WO2005014003A1 - Topical use of tyrosine kinase inhibitors of microbial origin to prevent and treat skin disorders characterised by excessive cell proliferation - Google Patents
Topical use of tyrosine kinase inhibitors of microbial origin to prevent and treat skin disorders characterised by excessive cell proliferation Download PDFInfo
- Publication number
- WO2005014003A1 WO2005014003A1 PCT/EP2003/008077 EP0308077W WO2005014003A1 WO 2005014003 A1 WO2005014003 A1 WO 2005014003A1 EP 0308077 W EP0308077 W EP 0308077W WO 2005014003 A1 WO2005014003 A1 WO 2005014003A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tyrosine kinase
- treatment
- kinase inhibitors
- prevent
- cell proliferation
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0066—Psoralene-activated UV-A photochemotherapy (PUVA-therapy), e.g. for treatment of psoriasis or eczema, extracorporeal photopheresis with psoralens or fucocoumarins
-
- 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
- A61P17/06—Antipsoriatics
Definitions
- the present invention relates to the use of tyrosine kinase inhibitors of microbial origin belonging to the K252 family to prepare topical medicaments able to inhibit the excessive keratinocyte proliferation characteristic of disorders such as psoriasis and skin tumours.
- BACKGROUND OF THE INVENTION Nerve Growth Factor is the archetype of a family of proteins called neurotrophins (1). All members of the neurotrophin family and tHeir receptors play a vital role in the development of the nervous system (2). In addition to this "classic" function, it is now known that NGF and the other neurotrophins are crucial molecules in modulating the inflammatory response and in tissue repair processes.
- NGF acts by binding to two classes of receptors, a receptor with low affinity of ⁇ 75 kd (p75) (3) and a tyrosine kinase receptor with high affinity of -140 kd (TrkA) (4).
- the keratinocytes express both of these receptors.
- NGF is released by the keratinocytes and acts in a autocrine manner on those cells. Through binding to TrkA, autocrine NGF stimulates the proliferation of normal human keratinocyte cultures.
- NGF is secreted by the keratinocytes in the basal layer of the epidermis, i.e. the ones which most express TrkA.
- NGF In addition to acting as mitogen, NGF also protects the keratinocytes against apoptosis (genetically programmed cell death).
- the activity of the tyrosine kinase proteins seems to play a crucial role in the action mechanism of the main types of phototherapy (use of light radiation for therapeutic purposes), photochemotherapy and photodynamic treatment.
- One of the main treatments for skin disorders like psoriasis and vitiligo involves the combined use of psoralens and ultraviolet light, a procedure known as PUVA treatment. This treatment profoundly alters cell growth and differentiation.
- an event that follows shortly after PUVA treatment is inhibition of the binding between EGF and its receptor through inhibition of the tyrosine kinase activity of the receptor (5).
- Photodynamic treatment is a recent procedure for the treatment of numerous malignant conditions, including skin tumours, involving the application of a photo sensitising substance followed by illumination of the lesion with visible light.
- a recent study, carried out in vivo and in vitro, has demonstrated that photodynamic treatment with phthalocyanine (Pc4-PDT), which induces apoptosis in human epidermoid carcinoma cells (A431), acts by modulating the expression and phosphorylation of EGFR (6).
- Another study has demonstrated the efficacy of a combination of photodynamic treatment and tyrosine kinase inhibitors in inducing anti-angiogenic and anti-tumoral activity in vivo and in vitro (7).
- K252 an alkaloid of microbial origin, known as K252 and originally studied as an anti-allergic and antihistamine drug (US 4555402), and some of its derivatives (US 4923986 and US 4877776), are powerful inhibitors of protein kinase C and NGF.
- K252 by inhibiting the TrkA phosphorylation induced by NGF, also inhibits the growth of human prostate carcinoma cell lines (8).
- US 6300327 also discloses the use of K252 and its analogues in the treatment of neurodegenerative disorders. It has also been reported that the addition of K252 to keratinocyte cultures significantly increases both spontaneous and UV-induced apoptosis (9).
