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WO1998050065A2 - Utilisation de principes actifs a effet biologique pour influer sur l'espace extracellulaire de cellules sensorielles et procede de commande d'administration de principe actif et dispositif approprie - Google Patents

Utilisation de principes actifs a effet biologique pour influer sur l'espace extracellulaire de cellules sensorielles et procede de commande d'administration de principe actif et dispositif approprie Download PDF

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Publication number
WO1998050065A2
WO1998050065A2 PCT/EP1998/001951 EP9801951W WO9850065A2 WO 1998050065 A2 WO1998050065 A2 WO 1998050065A2 EP 9801951 W EP9801951 W EP 9801951W WO 9850065 A2 WO9850065 A2 WO 9850065A2
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cells
sensory
calcium
use according
degeneration
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PCT/EP1998/001951
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German (de)
English (en)
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WO1998050065A3 (fr
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Marion Sangster Eckmiller
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Marion Sangster Eckmiller
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Priority to AU76417/98A priority Critical patent/AU7641798A/en
Priority to EP98924097A priority patent/EP0980256A2/fr
Priority to CA002288631A priority patent/CA2288631A1/fr
Publication of WO1998050065A2 publication Critical patent/WO1998050065A2/fr
Publication of WO1998050065A3 publication Critical patent/WO1998050065A3/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5082—Supracellular entities, e.g. tissue, organisms
    • G01N33/5088—Supracellular entities, e.g. tissue, organisms of vertebrates

Definitions

  • the invention relates to a use of at least one biologically active agent for influencing the extracellular space in the vicinity of the sensory cells of mammals, especially of humans with acquired or hereditary Dege ⁇ neration of the sensory cells and / or adjacent Epithelzel ⁇ len, glial cells and / or supporting cells, for the treatment of the intracellular milieu of the sensory cells, ' neighboring epithelial cells, of glial cells and / or supporting cells according to the preamble of claims 1 and 2 and a method for controlling the distribution of the active ingredients to be administered according to the preamble of the method claim.
  • a number of pathological conditions are known in which the normal visual, auditory and / or vestibular functions in humans and mammals are permanently disturbed or lost due to genetically inherited diseases, or through acquired disorders such as infections, injuries, postoperative complications , unphysiological sensory cell loads or side effects of drug treatment.
  • a retinal degeneration can be inherited or caused by light in animals, wi 's example, rodents, cats and dogs (Organisciak and the Wink ler, 1994).
  • Examples of retmal degeneration in humans include: stationary night blindness, retinitis pig entosa, rod / cone degeneration or dystrophy, cone / rod degeneration or dystrophy, macular degeneration or dystrophy, Stargardt's disease, pattern dystrophy, fundus flavbyaculatus, Sors s fundus Dy ⁇ strophie, myopic degeneration, Refsums disease, choroidal deremia and Punctus albmopunctatus.
  • eyesight can be seriously disturbed or lost as a result of retmal infection, ischemic damage to the external retina, or surgical treatment of retinal detachment, and night vision can be lost after chemotherapy with Vmcristm.
  • Usher's syndrome in humans is characterized by defects in visual, auditory, and vestibular function. People with Bardet-Biedl syndrome and liver congenital amaurosis have disorders in the visual and other sensory systems. A number of acquired degenerations in humans are also known, sensory cells and neighboring cells in the retina, the organ of Corti, and / or the organ of balance being damaged, for example. as the result of a lack of physiological sensory stimulation, the result of age-related smnes cell degeneration, the result of unphysiological sound exposure, or the result of unphysiological head acceleration. The normal functioning of the fine organ is not well understood in humans. However, the primary organ has cells that are closely related to retinal photoreceptors (for example, they synthesize the visual pigment Opsm and the hormone Melatonm) (Armstrong, 1998).
  • scientists have studied possible therapies to treat retmal degeneration in animals by transplanting healthy retmal cells, by gene therapy, and by administering survival or growth factors. (Bok et al., 1993; Milam, 1993).
  • the rate of light-induced and inherited retinal degeneration in animals can be somewhat slowed down by the administration of certain survival or growth factors; a path that is also followed for people.
  • 93/15608 describes the patent application WO, a method for reducing or preventing the degeneration retmaler neurons in mammals, which is caused by exposure to light or ⁇ particular environmental traumas, wherein prior to, wah ⁇ rend or subsequent to this exposure an administration of a therapeutically effective dose of a neurotropy factor, preferably Neurotrophm-3, Neutrophm-4, BNDF, CNTF, a leukemia inhibition factor, acidic FGF, basic FGF with Heparm, acidic FGF with Heparm, IL-1ß and TNF- ⁇ .
  • the aforementioned method further relates to the reduction or prevention of the degeneration of retmal neurons in suckers due to special diseases, as discussed in claim 21 there. There, however, the subject matter of the present invention, as claimed, is neither previously described nor suggested.
  • U.S. Patent 5,444,042 relates to a method of treating ischemic brain degeneration caused by, for example, stroke, heart attack, brain surgery, multiple infarct degeneration, or subarachnoid hamorrhage Mammals in which, after diagnosis of ischemia, the patient is administered a therapeutically effective dose of a calpai inhibitor, ie a peptide ketoamide compound or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
  • a calpai inhibitor ie a peptide ketoamide compound or a pharmaceutically acceptable salt thereof
  • the international patent application WO 94/21817 relates to a method for assessing whether a host receptive for a reversible antigen inducing immunodeficiency wherein it is first genwart a sample taken from the host Lymphocytprobe the Ge ⁇ examined by programmed cell death of the Lymphoczytprobe and then determining whether programmed cell death in the lymphocytes can be prevented by a calpam inhibitor and thus the lymphocyte function is restored.
  • the host is preferably and exclusively supported by examples, and is a person infected with HIV.
  • the cells are also treated with a calpam inhibitor, the treatment taking place m-vivo and ex-vivo.
  • a calpam inhibitor the treatment taking place m-vivo and ex-vivo.
  • International patent application WO 90/06123 relates to a method for treating a patient suffering from ischemia or edema on the retina or optic nerve, in which the patient is treated with a therapeutically effective amount of a calcium admission blocker, preferably a calcium channel antagonist.
