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WO2000033864A1 - Remedes contre les defaillances tactiles - Google Patents

Remedes contre les defaillances tactiles Download PDF

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Publication number
WO2000033864A1
WO2000033864A1 PCT/JP1999/006821 JP9906821W WO0033864A1 WO 2000033864 A1 WO2000033864 A1 WO 2000033864A1 JP 9906821 W JP9906821 W JP 9906821W WO 0033864 A1 WO0033864 A1 WO 0033864A1
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WO
WIPO (PCT)
Prior art keywords
neurotrophin
tactile
brain
therapeutic agent
dysfunction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1999/006821
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English (en)
Japanese (ja)
Inventor
Yoshihiro Arakawa
Machiko Watanabe
Yukihiro Endo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Regeneron Pharmaceuticals Inc
Original Assignee
Regeneron Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Regeneron Pharmaceuticals Inc filed Critical Regeneron Pharmaceuticals Inc
Publication of WO2000033864A1 publication Critical patent/WO2000033864A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a therapeutic agent for tactile dysfunction, and more particularly, to a therapeutic agent for tactile dysfunction containing neurotrophin as an active ingredient.
  • Skin sensation, pain sensation, temperature sensation (hot sensation Z cold sensation), touch sensation, vibration sensation, etc., which are generally called somatic perception, include vitamin deficiency, poisoning, inflammatory diseases, viral infections, diabetes, anticancer treatment, trauma Affected by various peripheral Z-centre neuropathies caused by physical irritation in the occupational environment, psychosomatic disorders, etc.
  • Tactile sensation, along with pain and temperature sensation, is an indispensable sensation for cognition of objects, and its decline or loss causes inconvenience, pain, or danger in the patient's daily life.
  • various therapeutic agents have been developed for hyperalgesia since ancient times, effective pharmacotherapy for lack of cutaneous sensation has not been clinically established.
  • neurotrophins are supplied in vivo from target cells or from neurons and glial cells and Schwann cells, and form a family of neurotrophic factors that act to maintain the survival of neurons and promote differentiation. Is a group of proteins. Representatives include nerve growth factor (hereinafter sometimes abbreviated as NGF), brain-derived neurotrophic factor (hereinafter sometimes abbreviated as BDNF), neurotrophin 3 (hereinafter sometimes abbreviated as NT-3), etc. And is known to act as a specific ligand for the trk receptor (Ken Nonomura, Hiroshi Hatanaka; Experimental Medicine, Vol. 13, pp. 376 (1995)).
  • NGF nerve growth factor
  • BDNF brain-derived neurotrophic factor
  • NT-3 neurotrophin 3
  • NT-3 neurotrophin 3
  • neurotrophins As for the pharmaceutical use of neurotrophins, its application to central peripheral neurodegenerative diseases such as ALS and diabetic neuropathy has been studied clinically (Biochem. Biophvsic. Res. Co. u. Vol. 238, p. 633). (1997)). Among them, NGF has been reported to be a factor that plays an important role in the survival, development and function maintenance of nerves that transmit pain sensation to noxious stimuli such as pressure and heat (ewin and Mendel 1, Trends in Neuroscience vol.16, p.353-359 (1933)) c Regarding brain-derived neurotrophic factor, it has been reported that exogenous brain-derived neurotrophic factor enhances the sensitivity of certain neuropathic nerves. (WE Snider, Nature
  • BDNF centrally administered BDNF exerts analgesic effects (Tokuheihei 8- 50 1 3 1 3) .
  • SAMs Smallly Adapting Mechano-receptors
  • An object of the present invention is to provide a novel therapeutic agent for tactile dysfunction which promotes functional recovery from a decrease or loss of tactile function of the skin.
  • the present inventors were examining the pharmacological effects of brain-derived neurotrophic factors on sensory nerves.In the rat model of adjuvant-induced hyperalgesia, when a brain-derived neurotrophic factor was administered, the tactile sensation caused by inflammation was reduced. It was found that the recovery of tactile sensation was promoted. Based on this finding, as a result of further studies, the present invention was completed. . BRIEF DESCRIPTION OF THE FIGURES
  • Figure 1 shows the response to hyperalgesia in an adjuvant-induced hyperalgesia rat model.
  • BDNF BDNF (1 g) was administered 5 hours after the adjuvant injection.
  • the open circles indicate the group to which the solvent was administered, and the solid circles indicate the group to which B DNF was administered (in each group, 6 animals).
  • FIG. 2 shows the effects of topical administration of BDNF on tactile blunting in an adjuvant-induced hyperalgesic rat model.
  • the horizontal axis of the graph indicates the elapsed time (time) after the adjuvant injection, and the vertical axis indicates the reaction frequency in the paint brush method (%;).
  • BDNF (1 ⁇ g) was administered 5 hours after adjuvant injection.
  • the open circles indicate the group to which the solvent was administered, and the solid circles indicate the group to which BDNF was administered (in each group, 6 animals). ** indicates a significant difference between groups with P ⁇ 0.01 in the Mann-Whitney test.
  • the present invention relates to the following medicaments.
