WO2018054489A1 - Traitement pharmacologique de la myopie - Google Patents

Traitement pharmacologique de la myopie Download PDF

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Publication number
WO2018054489A1
WO2018054489A1 PCT/EP2016/072729 EP2016072729W WO2018054489A1 WO 2018054489 A1 WO2018054489 A1 WO 2018054489A1 EP 2016072729 W EP2016072729 W EP 2016072729W WO 2018054489 A1 WO2018054489 A1 WO 2018054489A1
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WO
WIPO (PCT)
Prior art keywords
antagonist
agonist
gpcr
endothelin receptor
alpha
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PCT/EP2016/072729
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English (en)
Inventor
Finn HALLBÖÖK
Original Assignee
Hallboeoek Finn
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Priority to PCT/EP2016/072729 priority Critical patent/WO2018054489A1/fr
Publication of WO2018054489A1 publication Critical patent/WO2018054489A1/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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • A61K38/22—Hormones
    • A61K38/2285—Endothelin, vasoactive intestinal contractor [VIC]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia

Definitions

  • the present invention provides a new therapeutic method for treating myopia progression by blocking cell growth in the retina using alpha-2-adrenergic receptor agonists or antagonists.
  • the blockage will stop the progression of the myopia that is caused by growth and elongation of the eye- globe.
  • the present invention specifically relates to treatment of juvenile myopia or infantile axial myopia.
  • the present invention also relates to a pharmaceutical composition comprising an alpha-2- adrenergic receptor agonist or antagonist. Treatment is for example performed by using eye-drops on children and young adults comprising said pharmaceutical composition.
  • the present invention relates generally to methods and systems for the treatment of myopia progression.
  • Myopia or 'near-sightedness/short-sightedness' is one of the more prevalent human visual disorders, affecting up to 25% of European and American population.
  • the associated cost of correction and management has been estimated to be several billion dollars per year.
  • Myopia is a rapidly growing disorder and affects some 1.6 billion people in the world, and the prevalence is estimated to increase to 2.5 billion affected people by the year 2020.
  • Myopia typically develops during the early school years and tends to progress more rapidly in pre-teens than in older teenagers.
  • the early onset myopia is also called juvenile myopia or infantile axial myopia.
  • Treatments that control the progression of myopia early would have a widespread benefit because severe myopia has been associated with serious eye problems later in life, such as early cataract, myopic macular degeneration or even blindness from retinal detachment. It is also important to slow the progression of myopia because it may keep children from developing severe side effects or complications from myopia correction.
  • Juvenile myopia is generally believed to be a result of eye globe/eye-axis elongation.
  • the refraction focal point will therefore fall in front of the retina (Fig. 1).
  • Even a minor reduction of the elongation of the eye globe may relieve the need for refractive correction and thus reduces the risk for future severe complications due to progressive juvenile myopia.
  • myopia is commonly treated by correction of the light refraction of the eye either based on eyeglasses, contact-lenses or by LASIK "laser-assisted in situ keratomileusis". Lasik is corneal laser surgery that leads to reshaping of the cornea. Because the development of myopia is progressive in children a number of techniques have been developed to control or prevent myopia progression. The techniques are: pharmacological delivery of low-dose Atropine, multifocal contact lenses, multifocal eyeglasses or orthokeratology (Ortho-K).
  • Atropine is an anti-cholinergic drug that produce cycloplegia and mydriasis by inhibition of the parasympathetic system. Both the sympathetic and parasympathetic systems play roles in our ability to adapt successfully to sustained periods of near-vision tasks by regulating accommodation and vergence. Given the association between sustained near-vision and the onset and development of myopia, an aetiological role in myopia of sympathetic and parasympathetic regulation, has been suggested. Effects of anti-cholinergic and beta-adrenergic drugs, such as atropine and the non- selective beta-adrenergic receptor blocker, Timolol, have been studied. Clinical trials in Hong-Kong and Japan showed that the rate of progression of myopia is lower in children given atropine eye drops than those given placebo. The effect of Timolol was less pronounced. Atropine is associated with short term and possible long term adverse events.
  • US 2009/0156606 show that combinations of sympathetic agonists e.g. Brimonidine or sympathetic antagonists with parasympathetic agonists or antagonists have also been suggested to improve vision by ameliorating the effects of manifest presbyopia, myopia, hypermetropia or astigmatism.
  • the treatment-rationale is however based on regulation of long term adaptive accommodation and vergence.
  • Brimonidine is also used to treat glaucoma and to reduce the incidence of complications in connection with eye surgery or LASIK, such as subconjunctival hemorrhage, hyperemia, and photophobia and "flap" complications.
