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WO2012098143A1 - Utilisation d'inhibiteurs de canaux potassiques atp-dépendants pour le traitement de la perte d'audition - Google Patents

Utilisation d'inhibiteurs de canaux potassiques atp-dépendants pour le traitement de la perte d'audition Download PDF

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Publication number
WO2012098143A1
WO2012098143A1 PCT/EP2012/050683 EP2012050683W WO2012098143A1 WO 2012098143 A1 WO2012098143 A1 WO 2012098143A1 EP 2012050683 W EP2012050683 W EP 2012050683W WO 2012098143 A1 WO2012098143 A1 WO 2012098143A1
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Prior art keywords
atp
inhibitor
sensitive potassium
hearing loss
potassium channel
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English (en)
Inventor
Jochen Roeper
Silvi HOIDIS
Jean SMOLDERS
Manuel GROTH
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Goethe Universitaet Frankfurt am Main
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Goethe Universitaet Frankfurt am Main
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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
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals

Definitions

  • the present invention relates to the use of inhibitors of ATP-sensitive potassium channels for the protective (including preventive) therapy or the reduced progression of hearing loss, in particular age-related hearing loss (presbycusis) and/or noise-induced hearing loss (NIHL).
  • Preferred is the systemic or local administration of clinically established sulfonylureas, such as, for example, glibenclamide.
  • Presbyacusis is a major form of sensorineural age-related hearing loss that involves the degeneration and irreversible loss of hair cells (HC) in the mammalian inner ear. It affects about 70-80% of the elderly (> 65 years) and currently no protective or curative therapy exists.
  • the pathome- chanisms of presbyacusis are not well understood, but ischemia, oxidative stress and mutations of mitochondrial DNA might, among others, contribute to hair cell loss.
  • NIHL Noise-induced hearing loss
  • Glibenclamide is an example for the group of sulfonylureas and is used as an oral antidiabetic. Glibenclamide selectively blocks ATP-sensitive potassium channels in ⁇ -cel!s of the pancreas, which facilitates insulin release.
  • Herzog et al. in: Herzog M, Scherer EQ, Albrecht B, Rorabaugh B, Scofield MA, Wangemann P. CGRP receptors in the gerbil spiral modiolar artery mediate a sustained vasodilation via a transient cAMP-mediated Ca2+-decrease. J Membr Biol. 2002 Oct l; 189(3):225-36) describe the alteration of cochlear blood flow as may be involved in the etiology of inner ear disorders like sudden hearing loss, fluctuating hearing loss and tinnitus.
  • the K+-channel blockers iberiotoxin and glibenclamide partially prevented CGRP- or forskolin-induced vasodilations but failed to reverse these vasodilations.
  • the publication suggests that the vasodilation, amongst others, is mediated by a transient activation of glibenclamide-sensitive KATP channels. Glibenclamide can prevent vasodilation, but not reverse it. Furthermore, a connection with presbycusis is not mentioned.
  • Wu and Marcus (in: Wu T, Marcus DC. Age-related changes in cochlear endolymphatic potassium and potential in CD-I and CBA/CaJ mice. J Assoc Res Otolaryngol. 2003 Sep;4(3):353-62) describe the CD-I mouse strain as known to have early onset of hearing loss that is progressive with aging, and thus examined whether a disturbance of K+ homeostasis and pathological changes in the cochlear lateral wall were involved in the age-related hearing loss (AHL) of CD-I as compared to the CBA/CaJ strain which has minimal AHL. Old CD-I mice displayed a significantly reduced endolymphatic K+ concentration by 30% in both basal and apical turns.
  • AHL age-related hearing loss
  • WO 2010/042728 describes a method of inhibiting cellular uptake of pro-nerve growth factor (proNGF) in a cell expressing neurotrophin p75 receptor in a mammal by providing glyburide (glibenclamide) in hearing loss patients.
  • proNGF pro-nerve growth factor
  • glyburide glibenclamide
  • the neurotrophin receptor p75 may play a significant role in the maintenance of cochlear function, and mice carrying a mutation in the p75 gene could be a good animal model of early onset progressive hearing loss. Furthermore, the neurotrophin receptor p75 is not an ATP-sensitive potassium channel. Presbycusis is not described in WO 2010/042728.
  • US 2007-248690 describe the use of a composition for the treatment of the symptoms of neurotoxicity, which may be manifested auricularly as tinnitus, Meniere's Disease and hearing loss.
  • the composition for alleviating symptoms of neurotoxicity comprises at least one glutamate antagonist; at least one cAMP stimulating agent; at least one antioxidant; and vitamin B12.
  • a glutamate antagonist optionally a glutathione promoting agent (taurine) can be used. Presbycusis is not described, as this condition is not related to neurotoxicity.
  • a similar disclosure is found in US 2005-129783, which is related to neurophysiological conditions. Presbycusis is not described.
  • Kocher in: Kocher, "Presbycusis: Reversible with anesthesia drugs?”, Medical Hypotheses, 72, 2009, 157-159 describes that the author, as a patient, experienced a reversal of high- frequency hearing loss during a 2-day period following abdominal surgery with general anesthesia.
  • anesthetic agents such as lidocaine, propofol, or fentanyl.