- K252 and similar compounds that inhibit the tyrosine kinase receptor of NGF can also inhibit keratinocyte proliferation.
- the invention consequently relates to the use of the alkaloid K252 and its analogues or derivatives to prepare topical drugs for the treatment of disorders characterised by hyperproliferation of the keratinocytes, such as psoriasis, chonic eczema, acne, pitiriasis rubra pilaris, keloids, hypertrophic scars and skin tumours (keratoacanthoma, squamous cell carcinoma, basal cell carcinoma etc.).
- Compounds K252 will be optionally used in combination with PUVA treatment or photodynamic treatment.
- the invention also relates to topical pharmaceutical compositions containing an alkaloid K252 or an analogue or derivative thereof as active ingredient, in admixture with suitable vehicles and excipients.
- Alkaloid or compound K252 means the natural compounds disclosed in the above-mentioned patents, especially the compounds known as K252a and K252b, and their physiologically equivalent derivatives such as esters, amides, salts, N-alkylated or N-acylated derivatives or other derivatives obtained by chemical synthesis aimed to reduce the systemic absorption of the product, such as spacers associated to proteins or other physiologically inactive large molecules.
- K252 The pharmacological activity of K252 has been demonstrated by topically administering the compound directly to the skin of mice. K252 concentrations of 50 to 500 nM in glycerin or vaseline were used. Immunofluorescence studies demonstrated that the substance penetrates into the epidermis and the superficial dermis. K252 was thus applied to squamous cell papillomas, induced on the skin of SENCAR and SKH-1 nude mice irradiated with UVB, once a week for 10 weeks.
- K252 was also applied on the same experimental model one hour before photodynamic treatment.
- the mice pre-treated with K252 required fewer sessions of photodynamic treatment than the controls.
- the activity of K252, both alone and in combination with PUVA treatment was confirmed in an experimental psoriasis model.
- K252 compounds will be formulated in pharmaceutical compositions suitable for topical administration, such as ointments, gels, lotions, powders, medicated plasters and the like, using well known techniques and excipients.
- the human therapeutic dose will depend on a number of factors, and can easily be determined on the basis of pharmacotoxicological and clinical trials. Broadly speaking, concentrations of K252, its analogues or derivatives ranging from approx. 0.01% to 5% by weight of the total formulation can be used for application to the skin one or more times a day.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Dermatology (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP03817928A EP1653972A1 (en) | 2003-07-23 | 2003-07-23 | Topical use of tyrosine kinase inhibitors of microbial origin to prevent and treat skin disorders characterised by excessive cell proliferation |
PCT/EP2003/008077 WO2005014003A1 (en) | 2003-07-23 | 2003-07-23 | Topical use of tyrosine kinase inhibitors of microbial origin to prevent and treat skin disorders characterised by excessive cell proliferation |
AU2003250150A AU2003250150A1 (en) | 2003-07-23 | 2003-07-23 | Topical use of tyrosine kinase inhibitors of microbial origin to prevent and treat skin disorders characterised by excessive cell proliferation |
US10/565,170 US20060210553A1 (en) | 2003-07-23 | 2003-07-23 | Topical use of tyrosine kinase inhibitors of microbial origin to prevent and treat skin disorders characterised by excesssive cell proliferation |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/EP2003/008077 WO2005014003A1 (en) | 2003-07-23 | 2003-07-23 | Topical use of tyrosine kinase inhibitors of microbial origin to prevent and treat skin disorders characterised by excessive cell proliferation |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2005014003A1 true WO2005014003A1 (en) | 2005-02-17 |
