a target area.
  • Conventional forms for this purpose include wound dressings, coated bandages or other polymer coverings, ointments, lotions, creams, pastes, jellies, sprays, shampoos, salves, rransdermal patches, and aerosols.
  • the percent by weight of the active agent of the invention present in a topical formulation will depend on various factors, but generally will be from 0.005% to 95% of the total weight of the formulation, and typically 1-25% by weight.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emlusifying and suspending agents and sweetening, flavoring and perfuming agents.
  • the dosage and treatment regimen for treating or preventing alopecia with the active agents is based on a variety of factors, including the age, weight, sex, medical condition of the individual, the severity of the condition, the route of administration, and the particular compound employed.
  • the dosage regimen may vary widely, but can be on the order of between 0.1 ng/kg and 10 mg/kg of the active agents per body weight are useful for all methods of use disclosed herein, preferably between about 10 ng/kg and 1 mg/kg, more preferably between about 0.1 ⁇ g/kg and 200 ⁇ g/kg, and most preferably between about 1 ⁇ g/kg and 100 ⁇ g/kg.
  • treatment of alopecia using the composition may be accomplished by subcutaneous or topical application of the composition to the affected areas one or more times per day for as long as is needed.
  • kits for treating or preventing alopecia comprising an effective amount of the active agents of the invention to treat or prevent alopecia, and instructions for using the amount effective of active agent to treat or prevent alopecia
  • the kits also contain an effective amount to treat or prevent alopecia of one or more other compounds, including but not limited to minoxidol, keratinocyte growth factor (KGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), butyric acid and its derivatives, ammonium trichloro(dioxy ethylene-0,0') tellurate (AS 101), interleukin 1, prostaglandin E2, cyclosporine A, corticosteroids such as dexamethasone, ImuvertTM (immunomodulatory preparation of membrane and ribosomes from Serratia marcescens), and calcitriol (1,25 dihydroxyvitamin D).
  • KGF keratinocyte growth factor
  • FGF fibroblast growth factor
  • EGF epidermal growth factor
  • Effective dosages of the active agents of the invention to treat or prevent alopecia are between about 0.1 ng kg and 10 mg/kg, as discussed above.
  • pharmaceutical compositions are provided that comprise an amount effective to treat or prevent alopecia of one or more of the active agents of the invention in combination with an amount effective to treat or prevent alopecia of minoxidol, keratinocyte growth factor (KGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), butyric acid and its derivatives, ammonium trichloro(dioxy ethylene-0,0') tellurate (AS 101), interleulrin 1, prostaglandin E2, cyclosporine A, corticosteroids such as dexamethasone, ImuvertTM (immunomodulatory preparation of membrane and ribosomes from Serratia marcescens), and calcitriol (1,25 dihydroxyvitamin D).
  • KGF keratinocyte growth factor
  • FGF fibroblast growth factor
  • EGF epiderma
  • the Phase I/II study was a prospective, open-label, dose-escalation study comparing the effects of AH(l-7 (SEQ ID NO:4)) in patients with newly diagnosed breast cancer receiving doxorubicin 60 mg/m 2 and cyclophosphamide 600 mg/m 2 for at least 3 cycles of adjuvant chemotherapy following surgical tumor reduction.
  • a filgrastim comparator arm was used to compare safety and response variables and to assess synergy of AH(l-7) with filgrastim
  • a chemotherapy regimen containing doxorubicin 60 mg/m 2 - and cyclophosphamide 600 mg/m 2 was initiated.
  • AII(l-7) was administered for at least 10 days, or until the absolute neutrophil count (ANC) > 1500/ ⁇ L for 2 days, beginning two days after chemotherapy. Up to three chemotherapy cycles followed by AH(l-7) administration were repeated every 21 days, or as indicated by patient tolerance. Any patient that failed to achieve an
  • ANC > 1500/ ⁇ L by day 15 13 days of AII(l-7) received a filgrastim rescue of 5.0 ⁇ g/kg/day until the ANC > 1500/ ⁇ L for 2 days.
