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WO1998010757A2 - Utilisation d'antagonistes fonctionnels du n-methyl-d-aspartate pour reduire ou prevenir l'ototoxicite induite par l'aminoglucoside - Google Patents

Utilisation d'antagonistes fonctionnels du n-methyl-d-aspartate pour reduire ou prevenir l'ototoxicite induite par l'aminoglucoside Download PDF

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WO1998010757A2
WO1998010757A2 PCT/US1997/016605 US9716605W WO9810757A2 WO 1998010757 A2 WO1998010757 A2 WO 1998010757A2 US 9716605 W US9716605 W US 9716605W WO 9810757 A2 WO9810757 A2 WO 9810757A2
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aminoglycoside
functional
antibiotic
nmda
antagonist
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WO1998010757A9 (fr
WO1998010757A3 (fr
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Anthony S. Basile
Phil Skolnick
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US Department of Health and Human Services
Government of the United States of America
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US Department of Health and Human Services
Government of the United States of America
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Priority to AU44246/97A priority Critical patent/AU4424697A/en
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Publication of WO1998010757A3 publication Critical patent/WO1998010757A3/fr
Publication of WO1998010757A9 publication Critical patent/WO1998010757A9/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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

Definitions

  • the present invention relates to the use of a class of compounds to ameliorate and prevent aminoglycoside-induced ototoxicity. These compounds fall within the group of substances which reduce activity at N- methyl -D-aspartate (NMDA) receptors and are referred to as functional NMDA antagonists.
  • NMDA N- methyl -D-aspartate
  • Aminoglycoside antibiotics are polycations consisting of amino sugars connected to an aminocyclitol nucleus, and are derived from the fungi Streptomyces and Micromonospora (1,2). Aminoglycoside antibiotics potently inhibit protein synthesis at the ribosomal level and compromise membrane integrity in a range of Gram-negative and some Gram-positive bacteria. These agents are clinically valued for their rapid onset of bacteriocidal activity, synergism with ⁇ -lactam antibiotics and low cost. They are commonly used to treat Gram-negative sepsis, endocarditis, nosocomial infections and tuberculosis .
  • NMDA receptor mRNA in the synapses between cochlear hair cells and spiral ganglion neurons (9, 10), and of the enhancement of radioligand binding to the NMDA receptor by aminoglycosides in a polyamine-like fashion (11) . It is also known that there are a number of isoforms of NMDA receptors, some of which are not responsive to polyamines. The reports on NMDA receptor RNA did not discriminate among receptor isoforms, and, therefore, whether the isoforms in the tissues tested were sensitive or insensitive to polyamines.
  • One object of the invention relates to the prevention and/or amelioration of aminoglycoside induced ototoxicity by use of NMDA antagonists.
  • Another object of the invention relates to the use of functional NMDA antagonists to provide substantial protection against aminoglycoside- induced ototoxicity in a patient .
  • a further object of the invention relates to the use of NMDA antagonists as a pharmaceutical composition in the prevention or amelioration of aminoglycoside induced ototoxicity.
  • Yet another object of the invention is to provide an improved method of antibiotic treatment to prevent aminoglycoside-induced ototoxicity comprising the step of administering a therapeutically effective amount of a NMDA antagonist in combination with an aminoglycoside antibiotic .
  • An additional object of the invention relates to a bacteriocidal antibiotic composition comprising a therapeutically effective amount of an aminoglycoside and functional NMDA antagonists to control ototoxicity.
  • the aminoglycoside antibiotics are bacteriocidal agents whose clinical utility is limited by their ototoxicity. This ototoxicity can result in significant 5 hearing loss and/or a loss of balance.
  • NMDA receptors were identified at the cochlear hair cell-spiral ganglion neuron synapse. Further, a recent in vi tro study demonstrated the ability of aminoglycosides to modulate NMDA receptor function via the polyamine site.
  • the 0 present invention relates to the discovery that enhancement of glutamatergic neurotransmission at the hair cell synapse by aminoglycosides results in necrosis of either the hair cells and/or spiral ganglion neurons through excitotoxic mechanisms (12) which could be amenable to intervention with functional NMDA antagonists.