  • WO 2005/025293 describes fused ring heterocycles as potassium channel modulators, in particular in the treatment of diseases through the modulation of potassium ion flux through voltage-dependent potassium channels, such as central or peripheral nervous system disorders (e.g., migraine, ataxia, Parkinson's disease, bipolar disorders, trigeminal neuralgia, spasticity, mood disorders, brain tumors, psychotic disorders, myokymia, seizures, epilepsy, hearing and vision loss, Alzheimer's disease, age-related memory loss, learning deficiencies, anxiety and motor neuron diseases, maintaining bladder control or treating urinary incontinence).
  • WO 2005/025293 relates to the modulation of "voltage-dependent" potassium-channels, and therefore channels different in molecular composition, functional and pharmaceutical properties from those in the present invention.
  • this object of the present invention is solved by an inhibitor of an ATP-sensitive potassium channel for use in the treatment of hearing loss, preferably age-related hearing loss (presbycusis) and/or and noise-induced hearing loss (NIHL). Further preferred is the use of glibenclamide for the production of a medicament for the treatment of hearing loss, preferably age-related hearing loss (presbycusis) and/or noise-induced hearing loss (NIHL).
  • Another aspect of the present invention relates to a method for treatment of hearing loss, preferably age-related hearing loss (presbycusis) and/or noise-induced hearing loss (NIHL), comprising administering to a patient in need thereof a therapeutically effective amount of an inhibitor of an ATP-sensitive potassium channel.
  • hearing loss preferably age-related hearing loss (presbycusis) and/or noise-induced hearing loss (NIHL)
  • NIHL noise-induced hearing loss
  • treatment shall include both cell-protective (including preventive) therapy or the reduced progression and/or actual treatment of the disease symptoms of hearing loss, preferably, age-related hearing loss and/or noise-induced hearing loss (NIHL) as described herein, which can be alleviated and/or even completely abolished using said treatment.
  • cell-protective including preventive
  • NIHL noise-induced hearing loss
  • an inhibitor of an ATP-sensitive potassium channel is selected from ATP-sensitive potassium channels of the plasma membrane that comprise Ki r 6.1 and/or Ki r 6.2-type subunits as well as sulfonylurea receptors (SURl/SUR2a/b), and combinations thereof. More preferred is the inhibitor of an ATP-sensitive potassium channel according to the present invention, wherein said ATP-sensitive potassium channel is selected from ATP-sensitive potassium channels comprising an Ki r 6.2-type subunit, as well as a SUR1 subunit.
  • potassium channels can be identified by the person of skill based on channels based on methods as described in the literature, such as, for example in Shieh et al. (Shieh CC, Coghlan M, Sullivan JP, Gopalakrishnan M Potassium channels: molecular defects, diseases, and therapeutic opportunities Pharmacol Rev. 2000 Dec;52(4):557-94).
  • Shieh et al. Shieh CC, Coghlan M, Sullivan JP, Gopalakrishnan M Potassium channels: molecular defects, diseases, and therapeutic opportunities Pharmacol Rev. 2000 Dec;52(4):557-94
  • Over 50 human genes encoding various K(+) channel subunits have been cloned during the past decades, and precise biophysical properties, subunit stoichiometry, channel assembly, and modulation by second messenger and ligands have been elucidated to a large extent.
  • K(+) channels have been identified in diseases such as long-QT syndromes, episodic ataxia/myokymia, familial convulsions, hearing and vestibular diseases, Bartter's syndrome, and familial persistent hyperinsulinemic hypoglycemia of infancy.
  • Shieh et al. aim to 1) provide an understanding of K(+) channel function at the molecular level in the context of disease processes and 2) discuss the progress, hurdles, challenges, and opportunities in the exploitation of K(+) channels as therapeutic targets by pharmacological and emerging genetic approaches.
  • the present invention is based on the surprising finding that the application of sulfonylureas, such as, for example, glibenclamide in a mouse model showed a clearly protective effect on hearing of aging animals. A similar effect is expected in the human patient, whereby an irreversible loss of the inner and outer hair cells shall be prevented. Nevertheless, the detailed mechanisms for the effect of inhibitors of ATP-sensitive potassium channels are currently not known.
  • the inventors also investigated whether the degree of noise-induced hearing loss could be reduced by systemically blocking Kir6.2-containing K-ATP channels with the specific inhibitor glibenclamide (sulfonylurea).
  • any suitable inhibitor of an ATP-sensitive potassium channel according to the present invention can be used in order to provide a treatment.
  • the person of skill can identify new inhibitors through screening potential inhibitors using known ATP-sensitive potassium channels, such as, for example ATP- sensitive potassium channels comprising SURl/Ki r 6.2-type subunits.
  • a sulfonylurea compound containing a central S-phenyl sulfonylurea structure for example with at least one p-substitution on the phenyl ring
  • various groups terminating the urea N' end group such as acetohexamide, chlorpropamide, tolbutamide, tolaz
  • All sulfonylureas contain a central S-phenyl sulfonylurea structure with p-substitution on the phenyl ring and various groups terminating the urea N' end group. Further preferred are a 1. generation or 2.