  • the present invention relates to prevention of the development of progressive myopia by a pharmacological approach that inhibits or stops the eye-axis elongation of the eye globe. This elongation process is very prominent in infants and juveniles.
  • the present invention pharmacologically targets and inhibits cell proliferation and growth of specific cells in the retina.
  • the target is active cells with a potential for proliferation in the retina such as retinal progenitor cells located within the neural retina or in the peripheral rim of the retina called in the ciliary marginal zone.
  • the active cells may be MLiller cells, retinal progenitor cells derived from Muller cells or progenitor cells in the ciliary marginal zone of the retina.
  • the intent is to negatively regulate how prone the Muller cells are to de-differentiate and therefore to proliferate.
  • the negative regulation attenuates the cell proliferation and thereby growth of the eye.
  • the invention is to pharmacologically treat the eye with the aim to block or inhibit the cells to initiate proliferation using receptor antagonists or agonists.
  • the invention utilizes the fact that different G- protein coupled receptors (GPC s) may positively or negatively regulate signaling pathways, which are directly associated to cell proliferation.
  • GPC s G- protein coupled receptors
  • GPCR G-protein coupled receptor
  • the GPCR agonist or antagonist it is selected from an alpha 2-adrenergic receptor agonist or antagonist, an endothelin receptor agonist or antagonist or other GPCR agonist or antagonist that activate signaling molecules regulating cell proliferation.
  • the GPCR agonist or antagonist is selected from alpha 2- adrenergic receptor agonist is selected from Brimonidine, 7-Me-marsanidine, Agmatine,
  • the GPCR agonist or antagonist is Brimonidine.
  • the GPCR agonist or antagonist is selected from alpha 2- adrenergic receptor antagonist is selected from Aripiprazole, Asenapine, Atipamezole, Cirazoline, Clozapine, Efaroxan, Idazoxan, Lurasidone, Melperone, Mianserin, Mirtazapine, Napitane,
  • the GPCR agonist or antagonist is selected from endothelin receptor agonist or antagonist is selected from endothelin receptor type A antagonists Ambrisentan, Atrasentan, BQ-123, BMS 182874, CL1020, Sitaxentan, and Zibotentan.
  • the GPCR agonist or antagonist is selected from endothelin receptor agonist or antagonist is selected from endothelin receptor type B agonists IRL1620, BQ- 3020, [Alal,3,ll,15]-endothelin, and Sarafotoxin S6c.
  • the GPCR agonist or antagonist is IRL1620.
  • the GPCR agonist or antagonist is selected from endothelin receptor agonist or antagonist is selected from endothelin receptor type B antagonists BQ 788, IRL- 2500, and IRL 1038.
  • the GPCR agonist or antagonist is suitably administered topically to the eye, incorporated in for example a liquid, a gel, an ointment, and other suitable pharmaceutical vehicle, and combinations thereof.
  • said GPCR agonist or antagonist is administered incorporated in an eye drop solution.
  • a method for treatment of juvenile myopia or infantile axial myopia comprising administering a G-protein coupled receptor (GPCR) agonist or antagonist to a juvenile patient (5 - 20 years).
  • GPCR G-protein coupled receptor
  • Initiation of treatment may vary, but preferably it should be commenced in early phases of myopia development, which is probably between ages 6 and 15, for example 9-11 years.
  • the GPCR agonist or antagonist is selected from an alpha 2- adrenergic receptor agonist or antagonist, an endothelin receptor agonist or antagonist or other GPCR agonist or antagonist that activate signaling molecules regulating cell proliferation.
  • the alpha 2-adrenergic receptor agonist is selected from Brimonidine, 7- Me-marsanidine, Agmatine, Apraclonidine, Cannabigerol, Clonidine, Detomidine, Dexmedetomidine, Fadolmidine, Guanabenz, Guanfacine, Lofexidine, Marsanidine, Medetomidine, Methamphetamine, Mivazerol, Rilmenidine, Romifidine, Talipexole, Tiamenidine, Tizanidine, Tolonidine, Xylazine, and Xylometazoline.
  • the alpha 2-adrenergic receptor agonist is selected from Brimonidine.
  • the alpha 2-adrenergic receptor antagonist is selected from Aripiprazole, Asenapine, Atipamezole, Cirazoline, Clozapine, Efaroxan, Idazoxan, Lurasidone, Melperone, Mianserin, Mirtazapine, Napitane, Olanzapine, Paliperidone, Phenoxybenzamine, Phentolamine, Piribedil, Rauwolscine, Quetiapine, Norquetiapine, Setiptiline, Tolazoline, Yohimbine, Ziprasidone, and Zotepine.
  • the endothelin receptor agonist or antagonist is selected from endothelin receptor type A antagonists Ambrisentan, Atrasentan, BQ-123, BMS 182874, CL1020, Sitaxentan, and Zibotentan.
  • the endothelin receptor agonist or antagonist is selected from endothelin receptor type B agonists IRL1620, BQ-3020, [Alal,3,ll,15]-endothelin, and Sarafotoxin S6c. In a more specific embodiment, the endothelin receptor agonist or antagonist is selected from IRL1620.
  • the endothelin receptor agonist or antagonist is selected from endothelin receptor type B antagonists BQ 788, IRL-2500, and IRL 1038
  • the GPCR agonist or antagonist is suitably administered topically to the eye, incorporated in for example a liquid, a gel, an ointment, and other suitable pharmaceutical vehicle, and combinations thereof.
  • said GPCR agonist or antagonist is administered incorporated in an eye drop solution.
  • a pharmaceutical composition for treatment of juvenile myopia or infantile axial myopia comprising a G-protein coupled receptor (GPCR) agonist or antagonist.
  • GPCR G-protein coupled receptor