  • the present invention relates to the identification of functional NMDA antagonists, which are capable of ameliorating or preventing aminoglycoside- induced hearing loss or loss of balance .
  • These n antagonists act at a variety of sites on NMDA receptors including, but not limited to, the polyamine binding site, the ion channel, the glycine binding site and the glutamate binding site.
  • the effect of these functional NMDA antagonists is to reduce the activity of NMDA , receptors.
  • Preferred compounds of the present invention comprise quinoline and non-quinoline functional NMDA antagonists. The more preferred compounds are non- quinolines .
  • the compounds of the present invention are useful as a pharmaceutical composition either alone in the 5 amelioration or prevention of aminoglycoside-induced ototoxicity, (as in the treatment of patients receiving aminoglycosides) , or in combination with an aminoglycoside in order to prevent ototoxicity and simultaneously provide bacteriocidal activity.
  • the present invention is useful as a pharmaceutical composition either alone in the 5 amelioration or prevention of aminoglycoside-induced ototoxicity, (as in the treatment of patients receiving aminoglycosides) , or in combination with an aminoglycoside in order to prevent ototoxicity and simultaneously provide bacteriocidal activity.
  • 15 induced ototoxicity are also provided. These methods include an improved method of aminoglycoside antibiotic treatment which prevents aminoglycoside-induced ototoxicity.
  • FIG. 1 Schematic diagram of the NMDA receptor complex.
  • the NMDA receptor complex is composed
  • modulatory r j ⁇ sites including recognition sites for: glutamate; glycine; multiple polyamine associated sites (one within the ion channel) ; and the dizocilpine (or MK-801) binding site within the ion channel.
  • NMDA antagonists limit neomycin- induced decrements in the Preyer reflex response to 5 (Panel A), 7 (Panel B) , and 10 (Panel C) kHz tones.
  • Preyer reflex is a measure of hearing threshold well known in the art (17, 18) .
  • Two groups of guinea pigs received daily subcutaneous injections of either saline (•) or neomycin (O) for 14 days.
  • Two other groups of guinea pigs received subcutaneous injections of neomycin together with either dizocilpine (1 mg/kg/d, ⁇ ) or ifenprodil (10 mg/kg/d, A) delivered by subcutaneous osmotic minipumps .
  • the Preyer reflex was examined in these animals 2 weeks after completing the antibiotic regimen.
  • the "noise floor” is a sound level below ° that which can be detected by the measuring device at a particular frequency.
  • FIG. 4 A summary of the changes in inner (A) and outer (B) hair cell populations of cochleae from individual guinea pigs treated with neomycin ( ⁇ ) , neomycin + dizocilpine (•) , or neomycin + ifenprodil (A) in serial sections cut through the organ of Corti. Results are expressed as the percentage of cells missing compared to normal guinea pig cochleae. Note the total loss of both inner and outer hair cells between 13 to 18 mm from the apex of the cochlea in the neomycin treated guinea pig. Treatment of guinea pigs with either dizocilpine or ifenprodil resulted in complete protection against hair cell loss between 13 to 17 mm from the apex.
  • Figure 5 Effect of aminoglycosides on [ 3 H] dizocilpine binding to NMDA receptors: relationship to ototoxicity.
  • streptomycin O
  • amikacin ⁇
  • spectinomycin spectinomycin
  • the NMDA receptor is one of the major subtypes of fast excitatory neurotransmitter receptors in the mammalian central nervous system. These receptors are activated by the acidic amino acids glutamate and aspartate.
  • the NMDA receptor/ion channel complex contains an integral ion channel that gates Na + , K + and Ca 2+ ions and is blocked in a voltage dependent manner by Mg 2 * . Excessive or abnormally prolonged stimulation of
  • NMDA receptors leads to neuronal degeneration. Due to the structural arrangement of the NMDA receptor/channel, it is regulated at multiple sites. See Figure 1 .
  • activity can be blocked by competitive antagonists, that is, molecules that interact at the same site as glutamate or aspartate but which do not activate the receptor.
  • activity can be modulated by agents which block the ion channel, referred to as ion channel blockers .
  • ion channel blockers agents which block the ion channel
  • a number of other regulatory sites have been identified from which neurotransmitter activity can be modulated, including a receptor for glycine and two polyamine associated receptor sites, one of which lies within the ion channel.