  • a calcium admission blocker preferably a calcium channel antagonist.
  • These are preferably special dihydropyride ⁇ vate, diphenylpiperazme or benzothiazepme.
  • ⁇ makes this application a corresponding prophylactic treatment.
  • This treatment of ischemia or edema with these active ingredients neither anticipates nor suggests the treatment of other types of diseases according to the invention.
  • WO 92/17173 The subject of WO 92/17173 is the use of Riboflavm (Vitamin B2) for the manufacture of a medicament for the prophylactic or therapeutic treatment of viral Erkran ⁇ effects such as HIV-induced diseases, herpes, malaria, or retinitis pigmentosa. Since no vitamins are used as active substances according to the invention, the subject matter of the present invention, as claimed, is neither anticipated nor suggested.
  • US Pat. No. 5,421,818 relates to a device for therapeutic treatment in the middle and inner ear, in which active substances can be supplied to the inner ear through a membrane.
  • active substances can be supplied to the inner ear through a membrane.
  • the international patent application WO 96/41638 discloses a method of stabilizing or improving vision in macular degeneration of the human eye, said method ng the administration of at least 500 of the wax ⁇ tums compositions (growth factor) and peptide Transformmg Growth Factor-ß ( TGF-ß) in humans.
  • the aforementioned method preferably comprises the injection of at least part of the active substance into the subretal space and the rest immediately above the part of the retina to be treated. Since, according to the invention, no growth factors are set, the subject of the invention is neither anticipated nor suggested.
  • EPA-0 681 840 relates to the use of phosphate diesters of vitamins C and E for the manufacture of a pharmaceutical composition for the prophylactic and therapeutic treatment of diseases of the retina in humans. Since no vitamins are used as active substances according to the invention, the subject matter of the present invention, as claimed, is neither anticipated nor suggested.
  • US Pat. No. 5,281,607 relates to the treatment of neurodegenerative diseases and / or traumas of the central nervous system by stimulating the endogenous or in vivo recombinant expression of a nerve growth factor (NGF) in the central nervous system by administering an NGF of the central nervous system in an effective amount one ß
  • NGF nerve growth factor
  • Agonists an ⁇ i agonist and / or ⁇ _ agonist. These are preferably dobutamine, prenaterol, clenbuterol, isoproterol, epinephrine, fenoterol, albuterol, terbutaline, metaproterenol, salbutamol, zinterol, rimiterol, tazolol, phenylphenin, methoxamine, circazolin, modafinin, yohimbine, idazolone, folazone , Atipamizole. Since no ⁇ _-agonists, ⁇ ⁇ - ⁇ gonists or ⁇ -agonists are used as active substances according to the invention, the subject matter of the present invention, as claimed, is neither anticipated nor suggested.
  • US Patent US 5,457,135 relates to a method for treatmen ⁇ lung age-related macular degeneration in a patient suffering thereto, wherein this at least 120 mg / day of .beta.-carotene, are preferably administered systemically. Since according to the invention no vitamins are used as active ingredients , the subject matter of the present invention, as claimed, is neither anticipated nor suggested.
  • U.S. Patent U.S. 5,596,011 relates to a method of treating macular degeneration i.e. an aging human eye disease in which an effective dose of a glutathione enhancing agent is administered to increase the intracellular glutathione content.
  • the glutathione-enhancing agent is preferably used together with an antioxidant, preferably a vitamin or in connection with at least one anti-inflammatory agent
  • N-acetyl system and similar system de ⁇ vate, L-2-oxoth ⁇ azolm-4-carboxylate and mercaptopropionone glycine are specifically mentioned as glutathione-enhancing agents. This class of substances is excluded from a request for protection by a disclaimer. Since the subject of this US patent is exclusively the increase in the intracellular glutathione content and the resulting shrinkage of pathologically swollen glands in age-related macular degeneration, the subject of the present invention is not suggested.
  • U.S. Patent US 5,527,533 describes the use of astaxanthm for the prophylactic or therapeutic treatment of injuries or degenerative diseases of the human central nervous system or human eye, such as e.g. in age-related macular degeneration, damage by light, ischemia or inflammation. Since astaxanthm is not used as an active ingredient according to the invention, the subject matter of the present invention, as claimed, is neither anticipated nor suggested.
  • Calpam enzymes i.e. calcium-activated proteases
  • type I and type II Various inhibitors against these two enzymes (type I and type II) have been produced which specifically inhibit these enzymes and in some cases can also penetrate the cells (Wang, 1990; Croall and Demartmo, 1991; Mehdi, 1991; Michetti et al , 1995).
  • the next state of the art is known from the Russian patent application SU 1297862 AI, which is proposed to use a 10 ° solution with sodium adenosine triphosphate (ATP) for the treatment of inherited pigment degeneration of the retina.
  • ATP sodium adenosine triphosphate
  • the treatment also includes simultaneous treatment with microwaves, oxygen baths and vitamin B supplements.
  • the non-specific intramuscular application of the active ingredient does not specifically influence the intracellular milieu of the sensory cells. It is not one either targeted local application in the area of damaged sensory cells has been proposed.
  • Arnos LA and Arnos WB Molecules of the Cytoskeleton, 1991, Macmillan Educ. Ltd, London.
  • Hymel EC Murphey CR, and Christensen BN, A mathematical model of retina photoreeeptors, 79-85, 1995, In The Neurobiology of Computation, Bower JM (ed), Kluwer Press, Boston.
  • Marder E and Seiverston AI Modeling the stomatogastric nervous system, 161-196, 1992, In Dynamic Biological Networks, Harris-Warrick RM, Marder E, Slverston AI (eds) MIT Press, Cambridge. Mehdi S, Trends Biochem Be 16: 150-153, 1991, Cell penetration mg inhibitors of calpam.
  • Paseoletti T Em mathematical model of a neuromuscular synapse from prasynaptic depolarization to acetylcholme receptor, Ph. D. dissertation, Univ. Bonn, 1991.
  • the sensory cells of various sensory organs in vertebrates are closely related cells: their structure (a cilium is one important component of the receptor cell), their function (the transduction of the external sensory stimulus is converted into a change in the membrane voltage) and their biochemical reactions have many similarities.
  • the best studied and known types of smnes cells are the rod photoreceptors of the eyes.