Family
ID=34129882
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2003/008077 WO2005014003A1 (en) | 2003-07-23 | 2003-07-23 | Topical use of tyrosine kinase inhibitors of microbial origin to prevent and treat skin disorders characterised by excessive cell proliferation |
Country Status (4)
Country | Link |
---|---|
US (1) | US20060210553A1 (en) |
EP (1) | EP1653972A1 (en) |
AU (1) | AU2003250150A1 (en) |
WO (1) | WO2005014003A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006010628A1 (en) * | 2004-07-29 | 2006-02-02 | Creabilis Therapeutics S.P.A. | Use of k-252a and kinase inhibitors for the prevention or treatment of hmgb1-associated pathologies |
WO2007022999A1 (en) | 2005-08-25 | 2007-03-01 | Creabilis Therapeutics S.P.A. | Polymer conjugates of k-252a and derivatives thereof |
WO2010072795A1 (en) | 2008-12-22 | 2010-07-01 | Creabilis S.A. | Synthesis of polymer conjugates of indolocarbazole compounds |
JP2016523960A (en) * | 2013-07-11 | 2016-08-12 | プレシジョン ダーマトロジー インコーポレイテッドPrecision Dermatology, Inc. | Plaster therapy for localized scleroderma |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996011933A1 (en) * | 1994-10-14 | 1996-04-25 | Cephalon, Inc. | Fused pyrrolocarbazoles |
WO1997049406A1 (en) * | 1996-06-25 | 1997-12-31 | Cephalon, Inc. | Use of k-252a derivative for the treatment of peripheral or central nerve disorders, and cytokine overproduction |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6041489A (en) * | 1983-08-12 | 1985-03-05 | Kyowa Hakko Kogyo Co Ltd | Novel physiologically active substance k-252 and its preparation |
JPH07113027B2 (en) * | 1987-12-24 | 1995-12-06 | 協和醗酵工業株式会社 | K-252 derivative |
AU4787693A (en) * | 1992-08-12 | 1994-03-15 | Upjohn Company, The | Protein kinase inhibitors and related compounds combined with taxol |
AU2001261324A1 (en) * | 2000-05-08 | 2001-11-20 | Psoriasis Research Institute | Psoriasis treatment |
-
2003
- 2003-07-23 WO PCT/EP2003/008077 patent/WO2005014003A1/en active Application Filing
- 2003-07-23 EP EP03817928A patent/EP1653972A1/en not_active Withdrawn
- 2003-07-23 AU AU2003250150A patent/AU2003250150A1/en not_active Abandoned
- 2003-07-23 US US10/565,170 patent/US20060210553A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996011933A1 (en) * | 1994-10-14 | 1996-04-25 | Cephalon, Inc. | Fused pyrrolocarbazoles |
WO1997049406A1 (en) * | 1996-06-25 | 1997-12-31 | Cephalon, Inc. | Use of k-252a derivative for the treatment of peripheral or central nerve disorders, and cytokine overproduction |
Non-Patent Citations (2)
Title |
---|
AKINAGA: "Antitumor effect of KT6124, a novel derivative of protein kinase inhibitor k-252a, and its mechanism of action", CANCER CHEMOTHERAPY AND PHARMACOLOGY, SPRINGER VERLAG, BERLIN, DE, vol. 29, no. 4, 1992, pages 266 - 272, XP002104872, ISSN: 0344-5704 * |
See also references of EP1653972A1 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006010628A1 (en) * | 2004-07-29 | 2006-02-02 | Creabilis Therapeutics S.P.A. | Use of k-252a and kinase inhibitors for the prevention or treatment of hmgb1-associated pathologies |
WO2007022999A1 (en) | 2005-08-25 | 2007-03-01 | Creabilis Therapeutics S.P.A. | Polymer conjugates of k-252a and derivatives thereof |
WO2010072795A1 (en) | 2008-12-22 | 2010-07-01 | Creabilis S.A. | Synthesis of polymer conjugates of indolocarbazole compounds |
JP2016523960A (en) * | 2013-07-11 | 2016-08-12 | プレシジョン ダーマトロジー インコーポレイテッドPrecision Dermatology, Inc. | Plaster therapy for localized scleroderma |
Also Published As
Publication number | Publication date |
---|---|
AU2003250150A1 (en) | 2005-02-25 |
US20060210553A1 (en) | 2006-09-21 |
EP1653972A1 (en) | 2006-05-10 |
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