  • the present invention relates to the use of a specific group of compounds in the prevention and/or treatment of aminoglycoside-induced ototoxicity. These compounds are generally classified as functional NMDA antagonists since they reduce activity at NMDA receptors .
  • Optytoxicity includes cochleotoxicity which results in hearing loss, and vestibulotoxicity, which results in loss of balance. Although many of the examples are directed to cochlear toxicity, one skilled in the art will clearly recognize that the present invention encompasses treatment and prevention of aminoglycoside-induced ototoxicity in the form of vestibulotoxicity.
  • the functional NMDA antagonists of the present invention comprise compounds capable of acting on a number of different sites on the receptor ( Figure 1) .
  • the antagonists of the present invention may act at a regulatory site known as the glycine binding site: examples include 7-chlorokynurenic acid, indole-2- carboxylic acid, L-687414, HA-966 and 1-aminocylopropane carboxylic acid (see Figure 5) .
  • the compounds may act at the glutamate binding site: examples include 2- (2-carboxypiperazin-4-yl)propyl-l-phosphonic acid (“CPP") .
  • the functional NMDA antagonists of the present invention may act at a polyamine associated binding site: examples include diethylenetriamine, ifenprodil, eliprodil, conantokin-G and arcaine .
  • these compounds may act as ion channel blockers of the NMDA receptor: examples include 1- [1- (2- thienyDcyclohexyl] -piperidine (“TCP”), (+ ) 5-methyl-10, 11- dihydro-5H-dibenzo [a, d] cyclohepten-5 , 10-imine maleate ("MK-801" or "Dizocilpine”), phencyclidine (“PCP”), ketamine and memantine.
  • TCP 1- [1- (2- thienyDcyclohexyl] -piperidine
  • MK-801 or "Dizocilpine”
  • PCP phencyclidine
  • ketamine ketamine and memantine.
  • a particularly preferred group of functional NMDA antagonists comprises non-quinoline compounds, including but not limited to dizocilpine and ifenprodil.
  • the comparable efficacies of these antagonists which act at discrete sites on the NMDA receptor, indicates that aminoglycoside antibiotics damage vulnerable cochlear neurons through an excitotoxic process requiring NMDA receptor activation. Both their specificity and the modest dose range (approximately 1-20 mg/kg/day) required to limit aminoglycoside-induced hearing loss make these compounds ideal in its prevention and/or amelioration.
  • Ototoxicity limits the clinical usefulness of aminoglycoside antibiotics.
  • the present invention indicates that concurrent administration of functional NMDA antagonists in humans can attenuate aminoglycoside- 0 induced ototoxic damage.
  • many functional NMDA antagonists are highly charged and have limited access to the central nervous system. Since access to the cochlea is not limited by the blood brain barrier, such agents may limit aminoglycoside-induced damage to cochlear neurons 5 and be devoid of any behavioral side effects.
  • the schedule by which functional NMDA antagonists can be administered to prevent or ameliorate aminoglycoside-induced ototoxicity in humans will vary somewhat according to the circumstances and is within the Q skill of the health care provider to determine. In many circumstances, it will be desirable to administer the functional NMDA antagonists concurrently with the aminoglycoside antibiotic. If the patient has already commenced aminoglycoside therapy, functional NMDA c antagonists can be administered to ameliorate the ototoxicity which might otherwise occur. If aminoglycoside administration is contemplated, treatment with one or more functional NMDA antagonists can be commenced before the administration of the aminoglycoside, and continued during administration of the aminoglycoside.
  • aminoglycosides were used to irrigate the peritoneal cavity during abdominal surgery.
  • the present invention may permit restoration of this practice, which was discontinued largely due to ototoxicity.
  • Efficacious amounts of a functional NMDA antagonist to be used in the method of the instant invention may be varied over a wide range.
  • the typical range of the amount of a functional NMDA antagonist ° compound is between about 0.5 mg/day and 800 mg/day.
  • the efficacious amount and concentration of the compound to be administered are those which result in the composition exhibiting a reduction or prevention of aminoglycoside-induced ototoxicity.