  • the rods are highly specialized cells, each with an outer segment in which the phototransduction takes place.
  • Outer segments have a complex but well-structured structure. They consist of cytoplasmic compartments that are divided by many folds of membranes with protein molecules (eg Rhodopsm). The protol molecules are located in the membranes at suitable locations by binding to components of an internal cytoskeleton, e.g. B. attached to truncated microtubules. Every outer segment is renewed every day. Newly synthesized components are incorporated into the membranes at the base of the outer segment, while packets of old membranes are rejected from the tip of the outer segments and absorbed and degraded (phagocytosed) by neighboring pigment epithelial cells.
  • the calcium concentration can accordingly vary continuously and modulates the binding of certain calcium-encoding proteins to certain enzymes, their activity being modulated.
  • the activity of the protease "Calpam” is inhibited by binding Calpastatm, by oxidation of its sulphydryl groups, by a non-neutral pH and / or by a low calcium concentration. If these parameters are changed and Calpam is activated, Calpam hydrolytic degradation of certain proteins (e.g.
  • one of the first patho ⁇ logical changes is a disorder of adaptation of rod cells, indicating a fault their Calciumhomoostase.
  • the calcium concentrations may be too high or too low or too fast or too slow the Su ⁇ alteration follow the luminance.
  • Such calcium concentration disorders can have different consequences. Because the calciummdu involved activation of Calpam to the normal From ⁇ wagung the outer segment tip is involved, leads a too low calcium concentration to low repulsion so that the Stabchenaußensegmente grow abnormally long, it will be mechanically unstable and lose their normal structure and function.
  • Too high a calcium concentration leads to increased rejection, so that the rod outer segments become short from ⁇ normal, which reduces their light sensitivity.
  • a too fast or too slow change in calcium concentration can adversely affect the time-dependent coupling of various biochemical reactions ⁇ mixer, z. B. cause a slowdown ⁇ the normally leak-free, ie without damage to the membrane rejection.
  • the temporary ge ⁇ opened membrane then let an uncontrolled transfer of cytoplasmic components of the Stabchenaußensegmente m subretmalen space. Calpam can be released and activated due to the relatively high calcium content in the subretinal space in an uncontrolled manner, which results in an abnormal extra ⁇ cellular proteolytic effect on neighboring cells.
  • Another object of the present invention is to use a special, biologically active agent to influence the intracellular milieu of the sensory cells at risk of degeneration, the milieu of neighboring epithelial cells, the milieu of neighboring glial cells and / or the milieu of neighboring support cells of mammals by treating the milieu to provide the common extracellular space in the environment for prophylactic and therapeutic purposes.
  • An intracellular or extracellular environment in the sense of the present invention means an environment of a volume filled with various types of ions and biomolecules of different concentrations, ie the totality of the biophysical and biochemical parameters describing the functional state of the room in question. This object is achieved by the specially applied and brought into effect active ingredients according to claim 2.
  • the task is solved, in particular, on the basis of the measurement of the local and temporal distribution of substances, their concentrations and different types of cells at risk of degeneration, by means of a place and time-controlled release of active substance in accordance with the characteristic part.
  • the present invention therefore relates to the use of at least one biologically active substance for the treatment of the intracellular milieu of the sensory cells and / or neighboring epithelial cells and / or neighboring glial cells and / or supporting cells, of mammals with acquired and / or hereditary degeneration, which is characterized in that that the active ingredient is a physiologically effective amount of a compound containing alkaline earth metal or modifying its action and / or a nucleotide and / or an enzyme inhibitor and / or an enzyme activator and / or a protein and / or a peptide and / or a nitrogen oxide modifying compound, and / or a calcium to chelate or buffer, and / or a cytoskeletons modifi ⁇ ornamental active ingredient, and / or a Calciu channel blockers or calcium antagonists, and / or a Calmodulmantagom- most, and / or a Kationophors applied immediately outside of the cells and inside the cell brings effect.
  • the active ingredient is
  • various substances applied to the extracellular space in the vicinity of sensory cells can change the extracellular milieu and from there through the partially permeable cell membranes to the intracellular spaces of the neighboring sensory cells, epithelial cells, Penetrate glial cells or support cells and can influence the respective intracellular milieu prophylactically or therapeutically.
  • normal neighboring sensory cells can be protected by the disclosed invention from pathological disorders of the extracellular milieu, which were caused in particular by pathologically impaired sensory cells, in the common extracellular space by extensive neutralization of these pathological milieu disorders , which can stop the spread of cell degeneration.
  • the invention disclosed herein by modification of the extracellular milieu 's equal a number of different, acquired and / or hereditary De ⁇ generation forms of the genetic cause of the disease can be treated without precise knowledge, for example.
  • hereditary caused degenerations due to a single genetic defect capture multiple Smneszell species, such as with Usher's syndrome with degenerative impairment of sensory cells so ⁇ well of the eye, as well as the Hororgans and Vestibularor- goose and other degenerative diseases that can also affect the photoreceptors partially morphologically, biophysical and biochemical similar Pmealozyten the pineal treated by common principle em who the can ⁇ .
  • the disclosed invention because of the biophysical and biochemical interactions, can influence the intracellular milieu of sensory cells, as well as of the neighboring epithelial cells, glial cells and support cells, by means of milieu changes in the common extracellular space in the environment in a prophylactic or therapeutic manner. It is also advantageous that the disclosed invention affects both humans and other mammals due to the great structural, functional and biochemical similarities of the cell types in question and therefore both extends the field of application and considerably facilitates the further development of therapeutic details.
  • bioactive agents used are easily available, and that many of these active ⁇ materials already available for other medical applications in humans are used (eg, calcium channel Antagomsten, or calcium agonists are clinically against hypertension, angina pectoris and / or Cardiac rhythm disorders) or suggested (e.g. calpam inhibitors in ischemia-related neurodegenerative diseases in the brain, e.g. after a heart attack, neurosurgery or head injuries).
  • active ⁇ materials already available for other medical applications in humans are used (eg, calcium channel Antagomsten, or calcium agonists are clinically against hypertension, angina pectoris and / or Cardiac rhythm disorders) or suggested (e.g. calpam inhibitors in ischemia-related neurodegenerative diseases in the brain, e.g. after a heart attack, neurosurgery or head injuries).