  • Group 3 25.0 ⁇ g kg/day AH(l-7) (5.0 mg/mL)
  • Group 4 50.0 ⁇ g/kg/day AH(l-7) (5.0 mg/mL)
  • AE adverse event
  • the viscous vehicle was prepared from carboxymethylcellulose (CMC sodium salt, low viscosity, Sigma, St. Louis, MO, Lot Number 34H0310) consisting of 10% low viscosity CMC in 0.05 M phosphate buffer, pH. 7.2, and sterilized by autoclaving followed by niixing with sterile peptide solutions. For subcutaneous administration, the peptides were dissolved in Lactated Ringers' Solution.
  • a ⁇ (l-7) (SEQ ID NO:4) was prepared by Bachem under GMP conditions.
  • 9GD SEQ ID NO:41 was prepared by the Microchemical Core Laboratory at USC.
  • Surgical model During the experimental period, C57BL/Ksj-db/db diabetic mice (Jackson Laboratories, Cold Spring Harbor, ME) or Sprague Dawley rats were housed one per cage and maintained in a central animal care facility with a 12-hour light/dark cycle. Water and standard rodent laboratory chow were supplied ad libitum. All animals used for this study received humane care as defined by the National Research Council's criteria for humane care. The study protocols were approved by the University of Southern California's Institutional Animal Care and Use Committee before initiation of the studies.
  • mice On day 0, C57BL/Ksj-db/db diabetic mice were anesthetized with intramuscular ketamine/xylazine and backs were swabbed with 70% isopropyl alcohol followed by betadine. Afterwards, a 1.3 cm diameter full thickness skin area was excised on the back of each mouse. Wound margins were treated with Benzoin Tincture (Western Medical Supply, Arcadia, CA).
  • Rat Model Female Sprague-Dawley rats, 175 to 200 grams, were anesthetized with intramuscular ketamine/rompun. The backs of the rats were shaved with animal clippers, scrubbed with betadine, and washed with 70% alcohol before surgery. Two 2.25 cm 2 excisions, approximately 1 to 2 cm apart, extending to the panniculus carnosus were made mid-dorsally. After treatment, the wounds were covered with a semipermeable polyurethane dressing and the covering was sealed with benzoin solution. Rats were lightly anesthetized with intramuscular ketamine/rompun on day 2 and 4. After anesthesia, the bandages were removed and the area was cleaned before further administration of peptide in 10% carboxymethyl cellulose or by subcutaneous injection.
  • Example 3 Hair cycle synchronized animal model Adolescent, 6- to 8-week-old. female, C57BL/6 mice (Simonson, Gilroy, CA) with normal, black fur were purchased and housed in community cages with 12-hour light cycles with mouse chow and water ad libitum. In contrast to the mosaic cycling of human hair follicles, these mice display a unique hair cycle synchronization, which makes them a most productive model for hair research. Only mice in the resting stage of the hair cycle (telogen) are used for these studies. In the truncal skin of mice, all melanocytes reside in hair follicles, and pigment production (melanogenesis) occurs exclusively in anagen follicles.
  • telogen C57BL/6 mice can be recognized reliably by the homogeneously pink color of their back skin.
  • Predictable and highly synchronized anagen development can only be achieved with anagen induction by depilation, as opposed to spontaneous anagen development.
  • anagen was induced in the back skin of telogen mice by depilation so that, at the start of pharmacological manipulation, all hair follicles in the depilated back skin area of all mice are in exactly the same stage of anagen development.
  • anagen VI had been reached, all mice were injected once with a high dose of cyclophosphamide.
  • control and test mice were then compared for signs of hair loss, for skin color changes indicating the effect of test drugs on hair cycling and follicle melanogenesis, and for hair regrowth.
  • telogen mice that had gone through several postnatal hair cycles were induced to enter anagen by depilation of all telogen hair shafts. This was done by applying a melted wax/rosin mixture to the back skin and by peeling off this mixture after hardening. By this technique, all depilated telogen hair follicles immediately begin to transform into anagen follicles with their associated melanogenesis. This predictably resulted in progressive skin pigmentation and thickening within 5 to 6 days, in the development of mature anagen VI follicles and a gray to black skin color within 8 to 9 days.