  • glinides such as, for example, nateglinide, repaglinide, mitiglinide, meglitinide, gliptins, such as, for example, sitagliptin, vildagliptin, thiazolidinedione derivatives, such as troglitazone, englita- zone, ciclazindol, neomycin, (-)-epigallocatechin-3-gallate (EGCG), a major polyphenolic substance found in green tea, haloperidol, taurine, propofol, thiamylal, phenformin, metformin, benzo[c]quinolizinium compounds MPB-91, cyanoguanidine PNU-99963, midaglizole, LY397364, LY389382, stilbene disulphonates D1DS and SITS
  • the inhibitor according to the invention can be provided to the patient in any suitable and effective manner, such as orally, topically, subcutaneously, systemically, rectally or by injection. Preferred is systemically or locally.
  • the inhibitor according to the invention can be provided to the patient in any suitable and effective pharmaceutically acceptable form, such as in the form of a tablet, eardrops, subcutaneous pellet, drops, droplets, capsule, dragee, powder, suppository and/or gel.
  • Most preferred is the systemic or local administration of already clinically validated and established sulfonylureas, such as, for example glibenclamide.
  • the local intracochlear administration for example via an implanted device, such as, for example, a respectively modified drug eluting electrode, drug reservoir electrode, an electrode coated with a drug-releasing polymer, or the intrascalar application via implantable micro-fluidics technology systems (see, for example, Fiering J, et al., Local drug delivery with a self-contained, programmable, microfluidic system. Biomed Microdevices. 2009 Jun; l l(3):571-8).
  • an implanted device such as, for example, a respectively modified drug eluting electrode, drug reservoir electrode, an electrode coated with a drug-releasing polymer
  • implantable micro-fluidics technology systems see, for example, Fiering J, et al., Local drug delivery with a self-contained, programmable, microfluidic system. Biomed Microdevices. 2009 Jun; l l(3):571-8).
  • the inhibitor according to the invention can be provided to the patient in any suitable and effective amount or dosage, such as in an amount of between 0.1 mg to 10 mg, preferably 0.2 mg to 5 mg, and more preferably between 0.5 mg to 2 mg per dosage as administered. Further preferably, said inhibitor according to the invention is provided in a dosage of between 0.2 mg/kg of body weight to 5 mg/kg of body weight per day, preferably between 0.1 mg/kg of body weight to 2 mg/kg of body weight per day. Furthermore, the inhibitor according to the invention can be provided to the patient over any suitable period of time in one or more dosages per day, preferably said inhibitor is administered over a period of between 4 weeks to 12 months to the patient.
  • the patient preferably can be a mammalian patient, such as, for example, a human patient, of any age for protection against noise-induced hearing loss, and more preferably a patient having an age of more than 50 years, or 55 years for preventing presbyacusis.
  • the invention also includes younger patients with an increased risk of noise exposure, such as, for example, soldiers, musicians or hunters.
  • Another aspect of the present invention relates to a method for treating hearing loss, preferably age-related hearing loss (presbycusis), comprising administering to a patient in need thereof a therapeutically effective amount of an inhibitor of an ATP-sensitive potassium channel as described herein.
  • Yet another aspect of the present invention relates to a method for reducing the frequency, occurrence, and/or severity of hearing loss, preferably age-related hearing loss (presbycusis) and/or noise-induced hearing loss (NIHL), comprising administering to a patient in need thereof a therapeutically effective amount of an inhibitor of an ATP-sensitive potassium channel as described herein.
  • a method for reducing the frequency, occurrence, and/or severity of hearing loss preferably age-related hearing loss (presbycusis) and/or noise-induced hearing loss (NIHL)
  • NIHL noise-induced hearing loss
  • glibenclamide significantly reduces the progression of both, age-related hearing loss in a mouse model of presbyacusis as well as hearing loss a mouse model of noise- trauma (NIHL) .
  • NIHL noise- trauma
  • the inventors expect an even larger efficiency combined with smaller systemic side effects by local glibenclamide treatment of the inner ear, for example, by the use of established intratympanic drug delivery systems (see also above).
  • Figure 5 shows the time course of mean ABR thresholds of Kir6.2 knockout mice from 4 weeks up to 52 weeks of age (left panel) and wildtype mice (right panel) from 4 weeks up to 96 weeks of age.
  • Figure 6 shows the mean ABR-thresholds of 13 C57BL/6 mice treated with Placebo pellets (dashed line) and 13 C57BL/6 mice treated with glibenclamide pellets (continuous line) before treatment on day one (P0).
  • Figure 7 shows the mean ABR-thresholds of 12 C57BL/6 mice treated with Placebo pellets (dashed line) and 10 C57BL/6 mice treated with glibenclamide pellets (continuous line) 13 weeks after pellet implantation (P13W).
  • Figure 8 shows the mean ABR-thresholds of 13 C57BL/6 mice treated with Placebo pellets (dashed line) and 13 C57BL/6 mice treated with glibenclamide pellets (continuous line) 26 weeks after pellet implantation (P26W).