  • active substance release which is controlled locally and in terms of time and quantity, can take place, in particular for the treatment of the retina.
  • Verrin ⁇ pathological impairment delay of affected cells as well as the protection of normal cells prior to the impairment of pathological cells m the environment is achieved.
  • the active ingredient release is controlled as required by a sensor-controlled control and thus on the basis of the local and temporal distribution of relevant cell and substance types or concentrations and on the basis of a suitable, multidimensional mapping and analysis of these detected measured values over em control system or a control loop with sensory feedback, a demand of active compound distribution with mini ⁇ paint side effects is generated.
  • the invention disclosed here for the treatment of retmal degeneration in particular treats the pathologically changed renewal process of the outer photoreceptor segments or counteracts its pathological effects in the extracellular milieu. It is also advantageous that particular forms of retinitis pigmentosa or macular degeneration can be treated with very differing ⁇ chen genetic causes according to a uniform principle fect without the respective genetic De ⁇ , the m many cases is not yet defmierbar presently know to have to.
  • control or regulation of the spatially and temporally distributed release of active substance in particular in the case of the retina, on a multi-compartment model as a coupled differential equation system to take into account the concentrations and substance flows between the common compartment of the extracellular space and the compartments of several neighboring ones Intrazellularraume of photoreceptors, pigment epithelial cells, Muller glial cells and / or Stutz cells as well as on a dynamic, emperfahigen computer model for controlling or regulating individual intracellular environment by feeding a drug to a given site of the extracellular space, taking into ⁇ supply of retmalen, locally and measurement data distributed over time.
  • melanm particles with a size of approximately 1 ⁇ m to 20 ⁇ m m are applied to the extracellular space, they can remain there for a longer time and serve as adsorbents for toxic factors in this area, so that these factors are depleted in the environment.
  • the function of the pigment epithelial cells which make an important contribution to the nutrition of the photoreceptor cells and to the renewal process of the outer segments through phagocytosis of the rejected outer segment tips, and are in some cases themselves at risk of degeneration (e.g. in Macular degeneration) can be optimized.
  • the micro-containers implanted in the subretmal space can be designed in such a way that they function as active ingredients can meet a longer period of time, but cannot be phagocytized prematurely by the pigment epithelial cells and also do not interfere with the normal phagocytosis process.
  • the treatment disclosed influences the contribution of neighboring Muller glial cells, some of which are themselves at risk of degeneration, in the retina to achieve and maintain the normal intracellular milieu of the photoreceptors.
  • the intracellular milieu of degeneration-prone Pmealozyten and neighboring cells of the pineal gland is influenced prophylactically or therapeutically.
  • the intracellular milieu of degeneration-prone hair cells and neighboring epithelial, glial and support cells in the Corti 'see organ of the inner ear through drug release in the surrounding perilymph space with diffusion connection to the adjacent endolymph space and extracellular space of the hair cells and adjacent epithelial, glia - And support cells are modified for prophylactic or therapeutic purposes.
  • the sensory degenerative diseases mentioned which have so far been neither curable nor avoidable, can be treated both prophylactically and therapeutically.
  • genetic zel ⁇ lularen disease cause various sensory organs may disclosed herein, common treatment principle be advantageously employed.
  • An advantageous embodiment of the treatment of the intracellular milieu of the sensory cells of mammals is that its disturbing influence on the part of the surrounding extracellular space is minimized by modifying the extracellular milieu via a sensor-guided, controlled administration of calpammhibitor.
  • the sensory cells and / or adjacent epithelial cells and / or glial cells and / or support cells are the retina and / or the organ of hearing and / or the equilibrium organ and / or the pineal gland.
  • the cells to be influenced via the extracellular space in the case of the retina are photoreceptor cells and / or neighboring pigment epithelial cells and / or retmal Muller glial cells which interact with the extracellular space and with one another .
  • the mammal is humans, as well as farm animals or pets.
  • the acquired and / or hereditary degeneration of sensory cells and / or epithelial cells and / or glial cells and / or support cells in the case of retmal degeneration in humans are, for example: stationary night blindness, retinitis pigmentosa, rods / cones.
  • degenerations or dystrophies pin / Stabchen degenerations or dystrophies, degenerations or dystrophies Maku- la-, Stargardt- disease, pattern dystrophy, fundus flavimaculatus, Sorsby's fundus Dy ⁇ strophie, Punctus albmopunctatus, myopic degeneration, Refsum's disease, choroideremia, the result of retmal infection or surgical treatment of retinal detachment and, in the special case of night blindness, after treatment with Vmcristm and / or Vmblastm.
  • auditory and vestibular smear cell degeneration occurs in Usher's syndrome in humans.
  • people with Bardet-Biedl syndrome and liver congenital amaurosis disorders experience both visual and other sensory systems.
  • the active ingredient contains an effective amount of a compound containing cationic alkaline earth metals or modifying their action and / or a cation ionophore and / or a calcium chelate or buffer and / or a calcium channel blocker and / or calcium antagonist and / or a calcium acti - fourth neutral cyst protease (calpam) and / or a calpma activator and / or other enzyme activators and / or a calmodule antagonist and / or an exogenous or endogenous calpam inhibitor or other enzyme inhibitors and / or a cytoskeleton-modifying active substance and / or a peptide and / / or a protein and / or egg ⁇ nes nucleotide and / or nitrogen oxides modifying compound.
  • calpam neutral cyst protease
  • cation ionophores which increase the membrane permeability to cations such as calcium, for example Calcimycm, Gramicidm, Ionomycm, Monensm, Thapsigargm.
  • active ingredients are calpam inhibitors (Wang, 1990; Croall and Demartmo, 1991; Mendi, 1991), for example Aloxistatm, Antipa, Diethylpyrocarbonate, Benzyloxycarbonyldipeptidylaldehyd, Calpam mhibitor peptide, Calpam mhibitor I, Calpam mhibitor II, ZLLY-CH PD150606, AK275, AK295, E64, E64-C, E64-D, MDL-28170, Leupeptm, SJA 6017, thiol-reactive agents (for example joodacetamide, iodoacetic acid, p-chloromercubenbenzoate, N-ethyl-
  • Calcium chelates or buffers for example BAPTA, EDTA or EGTA, should also be mentioned.