  • Chemotherapy induced alopecia was manipulated pharmacologically by administration of the active agents of the present invention, topically or by subcutaneous injection once daily until necropsy. Pigmentation, hair regrowth, and follicle histology are analyzed as indicated. Particular attention is paid to any retarding or enhancing effects on the degree of alopecia, to the hair regrowth pattern, and to the pigmentation of regrowing hair shafts.
  • catagen follicles spontaneously enter catagen between days 17 and 20 p.d., mostly around day 18.
  • the development of catagen follicles was indicated macroscopically by a change in skin color from black to light gray and occurs in large waves, appearing first in the neck region, then on the flanks, until finally the tail region enters catagen.
  • the follicle enters telogen, as indicated by a skin color change from gray to pink.
  • alopecia and skin color changes are recorded separately for two distinct skin regions: region 1: lower quarter of paravertebral back skin above the insertion of the tail: region 2: upper quarter of paravertebral back skin (neck region).
  • Histological morphometry was performed to check whether the visible changes in skin pigmentation truly reflected changes in hair follicle cycling and not only isolated peptide effects on melanogenesis, and to classify and quantity the follicle subpopulations in a given skin area during the course of experimentation.
  • back skin from defined skin regions was harvested from test and control mice sacrificed by CO inhalation during defined time points.
  • full-thickness skin was harvested at the level of the subcutis perpendicular to the paravertebral line. Skin was fixed in 5% buffered formaldehyde and processed for routine histology (paraffin embedding, Giemsa stain).
  • the amount of hair regrowth was evaluated on day 13. As expected, only 1 of 5 control mice had hair regrowth by this day. At this time point, 4 of 5 mice treated with AH(l-7) (30 ⁇ g/kg/day) and 5 of 5 mice treated with 9GD (30 ⁇ g/kg/day) had observable hair regrowth. The percentage of the area with hair regrowth at this time point was significantly increased ( Figure 1). On day 19, the mice were sacrificed and the tissue placed in formalin for preparation for histological evaluation. The number of mature hair follicles present was also increased by administration of the peptides ( Figure 2).

Abstract

L'invention concerne des procédés, des nécessaires et des compositions pharmaceutiques perfectionnés destinés au traitement et à la prévention de l'alopécie chez un sujet nécessitant un tel traitement, par l'administration d'une dose efficace d'angiotensinogène, d'angiotensine I (AI), d'analogues AI, de ses fragments ou analogues AI, d'angiotensine II (AII), d'analogues AII, de ses fragments ou analogues AII, ou encore d'agonistes du récepteur de AII AT2 de type 2.
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CA2550459C (fr) 2003-12-18 2009-12-15 Biomas, Ltd. Derives du tellure pour la prevention et le traitement des processus neurodegeneratifs
WO2006030437A2 (fr) 2004-09-17 2006-03-23 Biomas Ltd. Nouveaux compose a base de tellure et leurs utilisations
AT508569A1 (de) 2009-07-23 2011-02-15 Affiris Ag Pharmaceutical compound
JP5469777B2 (ja) 2011-02-02 2014-04-16 ユニバーシティー オブ サザン カリフォルニア 糖尿病性足部潰瘍を処置するための方法
US8557958B1 (en) 2012-06-18 2013-10-15 Tarix Pharmaceuticals Ltd. Compositions and methods for treatment of diabetes
US8633158B1 (en) 2012-10-02 2014-01-21 Tarix Pharmaceuticals Ltd. Angiotensin in treating brain conditions
WO2014078929A1 (fr) * 2012-11-26 2014-05-30 Universidade Federal De Minas Gerais - Ufmg Formulations topiques pour la prévention et le traitement de l'alopécie et pour l'inhibition de la croissance des poils
US9333233B2 (en) 2014-02-25 2016-05-10 Tarix Pharmaceuticals Ltd. Methods and compositions for the delayed treatment of stroke

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US5567679A (en) * 1993-12-13 1996-10-22 Daly; Theodore J. Use of CGRP in treating alopecia
US5753226A (en) * 1995-04-11 1998-05-19 The Trustees Of The University Of Pennsylvania Methods of enhancing epithelial cell proliferation
US5804445A (en) * 1996-01-11 1998-09-08 Board Of Regents, The University Of Texas System High affinity mutants of nuclear factor-interleukin 6 and methods of use therefor
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