  • Our 5 results suggest that the amount of functional NMDA antagonists that provide substantial protection against hypoxic/ischemic insults (e.g., in models of rodent middle cerebral artery occlusion) also are sufficient to prevent aminoglycoside-induced ototoxicity. Physicians and other
  • Carrier materials for the pharmaceutical preparations of the present invention are well known in the pharmaceutical formulations art and include those carriers referred to as diluents or vehicles.
  • the pharmaceutical compounds of the present invention can be administered orally, topically (for example, in the form of patches) , or parenterally, in a vehicle comprising one or more pharmaceutically acceptable carriers, the proportion of which is determined by the Q solubility and chemical nature of the compounds, the chosen route of administration and standard biological practice.
  • the compounds can be formulated in unit dosage forms such as capsules or tablets each containing a predetermined amount of active
  • ingredient ranging from about 0.5 mg to 800 mg, in a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention can take the form of a lyophilized powder of the active substance, to be dissolved immediately before use in a physiological solution for the purpose of injection.
  • parenteral administration the compound is administered by either intravenous, subcutaneous or intramuscular injection, in compositions with pharmaceutically acceptable vehicles or carriers.
  • a sterile aqueous vehicle which may also contain other solutes such as buffers or preservatives as well as sufficient quantities of pharmaceutically acceptable salts or of glucose to make the solution isotonic.
  • the pharmaceutical composition according to the invention can also take a form which is suitable for oral administration.
  • suitable forms are tablets, food gelatin capsules, dragees, powders and granules.
  • the formulation of such oral forms is well- known to those skilled in the art. Any of the known formulations are useful in preparing the instant oral pharmaceutical compositions.
  • Suitable vehicles or carriers for the above noted formulations can be found in standard pharmaceutical texts, e.g. in "Remington's Pharmaceutical Sciences", 16th ed. Mack Publishing Company, Easton, Pa., 1980.
  • the present invention also relates to a kit for screening aminoglycosides for potential ototoxicity.
  • a kit for screening aminoglycosides for potential ototoxicity.
  • One embodiment of such a kit comprises the following components: a source of NMDA receptor; a labeled ligand that binds to sites inside the NMDA receptor coupled ion channel, such as dizocilpine or phencyclidine; a nonspecific binding molecule to estimate background binding levels; and a positive control.
  • Many sources of NMDA receptor are known in the art.
  • rat brain provides a rich source of NMDA receptors. It may be preferred to provide the NMDA receptor in a lyophilized form or in solution depending upon the format of the kit . Lyophilization may increase the shelf-life of the kit component.
  • Labeled ligands may comprise any of the known and routinely used labels.
  • commonly used labels include radioisotopes , biotin, fluorescent and chemiluminescent compounds, and luciferase.
  • Other labels known to the skilled artisan are also encompassed herein.
  • Molecules to be used for determining non-specific binding comprise unlabelled compounds such as phencyclidine, dizocilpine, ketamine and memantine.
  • dizocilpine and phencyclidine are preferred molecules for determining the non-specific binding.
  • Positive control molecules may include compounds that enhance the binding of labeled ligands and act at polyamine sites. Preferred examples are spermine and streptomycin.
  • the third group consisted of guinea pigs receiving either dizocilpine maleate or ifenprodil tartrate (Research Biochemicals,
  • Minipumps delivering 1 mg/kg of dizocilpine maleate per day in 40% DMSO/60% Milli-Q filtered water or 10 mg/kg ifenprodil tartrate per day in 40% DMSO/20% Emulphor/40% Milli-Q filtered water for 14 days were implanted subcutaneously under pentobarbital (25 mg/kg) and chloral hydrate (130 mg/kg) anesthesia.
  • the fourth group consisted of guinea pigs receiving combinations of aminoglycosides and functional NMDA antagonists concurrently.
  • the Preyer reflex consists of a flick or twitch of the pinnae (outer ear) in response to a tone of known frequency and intensity (17) .
  • Guinea pigs were evaluated beginning 4 weeks after the initiation of drug regimens. Animals were immobilized in mesh restraining cages and placed inside a sound attenuated chamber (18x12x12 in) facing a 3 in diameter speaker located 4 in from the subject. The speaker was connected to a signal generator with variable signal attenuator, a variable frequency narrow bandpass 10 dB/octave Butterworth filter, a pulse timing unit, and a 10 watt audio amplifier. The sound intensity of the speaker output at 4 in.