  • Calcium channel blockers or calcium antagonists such as Bep ⁇ dil, 1-c ⁇ s diltiazem, nifedipm, semotiadil fumarate (SD-3211) should also be mentioned here.
  • Calcium itself should also be mentioned because it activates Calpam I and II and modifies the stability of microtubules.
  • the calcium protease-activating protein (Croall and Demartmo, 1911) and isovaleryl carnite are also to be mentioned as calpam activators.
  • Calmodulm antagonists such as mastoparen, calmidazolium, trifluoperazme, melitt or the active ingredients W-5, W-7, W-12 and W-13.
  • Another drug class includes ⁇ calciumbmdende proteins, for example Calmodulm, whereby the Calciumbmdung the photoreceptor proteins is modified.
  • proteases in particular calpam type I or type II, are used, that is, a short word for calcium-activated neutral protease.
  • Calpammhibitoren example Calpastatm or low molecular weight Kmmogene can be used (Croall and Demartmo, 1991).
  • Microfilament destabilizers such as cytochalasm can be used as the active ingredient class.
  • Microtubule stabilizers and / or cytostatics such as, for example, cis-diamodichloroplate, Demecolcme, Colchicm, Nocodazole, Tamoxifen, Vmblastme or Vmcristm can be used as a further class of active substance.
  • a Another group of active substances are the cell-permeable analogs of 3, 5 -cyclic adenosmemonophosphate (cAMP) which modify the microtubule stability, such as dibutyryl-cAMP or 8-bromine-cAMP.
  • cAMP 3, 5 -cyclic adenosmemonophosphate
  • Another group of active ingredients relates to the cell-permeable analogs of 3 ' , 5' -cyclic guanosmon monophosphate (cGMP), which modify the microtubule stability, such as, for example, dibutyryl-cGMP or 8 -Bro -cGMP.
  • cGMP 3 ' , 5' -cyclic guanosmon monophosphate
  • Another group belongs to diethothreitol, which cancels the action of sodium nitroprusside, ie it hydrolyzes to nitric oxide.
  • a further preferred class of drugs includes, for example cations of ionic compounds of barium, lithium, potassium, selenium, sodium, manganese, magnesium or zinc which modify the competitively We ⁇ effects of calcium.
  • the further class of phosphodiesterase inhibitors include, for example, IBMX and Papave ⁇ n and the active ingredient SQ 65442.
  • Paclitaxel, taxol-releasing compounds (protaxols) and doxetaxel for example, can also be used only as microtubule stabilizers.
  • sodium nitroprusside itself should be mentioned, which forms nitric oxide, which can inactivate calpam. Otherwise, the special active ingredients mentioned in the claims are used.
  • the active substance or substances are applied enterally, parenterally, locally, in particular by local injection, systemically to the site of action or by delayed release of active substance, in particular by means of at least one implant or catheter.
  • Systemic administration takes place orally or by subcutaneous, intravenous or intramuscular injection.
  • the delayed release of active ingredient can take place, for example, via a catheter or by means of an implant, the implant consisting of a porous, non-porous or a hydrogel-like material, which may contain membranes or fibers, biodegradable polymers or a protein-containing material.
  • mtraocular administration or topical administration to the eye or mtraocular injection may also be considered, for example in the area of the vitreous or subretally in the area between the photoreceptor cells and pigment epithelial cells.
  • the treatment is carried out as a prophylactic and / or therapeutic treatment, in particular to maintain the extracellular and intracellular physiological milieu, to improve the pathological milieu and / or to eliminate pathological disorders.
  • the locally and time-controlled application takes place on the basis of measurements carried out before and during the administration using measurement and analysis methods such as are used, for example, in ophthalmology or otolaryngology, in which the proportion of pathological sensory cells and the substance concentrations in their environment are determined, in particular mapped and analyzed.
  • measurement and analysis methods include, for example, computer-based optical, electrophysiological and ultrasound standard methods Consideration.
  • the mapping is carried out, for example, in such a way that the measurement data or analysis results are displayed as two- or three-dimensional maps at different measurement times.
  • the control itself takes place, for example, in that, based on the measurement and analysis data prepared in this way, the amount of active substance released with or without sensory feedback is determined as a function of time and place.
  • the above method is, for example, in influencing such cells of the retina m in the manner performed that relevant functional and structural Pa ⁇ parameters of photoreceptors, subretmalem space, glial cells and pigment epithelial cells in particular by focal electric - retinography .
  • ERG ERG
  • SLO scanning laser ophthalmoscopy
  • fundus reflectometry confocal m-vivo microscopy and / or fluorescence microscopy with the use of non-toxic fluorescence markers as a function of the retmal location, the luminance adaptation and / or the time as well as the Patoscuro rhythm monitored mapped and for determining mor ⁇ pho striger, physiological and / or biochemical parameters are analyzed and that the measurement and analysis result ⁇ se as a function of place and time to determine the optimal drug administration control, to select or to be administered active ingredients , for therapy ⁇ course monitoring and as sensor information for a sensor-based active ingredient administration control or regulation.
  • the local and temporal application for the treatment of the photoreceptor outer segments is carried out in such a way that laying the pathological and normal photoreceptor areas of the retina, the normal photoreceptors are protected from pathological impairment by the pathological, neighboring photoreceptors by subret ale active substance administration, especially in the intermediate border area, and that their normal outer segment renewal without pathological changes, in particular the long, change of extracellular milieu 's, the membrane permeability and the coordinated rejection and phagocytosis process of the tip is continued and / or maintained with the help of pigment epithelial cells.
  • the present invention further relates to a method for controlling the local and temporal distribution of the various active substances to be administered, which are to be administered in the extracellular space of the sensory cells, in particular retinal photoreceptors, which is characterized in that on the basis of the measurement data obtained in the aforementioned manner, a suitable, dynamic multi-compartment model for computer simulation of the material flows in the area of photoreceptors, pigment epithelial cells, glial cells, support cells and extracellular space is developed that furthermore a suitable model as a computer simulation for controlling and feedback-controlled regulation of intracellular parameters in the photoreceptor cells by external administration supplied substances is developed and that the use of these models delays the local and temporal distribution of the substances to be administered, possibly also by selective control of locally distributed, implanted micro-containers
  • the active substance release with suitable substances of the aforementioned type with the aim of therapeutically optimizing the intracellular photoreceptor milieu is controlled by caring experts and / or the patient and / or by partially autonomous control loops.