  • the GPCR agonist or antagonist is selected from an alpha 2-adrenergic receptor agonist or antagonist, an endothelin receptor agonist or antagonist or other GPCR agonist or antagonist that activate signaling molecules regulating cell proliferation.
  • the alpha 2-adrenergic receptor agonist is selected from
  • the alpha 2-adrenergic receptor agonist is selected from Brimonidine.
  • the alpha 2-adrenergic receptor antagonist is selected from Aripiprazole, Asenapine, Atipamezole, Cirazoline, Clozapine, Efaroxan, Idazoxan, Lurasidone, Melperone, Mianserin, Mirtazapine, Napitane, Olanzapine, Paliperidone, Phenoxybenzamine, Phentolamine, Piribedil, Rauwolscine, Quetiapine, Norquetiapine, Setiptiline, Tolazoline, Yohimbine, Ziprasidone, and Zotepine.
  • the endothelin receptor agonist or antagonist is selected from endothelin receptor type A antagonists Ambrisentan, Atrasentan, BQ-123, BMS 182874, CL1020, Sitaxentan, and Zibotentan.
  • the endothelin receptor agonist or antagonist is selected from endothelin receptor type B agonists IRL1620, BQ-3020, [Alal,3,ll,15]-endothelin, and Sarafotoxin S6c. In a more specific embodiment, the endothelin receptor agonist or antagonist is selected from IRL1620.
  • the endothelin receptor agonist or antagonist is selected from endothelin receptor type B antagonists BQ 788, IRL-2500, and IRL 1038. In a more specific embodiment, the endothelin receptor agonist or antagonist is selected from IRL1620.
  • the pharmaceutical composition may be a liquid, a gel, an ointment, and other suitable
  • composition may also comprise suitable adjuvants.
  • the composition is adapted for topical application, such as an eye drop solution.
  • Fig 1. Schematic diagram showing an elongated eye.
  • Fig 2. Bar graph showing the dose response for the effect of N-methyl-D-aspartate (NMDA) on cell survival in the chicken retina.
  • the x-axis shows the time of measurement (14 days) and the y-axis degree of cell survival in percent. All solutions used comprised saline.
  • Fig 3. Image showing the eye-axis of a chicken eye.
  • FIG. 1 Representative images of (A) NMDA-treated and (B) control eye, and (C) a bar graph showing effect of Brimonidine (BMD) on eye-axis elongation triggered by NMDA.
  • BMD Brimonidine
  • Fig 5. Western blot and bar graph showing phospho-ERKl/2 levels in chicken retina after endothelin receptor stimulation.
  • Fig 6. Western blot and bar graph showing phospho-ERKl/2 levels in primary chicken Miiller cells after endothelin receptor stimulation.
  • Alpha 2-adrenergic receptor stimulation was achieved by treatment with an alpha 2-adrenergic receptor agonist.
  • NMDA, saline or Brimonidine solutions were intraocularly injected at embryonic day 18 and the eye axis length was studied after 14 days.
  • Fertilized White Leghorn eggs from a local breed were incubated at 38°C in a humidified incubator. After hatching, chicks were marked with a numbered plastic ring in the leg and moved to a poultry farm. The chicken were fed ad libitum and kept under standard conditions according to experimental animal guidelines.
  • NMDA neuropeptide deacetylase
  • a pilot experiment was carried out. A single intraocular injection of 10 ⁇ was made in embryonic day 18 chick embryos, with four different doses of NMDA, 0.1, 1, 10, and 100 ⁇ g. Eggs were opened at the blunt end and a hole was opened in the eggshell. The head was pulled and intraocular injection was performed through the amniotic membranes in the right eye with a 27-gauge needle in the center of the eye. After injection, the egg was closed with an adhesive tape and incubated. The effect of NMDA was analyzed on cross-sections at 14 days post-injection (0.1, 1, 10, 100 ⁇ g NMDA) and the effect was monitored by the extent of tissue damage and loss of cells. A concentration was selected that produced a minimum amount of damage as analysed by surviving cells, but with a response of the eye-axis elongation. Injection of 1 ⁇ g NMDA was used for further analysis (Fig. 2).
  • the eyes were dissected and the eye-axis length was determined as the perpendicular length from the tip of the cornea to the posterior-most aspect of the eye globe, as indicated in (Fig. 3).
  • Example 1 - Stimulation of alpha 2-adrenergic receptors using Brimonidine Alpha 2-adrenergic receptor stimulation was achieved by treatment using the alpha 2-adrenergic receptor agonist Brimonidine (80 ⁇ g Brimonidine in 10 ⁇ sterile saline, 0.15 M NaCI, UK 14,304 tartrate; Tocris Bioscience). NMDA-injured (1 ⁇ g NM DA in 10 ⁇ ) eyes were treated one hour before NMDA injection. Saline- and Brimonidine-only-treatment was also analyzed.
  • Brimonidine 80 ⁇ g Brimonidine in 10 ⁇ sterile saline, 0.15 M NaCI, UK 14,304 tartrate; Tocris Bioscience.
  • NMDA-injured (1 ⁇ g NM DA in 10 ⁇ ) eyes were treated one hour before NMDA injection. Saline- and Brimonidine-only-treatment was also analyzed.
  • Axis length of treated eyes were measured and the NMDA treated eyes that were treated with saline had a longer eye-axis than the eyes that were treated with Brimonidine or the ones that had not received any NMDA (Fig. 4 and table 1).
  • the axis length of eyes treated with only Brimonidine were similar to the eyes that were not treated with NMDA.
  • BM D (Brimonidine + saline)
  • the Miiller cell contributes to eye growth and eye-axis elongation.
  • ERKl/2 is a major intracellular regulator of cell proliferation and growth.
  • IRL1620 endothelin receptor agonist
  • ERKl/2 was studied using western blot analysis after injections of endothelin receptor agonist IRL1620. ERKl/2 was analyzed 2, 4, 6 and 24 h after stimulation.
  • DMEM Dulbecco's modified Eagle's medium