  • the stimulus tones consisted of a 300 msec long square-wave pulse (at 5,7, or 10 kHz) given once per second for five seconds.
  • the number of ear flicks per stimulus train of 5 tones was recorded as the "percent response" (e.g. 3 ear flicks per train of 5 stimuli is a 60% response) .
  • the tone stimulus train was then repeated at a higher sound intensity until either the maximum response rate (100%) was achieved or the maximum sound output at that frequency attained.
  • Sigmoidal curves were fitted to the data via non-linear regression techniques for determination of the ER 50 and E-- ⁇ values .
  • Guinea pigs respond to intense 5-10 kHz tones with a pinna flick referred to as the Preyer Reflex (13) .
  • the presence of a Preyer reflex is dependent upon the sound pressure level (SPL) and the audibility magnitude to the animal.
  • SPL sound pressure level
  • 87 ⁇ 1.1, 72 ⁇ 0.9 and 75 ⁇ 0.9 dB are required to effect a 50% response rate (ER 50 ) to trains of 5, 7 and 10 kHz tones, respectively (Tables 1, la, Figure 2), while a 100% response rate is obtained with 5-10 kHz tones of -100 dB SPL ( Figure 2) .
  • ER 50 values in response to 5 kHz tones were not significantly different (99 to 109% of control) from saline-treated animals when these antibiotics were administered together with either NMDA antagonist (Tables 1, la, Figure 2) .
  • Small (14-35%) increases in ER ⁇ values in response to 7 and 10 kHz tones were observed in animals treated with combinations of these antibiotics and NMDA antagonists.
  • concurrent administration of NMDA antagonists restored the maximum response rates in antibiotic-treated animals to values approaching 100% (Tables 1, la, Figure 2) .
  • Neomycin > 120** > 120** > 120**
  • Example 1 Male, albino Hartley guinea pigs (250-300 g, Charles Rivers, Raleigh, NC) were maintained under similar conditions, and received the same drug treatments as described in Example 1.
  • DPOE distortion product otoacoustic emissions
  • guinea pigs were anesthetized (ketamine 40 mg/kg and xylazine 4 mg/kg) and a CUBDISPTM system (consisting of microphones and high fidelity earphones (Etymotic Research, Oak Grove Village, IL) placed in each ear.
  • Pairs of continuous tones (65 and 50 dB SPL for fl and f2, respectively) ranging from 1-16 kHz were presented in descending sequences.
  • the 2fl-f2 DPOE together with associated background noise were recorded by the CUBDISPTM system and plotted as a function of stimulus frequency.
  • the DPOE recorded from saline-treated guinea pigs were characteristic of intact cochleae (24) ( Figure 3) .
  • Concurrent administration of NMDA antagonists increased DPOE amplitudes well above the noise floor ( Figure 3) to values approaching those obtained in control subjects.
  • NMDA Receptor antagonists attenuate aminoglycoside-induced hearing loss: Effects on DPOE amplitude.
  • Neomycin 16 0 0 16**
  • DPOE Distortion product otoacoustic emissions
  • mice Male, albino Hartley guinea pigs (250-300 g, Charles River, Raleigh, NC) were maintained under similar conditions, and received the same drug treatments as described in Example 1. 5 After DPOE measurements, some guinea pigs were euthanized with an overdose of chloral hydrate anesthesia. Guinea pigs treated with saline, neomycin, neomycin + dizocilpine, and neomycin + ifenprodil (2 animals/group) were then transcardially perfused with Tyrode's solution
  • mice Male, Sprague-Dawley rats (200-300 g, Taconic Farms, Germantown, NY) provided the brain tissue used for the radioligand binding assays. These animals were maintained under similar conditions as described in Example 1 for guinea pigs, but in separate facilities.