  • retinal pigment epithelial cells for the indirect improvement of the intracellular photoreceptor medium 's are influenced ⁇ fen by the administration / implantation m the subretmalen space of implanted Mikrobehalter with suitable active compound, with or without binding to a carrier matrix e.g.
  • these substances are released over a longer period of time from the micro-containers within the pigment epithelial cells and then in the extracellular space, which are used for the improvement of the intracellular photoreceptor -Milieus can bind or release suitable, specific active ingredients.
  • calpam inhibitor as suitable active substances which are released with a delay by implanted active substance containers.
  • dungsge134en use is in the sense cells to photoreceptors, with retinal glial cells for direct improvement of the intracellular photoreceptor medium 's, or for influencing the extracellular space are affected by administration of the active ingredients of the aforementioned type, m the subretmal space for influencing the glial cell functions m appropriately.
  • the sensory cells and neighboring cells are premealocytes and neighboring cells, disorders of their intracellular milieu being minimized by injection of active substance into the cerebrospmal fluid in the vicinity of the third ventricle.
  • the sensory cells and neighboring cells are hair cells, epithelial cells and glial and support cells in the cortical organ of the inner ear, disorders of their intracellular milieu caused by active substance injection into the neighboring perilymph. Space can be minimized, for example, by the round window.
  • erfm- dungsge feliciten use is in the sense cells and adjacent cells to hair cells and epithelial, glial, and Stutz cells in the vestibular organ, wherein disruption of their intracellular milieu 's disclosed by drug injection into the Benach ⁇ perilymph room minimized become.
  • the present invention further relates to a modification of the use according to the invention of the aforementioned type for improving the intracellular smn cell milieu and / or intracellular milieu of epithelial cells and / or glial cells and / or support cells, monocytes, macrophages, or microglia cells or other suitable endogenous or healthy people or mammals treated cells removed, subzel ⁇ lulare structures, or biomolecules ex-vivo or m suitably modified and reinserted that the extracellular space were introduced previously by appropriate locations of the patient's organism and then removed m.
  • the active agent depot means for controllably, preferably externally controllable drug delivery, the drug release can be locally and are time-dependently controlled.
  • Em implanting and explanting optionally is easily possible, when several drug depots are provided, which are connected via traction ker each other or to a common Switzerland ⁇ .
  • the active ingredient depots have sensory and / or actuator functions that can be carried out autonomously or in a coupled manner.
  • SLO Scannmg laser ophthalmoscopy
  • the sensory and / or actuator functions include the local measurement of the parameter in the environment and the local application of the active ingredient.
  • a flexible use of the implant is possible with a wide range of functions if an interface with an external control unit is provided for drug administration and the interface is preferably wireless and transmits both sensor signals as well as control commands and energy.
  • Figure 1 the subretmal extracellular space of the retina
  • Figure 2 the structure of retmal photoreceptors
  • Figure 3 the extracellular space of the pineal gland and a Pmealozyt
  • Figure 4 the extracellular space of the inner ear
  • Figure 5 the extracellular space of the Corti 'see organ
  • Figure 6 the extracellular space of the vestibular organs
  • Figure 7 the sensory hair cells of the vestibular organs
  • FIG. 8 a light microscopic section of a Xenopus laevis retina before injection of the active substance
  • FIG. 9 a light microscopic section of a Xenopus laevis retina after injection of nocodazole
  • FIG. 10 the number of rods of external segment phagosomes per 100 ⁇ m pigment epithelium of the Xenopus laevis Re- tina m dependence on the mtraocular drug concentration;
  • FIG. 11 the effect of calpam inhibitor and a high concentration of calcium and on the structure of the rods of the Xenopus laevis retina;
  • FIG. 12 a sen cell region of the retina with drug depots implanted there, which are connected to an external tie rod via connecting structures;
  • FIG. 13 an exemplary representation of the implantation of these active substance depots between the epithelial cells and the retina by means of a transport fluid and an injector;
  • Figure 14 the internal structure of a drug depot according to
  • FIG. 15 a schematic cross section through a typical smnes cell region, from which the relative arrangement of the different cells emerges.
  • the subretmal extracellular space 2 according to FIG. 1 is essentially delimited by the pigment epithelial cells 1 and the retmal Muller (glia) cells 5.
  • the space is further delimited by rod photoreceptors 3 and cone photoreceptors 4.
  • FIG. 2 shows schematically: an electron microscopic section through a retinal rod photoreceptor cell-e 6, a rod marrow photoreceptor 7 and a cone photoreceptor 8 from the human retina and the enlargement of an outer segment (OS) 9 of a retmal rod photoreceptor.
  • OS outer segment
  • FIG. 3 shows the pineal gland 12, also called epiphysis or glanula pmealis, of a mammal.
  • the extracellular space 13 of this organ has a direct connection to the 3rd ventricle.
  • Figure 4 shows a schematic overview of the inner ear with the snail (cochlea) with Corti's organ 16, the three arches 17 of the vestibular organ, the macula sacculi 18 of the vestibular organ, the macula utriculi of the vestibular organ 19 and the endolymphatic extracellular space 20 des Vestibular organ.
  • FIG. 6 describes a diagram of the vestibular organs with the macula statica 25 corresponding to the macula utriculi or macula sacculi, the sensory hair cells 26 of the macula statica, the crista ampulla ⁇ s 27 (normal and enlarged), the sensory hair cells 28 of the crista ampullaris, the arch 29 with sensory hair cells and the perilymphatic extracellular space 30 of the arches.
  • Figure 7 shows a schematic elekronenmikroskopische on ⁇ acquisition of the sensory hair cells of the vestibular organs with the vestibular sensory hair cells 31 and the Kmozili- to 32 of a hair cell.
  • a controlled treatment of the subretmal space with an active ingredient which induces the rejection of the outer rod segments shows that abnormally elongated outer rod segments can be shortened and their further degradation prevented.