  • Figure 9 shows the time course of mean ABR thresholds of the glibenclamide treated mice (left panel) and the placebo group (right panel) from experimental day one (P0) up to 26 weeks after pellet implantation (P26W).
  • Figure 10 shows in A: Mean ABR-thresholds at the age of 10 weeks (BlOW), two weeks after low dose pellet implantation (27.8 ⁇ g/day), of 5 C57BL/6 mice treated with controls pellets (dashed line) and 10 C57BL/6 mice treated with glibenclamide pellets (continuous line).
  • B Mean ABR-thresholds of the same groups of animals 14 days after noise exposure. The two audiograms show the permanent sound induced threshold shift (PTS).
  • Figure 11 shows in A: Mean ABR-thresholds at the age of 10 weeks (BlOW), two weeks after high dose pellet implantation (277.8 ⁇ g/day), of 10 C57BL/6 mice treated with control pellets (dashed line) and 10 C57BL/6 mice treated with glibenclamide pellets (continuous line).
  • B Mean ABR-thresholds of the same groups of animals 14 days after noise exposure. The two audiograms show the permanent sound induced threshold shift (PTS).
  • Example 1 K-ATP channel knockout mice are protected against presbyacusis
  • Kir6.2 knockout mice showed a statistically significant slowing and reduction of the age-dependent high-frequency hearing loss by about 50 dB at one year of age.
  • ABR thresholds of Kir6.2 KO mice and C57BL/6 mice were similar.
  • Kir6.2 KO mice showed significantly lower thresholds (Fig. 1).
  • age-related hearing loss proceeds from high to low frequencies. In the wildtype mice, it has reached 16 kHz at 12 week of age (Fig. 2). However, a moderate hearing loss also occurs at the lower frequencies (2.8 and 4 kHz). In contrast, there was no significant hearing loss at any frequency in the Kir6.2 KO mice:
  • Kir6.2 knockout mice showed a significant slowing of age- dependent hearing loss and reduction of the age-dependent high-frequency hearing loss by about 50 dB at one year of age (Fig. 5).
  • the inventors verified by histological analysis that presbyacusis was associated with hair cell loss.
  • Global genetic inactivation of K- ATP channels containing the Kir6.2 subunit significantly reduces the progression and severity of age-related hearing loss in a mouse model of presbyacusis.
  • Kir6.2-mediated K-ATP channels in cochlear hair cells
  • the data show that Kir6.2-containing K-ATP channels in hair cells might control the vulnerability for age-related hearing loss.
  • Kir6.2 knockout model more indirect and systemic effects cannot be excluded.
  • the main systemic effect in the Kir6.2 KO mouse is a diabetic metabolic state with reduced glucose tolerance, which is expected to accelerate presbyacusis.
  • our aging study establishes K-ATP channels as novel and promising drug targets to treat age-related hearing loss.
  • Example 2 Pharmacological inhibition of ATP-sensitive potassium channels reduces age- related hearing loss in a mouse model of presbyacusis
  • Wild-type C57BL/6 mice (8 week old males, obtained from Charles River WIGA GmbH, Germany) were implanted with subcutaneous pellets, releasing glibenclamide (glyburide) at a concentration of 27.8 ⁇ g per day over a period of up to 7 months.
  • An age matched control group was implanted with placebo pellets (pellets without glibenclamide).
  • Pellets were obtained from Innovative Research of America (Sarasota, FL).
  • the occurrence and progression rates of age- related hearing loss were monitored by recording auditory brainstem response (ABR) thresholds. All data are plotted as mean ⁇ SEM. Fishers F-test and Student's t-test were used to assess statistical differences of mean ABR thresholds at a significance level of 0.05 (*) or 0.01 (**).
  • mice treated with glibenclamide showed less age-related hearing loss compared to the placebo group.
  • the lower ABR thresholds in the glibencla- mide-treated group compared to the placebo-treated group, especially at the higher frequencies (p ⁇ 0.05).
  • the threshold of the glibenclamide-treated group was about 15 dB below that of the placebo-treated control group (Fig. 7).
  • glibenclamide significantly reduces the progression of age-related hearing loss in a mouse model of presbyacusis.
  • the inventors' results indicate that glibenclamide, a licensed drug in human therapy of diabetes mellitus, promises to have a therapeutic potential against age-related hearing loss also in humans.
  • the inventors expect an even larger efficiency combined with smaller systemic side effects by local glibenclamide treatment of the inner ear, for example by the use of already established intratympanic drug delivery systems or the ones as described above.
  • Example 3 Protective effect of the ⁇ -blocker glibenclamide on sound trauma in C57B1/6 mice
  • mice were implanted with pellets comprising the KATP-channel blocker glibenclamide at a concentration of either 27.8 ⁇ g/day or 277.8 ⁇ g/day.
  • ABR auditory brainstem response
  • mice were implanted with pellets comprising the KATP-channel blocker glibenclamide at a concentration of either 27.8 ⁇ g/day or 277.8 ⁇ g/day.
  • placebo pellets were obtained from Innovative Research of America (Sarasota, FL).
  • PTS permanent sound induced threshold shift
  • glibenclamide in contrast to the lower dosage the concentration of 277.8 ⁇ g glibenclamide per day showed a statistically significant protective effect two weeks after sound overexposure (Fig 1 IB).
  • the systemic application of the high dose of glibenclamide reduces permanent threshold shift after noise exposure in C57B1/6.
  • the glibenclamide treated animals show significantly better thresholds than the control group (p ⁇ 0.05).