  • Rat cerebral cortex was homogenized in preparation buffers (15,16) with a Polytron (Brinkmann Instruments, Westbury, New York) and extensively "washed” (resuspended and recentrifuged) to remove endogenous materials (e.g. glycine, glutamate, polyamines) that affect radioligand binding to NMDA receptors. Extensively washed membranes were suspended in 5-10 volumes (original wet weight) of 5 mM HEPES/4.5 mM Tris (HTS) buffer (pH 7.4) at stored at -70°.
  • preparation buffers 15,16
  • Polytron Warner Instruments, Westbury, New York
  • endogenous materials e.g. glycine, glutamate, polyamines
  • Extensively washed membranes were suspended in 5-10 volumes (original wet weight) of 5 mM HEPES/4.5 mM Tris (HTS) buffer (pH 7.4) at stored at -70°.
  • Incubations were conducted at room temperature and terminated after 2 hours by rapid filtration over Schleicher and Schuell #32 filters (Keene, NH) pretreated with 0.03% polyethylenimine . Filters were rapidly washed with 2 x 2.5 ml of ice cold HTS.
  • Duplicate tubes contained: 50 ⁇ l of aminoglycoside (0.1 - 1000 ⁇ M) , 50 ⁇ l membrane suspension, 50 ⁇ l (+) -pentazocine (10 ⁇ M, to block ⁇ sites), 50 ⁇ l of [ 3 H] ifenprodil (5 nM) and HTS buffer to a final volume of 500 ⁇ l .
  • Non-specific binding was determined using 10 ⁇ M ifenprodil.
  • the assay was incubated at 4°C for 2 hours and terminated by rapid filtration over S+S #32 filters pretreated with 0.03% polyethylenimine. Filters were washed with 2 x 2.5 ml of ice-cold HTS. All binding data were analyzed by nonlinear regression.
  • Endogenous polyamines such as sper ine initially enhance, and at higher concentrations inhibit [ 3 H] dizocilpine binding (29, 30) .
  • Endogenous polyamines such as sper ine initially enhance, and at higher concentrations inhibit [ 3 H] dizocilpine binding (29, 30) .
  • Aminoglycoside antibiotics also inhibit [ 3 H] ifenprodil binding to polyamine-associated sites (15,31) on NMDA receptors with potencies similar to those required to enhance [ 3 H] dizocilpine binding (Table 3a) .
  • Table 3 Aminoglycoside Modulation of [ 3 H]Dizocilpine Binding to NMDA receptors.
  • EC S0 values are the aminoglycoside concentrations that increase [ 3 H] dizocilpine (3.5 nM) binding to rat forebrain homogenates by 50% of maximum.
  • E- na - is the maximal enhancement of [ 3 H] dizocilpine binding expressed as the % increase above basal (non-stimulated) values.
  • IC 50 values are presented for those aminoglycosides exhibiting a biphasic effect on [ 3 H] dizocilpine binding.
  • NMDA antagonists are tested in humans being treated with the aminoglycosides neomycin, genta ycin and kanamycin.
  • Patients are treated with 1-3 mg/kg gentamycin 3 times daily for the duration of an infection; 500-2000 mg neomycin 4 times daily for a period of 4 days; or 5-7.5 mg/kg amikacin every 8-12 hr. for the duration of the infection.
  • the functional NMDA antagonists used in combination with these aminoglycosides include at least one of ifenprodil, memantine or dizocilpine.
  • EXAMPLE 6 The functional NMDA antagonists, dizocilpine and ifenprodil are administered to patients at dosages of 0.1 mg/kg/day and 2 mg/kg/day respectively prior to beginning aminoglycoside treatment. The bacterial infection is cured and the subject suffers no ototoxic damage.
  • Neomycin is an agonist at a polyamine site on the N-methyl-D-asparate receptor. J.
  • N-methyl-D-aspartate receptor pharmacological evidence for the existence of a polyamine recognition site. Mol . P ⁇ arm. 36, 575-581, (1989) .

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Abstract

La présente invention concerne des antagonistes fonctionnels du NMDA et leur capacité à réduire l'ototoxicité provoquée par l'aminoglucoside. Ces compositions sont utiles dans le traitement ou la prévention d'une perte d'audition et/ou d'une perte d'équilibre. Une composition pharmaceutique comprenant un aminoglucoside et au moins un antagoniste fonctionnel des récepteurs de NMDA administré simultanément assurent une activité bactéricide et une protection contre l'ototoxicité induite par l'aminoglucoside.