  • FIG. 8 shows a light microscopic section of a retina of the toad Xenopus before / without injection of nocodazole (as a comparison). There are no phagosomes m in the upper area the pigment epithelium, which clearly shows that almost no membranes have been rejected from the tip of the rod outer segments.
  • FIG. 9 shows a light microscopic section of a retina of the toad Xenopus after the injection of 1.0 ng No ⁇ codazole.
  • the pigment epithelium has many phagosomes (indicated by arrows), which proves that numerous outer segment membranes fragments of the tip of the rod outer segments have been rejected.
  • Fig. 10 shows a graphical bar graph of the number of rod outer segment phagosomes in the Xenopus retina per 100 ⁇ m pigment epithelium without injection, against DMSO as a solvent, at low, medium and high concentrations of nocodazole (from left to right) as they are was obtained according to application example 1. The standard deviation is also shown above the bars.
  • a highly injected concentration of nocodazole is understood to mean approximately 2.5 mg nocodazole / ml DMSO (diethyl sulfoxide, the solvent for nocodazole), a medium concentration approximately 0.25 mg nocodazole / ml DMSO and a low concentration approximately 0.025 mg Nocodazole / ml DMSO and under DMSO (solvent) em solvent containing no nocodazole.
  • concentrations of nocodazole in the eye can be estimated from the aforementioned concentrations:
  • FIG. 11 shows various retinal sections as vital prepaprates to illustrate the effect of a high calcium and calpam concentration on the structure of the rods of the Xenopus retina.
  • FIG. 11 a shows a retinal section at the beginning of the perfusion with a high calcium concentration (1.8 mM CaCl) and one
  • FIG. 11 b shows the same retinal section as FIG. 11 a after 30 minutes of perfusion with a high calcium concentration and a calcium ionophore: almost all of the outer segments of the rod are bent and show an abnormal hook-like shape.
  • FIG. 11 c shows another retinal section after 30 minutes of perfusion with a high calcium concentration (1.8 mM CaCl), a calcium ionophore (4 ⁇ M A23187) and additionally a calcium inhibitor (50 mg / ml E64-d): a small percentage Stabchen of outer segments has a distal groove or is buckled at two locations, but the majority of agessegmenten Stabchen Au ⁇ does not have the normal saulen shame form.
  • a high calcium concentration 1.8 mM CaCl
  • a calcium ionophore 4 ⁇ M A23187
  • a calcium inhibitor 50 mg / ml E64-d
  • FIG. 11 d shows the same retinal section as FIG. 11 c after 60 minutes of perfusion with a high calcium concentration, a calcium ionophore and also a calcium inhibitor: some rods outside segments have an abnormal hook-like shape, but many other rods outside segments are only beginning to buckle.
  • FIG. 12 schematically shows a smnes cell region 50 of the retina in a plan view in the direction of the viewing axis.
  • the active substance depots 51 in turn are connected to a common tie rod 53 via thread-shaped traction means 52, which can also be used for the transport of active substance or for signal transmission.
  • the tie rod 53 can remain outside the smnes cell region 50 and can be fastened, for example, inside the eyeball.
  • FIG. 13 shows a symbolic cross section through the smnes cell region 50 with a retina 55 and an epithelial cell
  • the active substance depots 51 are introduced into a region between the retina 55 and the epithelial cells 56 by injecting a transport liquid 58 between the retina 55 and the epithelial cells 56 with an injector 57.
  • the active substance depots 51 float in the transport liquid 58 and, when injected, are washed together with the transport liquid 58 in the intermediate space.
  • the active substance depots are introduced in a similar manner into the fluid space that surrounds the sensory epithelium.
  • the traction means 52 are guided through an opening 59 of the injector 57.
  • the active substance depots 51 After the active substance depots 51 have been placed, they remain in the subretmal space between the retina 55 and the epithelial cells 56, while the space created by the transport liquid 58 closes again over time after suction or absorption of the transport liquid 58.
  • the pulling means 52 and the Switzerland ⁇ ker 53 can also be used in addition to the use in placing the active substance depots 51 to the Wirkstoffde- pots 51 after they have been emptied or after completion of treatmen ⁇ lung again to remove or animals, the overall structure to explanted .
  • FIG. 14 shows an exemplary embodiment of an active substance depot 51 with a complex inner structure.
  • the active substance depot 51 contains a drive 61 for automatic or controlled locomotion, a signal processing unit 62, an interface 63 for the optical signal exchange, a detector 64 for detecting parameters characterizing the extracellular space, an active substance dispenser 65 with an inlet valve 66 and one exhaust valve 67 and an interface 68 for a material and signal ⁇ ⁇ exchange 52 ent with the traction means 52.
  • the drawing means latched em valve 69 and a signal line 70 and a Flus- liquid line 71 through which the active substance dispenser 65 can be passed via the interface 68 m.
  • FIG. 15 shows an enlarged cross section through a typical smnes cell region of mammals, for example the retina in a view corresponding to FIG. 13 or a smnes cell region constructed in a similar manner in principle, such as that of the organ of Corti or of the equilibrium organs.
  • the relative arrangement of the sensory cells 55, the epithelial cells 56 and the glial cells or support cells 57 is illustrated here.
  • the preferred location of the active substance depots 51 is illustrated in the immediate vicinity of the sensory cells 55, where the active substance is to be released in order to influence the extracellular milieu.
  • the drug depots 51 with an active ingredient or active ingredient mixture are befullt, which is suitable for the extracellular milieu and thus the intracellular Mi ⁇ lieu of the sensory cells 55, of the epithelial cells 56, the glial cells and / or the neck cells to modify 57th They are then connected to one another or to a common coupling structure, namely the tie rod 53, by means of traction means 52 and suspended in a transport fluid.
  • the transport fluid is then introduced with an injector between the epithelial cells and the retina or in any case near the cells to be treated, so that the active substance deposits land spatially distributed in the area of the retina 55 to be treated. There they can release the active ingredient locally and at a time if required.
  • the need is either determined externally by laser ophthalmoscopy or other suitable methods for local diagnosis, or the drug depots themselves or sensors deployed together with the drug depots determine the need m situ.