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Abstract

La présente invention concerne l'utilisation d'inhibiteurs de canaux potassiques ATP-dépendants pour la thérapie protectrice (notamment préventive) ou la progression amoindrie de la perte d'audition, en particulier la perte d'audition liée à l'âge (presbyacousie) et/ou la perte d'audition induite par le bruit (NIHL). Est préférée l'administration systémique ou locale de sulfonylurées cliniquement établies, telles que, par exemple, le glibenclamide.
PCT/EP2012/050683 2011-01-18 2012-01-18 Utilisation d'inhibiteurs de canaux potassiques atp-dépendants pour le traitement de la perte d'audition Ceased WO2012098143A1 (fr)

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GB1100783.8 2011-01-18

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US10183972B2 (en) 2016-07-14 2019-01-22 University Of South Florida BK channel-modulating peptides and their use

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US20050129783A1 (en) 2001-04-19 2005-06-16 Mccleary Edward L. Composition and method for treatment of neurophysiological conditions and maintenance of neurophysiological health
US20070248690A1 (en) 2006-04-24 2007-10-25 Trager Seymour F Composition and methods for alleviating symptoms of neurotoxicity
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WO2005025293A2 (fr) 2003-09-10 2005-03-24 Icagen, Inc. Anneaux condenses heterocycliques modulateurs des canaux de potassium
US20070248690A1 (en) 2006-04-24 2007-10-25 Trager Seymour F Composition and methods for alleviating symptoms of neurotoxicity
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10183972B2 (en) 2016-07-14 2019-01-22 University Of South Florida BK channel-modulating peptides and their use
US11214595B2 (en) 2016-07-14 2022-01-04 University Of South Florida BK channel-modulating peptides and their use

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