PCT/US1997/016605 1996-09-11 1997-09-11 Utilisation d'antagonistes fonctionnels du n-methyl-d-aspartate pour reduire ou prevenir l'ototoxicite induite par l'aminoglucoside Ceased WO1998010757A2 (fr)

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WO2009033650A1 (fr) * 2007-09-12 2009-03-19 Merz Pharma Gmbh & Co.Kgaa Dérivés de 1-amino-alkylcyclohexane pour le traitement et la prévention d'une déficience auditive
WO2008113364A3 (fr) * 2007-03-20 2009-04-16 Recepticon Aps Prévention de la néphrotoxicité iii
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WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
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US8268866B2 (en) 2004-03-29 2012-09-18 Matthieu Guitton Methods for the treatment of tinnitus induced by cochlear excitotoxicity
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
US8507525B2 (en) 2004-03-29 2013-08-13 Auris Medical Ag Methods for the treatment of tinnitus induced by cochlear excitotoxicity
WO2013178763A1 (fr) * 2012-05-30 2013-12-05 Sensorion Procédés pour traiter une vestibulotoxicité
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
US9072662B2 (en) 2004-03-29 2015-07-07 Auris Medical Ag Methods for the treatment of tinnitus induced by cochlear excitotoxicity
CN104840416A (zh) * 2005-09-28 2015-08-19 奥里斯医学股份有限公司 治疗内耳疾病的药用组合物
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase
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EP1201234A3 (fr) * 2000-09-21 2003-03-12 Tinnitus Forschungs- und Entwicklungs GmbH Traitement de maladies avec des dérivés adamantanes
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US8268866B2 (en) 2004-03-29 2012-09-18 Matthieu Guitton Methods for the treatment of tinnitus induced by cochlear excitotoxicity
EA017264B1 (ru) * 2005-09-28 2012-11-30 Аурис Медикаль Аг Применение композиции арилциклоалкиламида для получения лекарственного препарата для лечения нарушения внутреннего уха
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WO2007038949A1 (fr) 2005-09-28 2007-04-12 Auris Medical Ag Compositions pharmaceutiques pour le traitement de pathologies de l’oreille interne
US9066865B2 (en) 2005-09-28 2015-06-30 Auris Medical Ag Pharmaceutical compositions for the treatment of inner ear disorders
EP2792347A1 (fr) * 2005-09-28 2014-10-22 Auris Medical AG Compositions pharmaceutiques pour le traitement de troubles de l'oreille interne
WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
EP2481408A2 (fr) 2007-03-01 2012-08-01 Probiodrug AG Nouvelle utilisation d'inhibiteurs glutaminyle cyclase
WO2008104580A1 (fr) 2007-03-01 2008-09-04 Probiodrug Ag Nouvelle utilisation d'inhibiteurs de la glutaminyl cyclase
WO2008113364A3 (fr) * 2007-03-20 2009-04-16 Recepticon Aps Prévention de la néphrotoxicité iii
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
WO2009033650A1 (fr) * 2007-09-12 2009-03-19 Merz Pharma Gmbh & Co.Kgaa Dérivés de 1-amino-alkylcyclohexane pour le traitement et la prévention d'une déficience auditive
US8877814B2 (en) 2007-09-12 2014-11-04 Merz Pharma Gmbh & Co. Kgaa Titration package for neramexane and its use in the treatment of an inner ear disorder
US9498450B2 (en) 2007-09-12 2016-11-22 Merz Pharma Gmbh & Co. Kgaa 1-aminocyclohexane derivatives for the treatment of cochlear tinnitus
US9468610B2 (en) 2007-09-12 2016-10-18 Merz Pharma Gmbh & Co. Kgaa 1-aminocyclohexane derivatives for the treatment of hearing loss
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
US10709682B2 (en) 2011-12-12 2020-07-14 Otolanum Ag Treatment of tinnitus through modulation of chloride co-transporter NKCC1 in the auditory system
WO2013178763A1 (fr) * 2012-05-30 2013-12-05 Sensorion Procédés pour traiter une vestibulotoxicité
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

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