  • the detector 64 can be used, for example, as a conductivity sensor or as a detector for the ion concentration of calcium ions. If a need is identified, a small amount of the active ingredient is released. This can be done either via the internal control 62 of the active substance depot 51 itself or via an externally supplied signal. In the case of the eye, an optical signal exchange via the interface 63 is suitable for this.
  • the active substance dispenser 65 When the active substance dispenser 65 is completely emptied, it can be refilled via the liquid line 71 of the traction device 52. In the simpler case of non-refillable drug depots, all of the drug depots 51 are removed from the implantation site by pulling on the pulling means 52 and replaced by new drug depots 51 which are placed in the manner already described.
  • a particularly simple from chtungsform may provide that the drug depots are configured 51 with traction means 52 as permanently stable ⁇ le bubble-like container (or without traction means as karfri ⁇ stig phagocytable or degradable container) with an impermeable at normal temperature envelope enclosing the active ingredient.
  • These containers are only connected to one another by plastic or carbon fiber thread as traction means 52, the traction means 52 having no internal structure whatsoever. If there is a need for drug delivery, the blister-shaped drug containers are heated slightly above body temperature by external irradiation with a suitable wavelength and power, whereby they release the drug locally and modify the extracellular environment accordingly.
  • active substances are named with their short names. It means:
  • AK 275 L, L isomer of Z-Leu-Abu-CONH-CH2-CH2
  • AK 295 CBZ-Leu-Abu-CONH- (CH2) 3
  • Calpam inhibitor peptide Asp-Pro-Met-Ser-Ser-Thr-Tyr-Ile-Glu-Glu-Leu-Gly-Lys-Arg-Glu-Val-Thr-Ile-Pro-Pro-Lys-Tyr-Arg- Glu-Leu-Leu-Ala
  • DY-9760e 3- [2- [4- (3-chloro-2-methylphenyl) -1- p ⁇ peranzmyl] ethyl] -5, 6-d ⁇ methoxy-l- (4- ⁇ m ⁇ dazolylmethyl) -1H-mdazole dihydrochloride 3.5 hydrates
  • E64 trans-EPOXYSUCCINYL- ⁇ -LEUCYLAMIDO- (4-GUANIDINO) BUTANE
  • E-64c (2S, 3S) -trans-EPOXYSUCCINYL- L -LEUCYLAMIDO-3-METHYL-BUTANE
  • E-64d (2S, 3S) -trans-EPOXYSUCCINYL- -LEUCYLAMIDO-3-METHYL-BUTANE ETHYL ESTER
  • H-7 1- (5- ⁇ soqumolmylsulfonyl) -2-methylp ⁇ perazm
  • H-89 N- [2-bromochmnamyl (ammo) ethyl] -5- isoqumolmsulfona id
  • H-9 N- (2-aminoethyl) -5-isoquinoline sulfonamide
  • HA-1004 N- (2-guanidinoethyl) -5-isoquinoline sulfonamide
  • MDL 28170 carbobenzoxyl-val-phe-H
  • SD-3211 semotiadil fumarate
  • W-12 N- (4-aminobutyl) -1-naphthalenesulfonamide
  • W-13 N- (4-aminobutyl) -5-chloro-l-naphthalenesulfonamide
  • W-7 N- (6-aminohexyl) -5-chloro-l-naphthalenesulfonamide
  • ZLLY-CHN2 carbenzoxy-leu-leu-tyr-CHN2

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Abstract

L'invention concerne l'utilisation d'un principe actif influant sur l'homéostasie du calcium de cellules pour traiter les dégénérescences de cellules sensorielles et de cellules adjacentes.
PCT/EP1998/001951 1997-05-05 1998-04-02 Utilisation de principes actifs a effet biologique pour influer sur l'espace extracellulaire de cellules sensorielles et procede de commande d'administration de principe actif et dispositif approprie WO1998050065A2 (fr)

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AU76417/98A AU7641798A (en) 1997-05-05 1998-04-02 The use of biologically active substances for influencing the extracellular areaof sensory cells and method for controlling the administration of active substa nces and device used therein
EP98924097A EP0980256A2 (fr) 1997-05-05 1998-04-02 Utilisation de principes actifs a effet biologique pour influer sur l'espace extracellulaire de cellules sensorielles et procede de commande d'administration de principe actif et dispositif approprie
CA002288631A CA2288631A1 (fr) 1997-05-05 1998-04-02 Utilisation de principes actifs a effet biologique pour influer sur l'espace extracellulaire de cellules sensorielles et procede de commande d'administration de principe actif et dispositif approprie

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DE19718826.5 1997-05-05
DE1997118826 DE19718826A1 (de) 1997-05-05 1997-05-05 Verwendung biologisch aktiver Wirkstoffe zum Beeinflussen des Extrazellulär-Raumes von Sinneszellen und Verfahren zur Wirkstoff-Administrationssteuerung

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WO2000020006A1 (fr) * 1998-10-02 2000-04-13 Inserm (Institut National De La Sante Et De La Recherche Medicale) Utilisation du diltiazem pour le traitement de pathologies de la retine
US6716835B1 (en) 1998-10-02 2004-04-06 Inserm (Institut National De La Sante Et De La Recherche Medicale) Use of diltiazem for treating retinal pathologies
WO2001087913A3 (fr) * 2000-05-12 2002-05-30 Inspire Pharmaceuticals Inc Procede de traitement de la degenerescence retinienne avec des agonistes de recepteur purinergique
WO2005056519A1 (fr) * 2003-12-12 2005-06-23 Senju Pharmaceutical Co., Ltd. Derive d'alpha-cetoamide, son procede de production et d'utilisation
JP2006076989A (ja) * 2003-12-12 2006-03-23 Senju Pharmaceut Co Ltd α−ケトアミド誘導体、その製造方法、及びその用途
US7491705B2 (en) 2003-12-12 2009-02-17 Senju Pharmaceutical Co., Ltd. Alpha-ketoamide derivative, and production method and use thereof
US11040019B2 (en) 2016-08-19 2021-06-22 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Selective estrogen-receptor modulators (SERMs) confer protection against photoreceptor degeneration

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AU7641798A (en) 1998-11-27
DE19718826A1 (de) 1998-11-12
WO1998050065A3 (fr) 1999-06-10
EP0980256A2 (fr) 2000-02-23

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