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Abstract

La présente invention concerne un nouveau procédé thérapeutique de traitement de la progression de la myopie en bloquant la croissance des cellules dans la rétine en utilisant des agonistes ou des antagonistes de récepteur alpha-2-adrénergique. Le blocage arrêtera la progression de la myopie qui est provoquée par la croissance et l'allongement du globe oculaire. La présente invention concerne particulièrement le traitement de la myopie juvénile ou de la myopie axiale infantile. La présente invention concerne également une composition pharmaceutique comprenant un agoniste ou un antagoniste de récepteur alpha-2-adrénergique. Le traitement est par exemple exécuté en utilisant des gouttes oculaires comprenant ladite composition pharmaceutique chez les enfants et les jeunes adultes.
PCT/EP2016/072729 2016-09-23 2016-09-23 Traitement pharmacologique de la myopie WO2018054489A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090156606A1 (en) 2007-12-15 2009-06-18 Anant Sharma Optical correction
WO2009112878A1 (fr) * 2008-03-11 2009-09-17 Raouf Rekik Administration de médicament aux segments antérieur et postérieur de l'œil à l'aide de gouttes ophtalmiques
WO2010125416A1 (fr) * 2009-04-27 2010-11-04 Raouf Rekik Administration de médicaments dans le segment antérieur et le segment postérieur de l'oeil
CN105434439A (zh) * 2015-11-11 2016-03-30 温州医科大学 一种多巴胺d2受体的部分激动剂在制备抑制近视药物上的应用及其使用方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090156606A1 (en) 2007-12-15 2009-06-18 Anant Sharma Optical correction
WO2009077736A2 (fr) * 2007-12-15 2009-06-25 Anant Sharma Correction optique
WO2009112878A1 (fr) * 2008-03-11 2009-09-17 Raouf Rekik Administration de médicament aux segments antérieur et postérieur de l'œil à l'aide de gouttes ophtalmiques
WO2010125416A1 (fr) * 2009-04-27 2010-11-04 Raouf Rekik Administration de médicaments dans le segment antérieur et le segment postérieur de l'oeil
CN105434439A (zh) * 2015-11-11 2016-03-30 温州医科大学 一种多巴胺d2受体的部分激动剂在制备抑制近视药物上的应用及其使用方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Week 201639, Derwent World Patents Index; AN 2016-23082J, XP002769994 *
MOHAMMAD HARUN-OR-RASHID ET AL: "Transactivation of EGF Receptors in Chicken Müller Cells by [alpha]2A-Adrenergic Receptors Stimulated by Brimonidine", INVESTIGATIVE OPTHALMOLOGY & VISUAL SCIENCE, vol. 55, no. 6, 2 June 2014 (2014-06-02), US, pages 3385, XP055370921, ISSN: 1552-5783, DOI: 10.1167/iovs.13-13823 *

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