  • a therapeutic agent for tactile dysfunction comprising neurotrophin as an active ingredient.
  • the neurotrophin is a type selected from the group consisting of brain-derived nerve factor, nerve growth factor, neurotrophin_3, neurotrophin-1, neurotrophin-5, and neurotrophin-1 6. ⁇ .
  • neurotrophin is a brain-derived neurotrophic factor.
  • a therapeutic agent for tactile dysfunction comprising an agonist of trkB receptor as an active ingredient.
  • neurotrophin is one selected from the group consisting of brain-derived nerve factor, nerve growth factor, neurotrophin-3, neurotrophin-1, neurotrophin-5, and neurotrophin-6 .
  • neurotrophin is a brain-derived neurotrophic factor.
  • a method for treating tactile dysfunction which comprises administering an effective amount of neurotrophin to a patient whose skin tactility has been reduced or lost.
  • New mouth trophin is a member selected from the group consisting of brain-derived nerve factor, nerve growth factor, neurotrophin-3, neurotrophin-1, neurotrophin-5, and neurotrophin-16 (11) ) Treatment method.
  • neurotrophin is a brain-derived neurotrophic factor.
  • a method for treating tactile dysfunction which comprises administering an effective amount of a trk B receptor agonist to a patient whose skin tactility is reduced or lost.
  • Neurotrophins are secreted from cells that are the target of nerve growth in the living body, or help the growth, differentiation, and survival of nerves (neurons) through autocrine and paracrine secretions, thereby forming neural circuits (synapses). Means the neurotrophic factor to be formed. More specifically, brain-derived neurotrophic factor, nerve growth factor, neurotrophin-1, neurotrophin-4 (hereinafter sometimes abbreviated as NT-4), neurotrophin-1 5 (abbreviated as NT-15) ), Neurotrophin-1 (hereinafter sometimes abbreviated as NT-6), and the like. Preferable ones include BDNF, NT_3, NT-4, and NT-15, which express a physiological activity through trkB receptor or trkC receptor.
  • tr kA, trk B and Z or trk C receptor agonist refers to trkA, trkB or trk C, which binds to trkA, trkB or trk C among the trk gene expression products It is a general term for substances that activate receptors and express their effects. Specific examples of known neurotrophins include NGF binding to trkA, BDNF binding to trkB, NT_4, and NT-3 binding to trkC.
  • This concept includes trk A, trk B or trk B, as well as variants of each "neurotrophin” (amino acid substitutions, deletions, additions, glycosylation) as well as lower molecular weight peptides and organic compounds. as long as it has the ability to bind and activate the trk C receptor, such as phosphorylation of tyrosine residues.
  • BDNF was first isolated from porcine brain by Barde, Y.—A. (The EMBO J., vol. 5, p. 549-553 (1982)), and then It is a neurotrophin whose primary structure consisting of amino acids has been analyzed (Leiblock, J. et al.-Nature, vol.341 p.149 (1989)).
  • Met-BDNF having a methionine residue at the N-terminus, a recombinant B prepared by substituting, deleting or adding a part of the above-mentioned natural sequence by a currently known method DNF variants are also within the technical scope of the present invention, as long as they have BDNF activity.
  • BDNF activity refers to the survival of dorsal root ganglia, vagus subganglia, motor neurons, retinal ganglia, substantia nigra dopaminergic neurons, basal forebrain cholinergic neurons, etc. Maintenance ⁇ Means promoting differentiation. This effect can be confirmed by invitro or invivo (Japanese Patent Application Laid-Open No. 5-32898).
  • the “agent for treating tactile dysfunction” is a generic term for a drug that restores its function by being administered to a patient suffering from reduction or loss of skin tactile sensation.
  • “simple tactile sensation of the skin” means that the sensation of light physical irritation on the skin surface is reduced or lost. Clinically, this sensation is determined by whether it responds to the stimulus of rubbing comfortably without squeezing the subject's skin surface with cotton, a soft brush, or the examiner's finger (Akira Takahashi, supra. ).
  • Neurotrophins (NGF, BDNF, NT-3, NT-4, etc.) used in the therapeutic agent for tactile dysfunction of the present invention are produced by extraction from biological tissues or culture of host cells into which recombinant DNA has been introduced. In general, extraction from a host into which recombinant DNA has been introduced is suitable for mass production at an industrial level. Methods for producing BDNF using various hosts as shown in the following (1) to (4) have been reported in articles and patents, and BDNF produced in any recombinant host has the same activity as the native type. As far as shown, it can be used for the therapeutic agent of the present invention. It can also be purchased from Promega, etc.
  • NGF can be purchased from Serotech or the like, or can be manufactured by the method described in the following publication.
  • NT-3 can be purchased from Promega or the like, or manufactured / assessed by the method described in the following publication.
  • NT-4 can be purchased from Promega, etc., or manufactured / processed by the method described in the following publication.
  • Neurotrophins produced by recombinant techniques can be regenerated or purified by methods known in the field of biochemistry. Treatment with a denaturing agent and a reducing agent, ion exchange chromatography, gel filtration, reversed-phase HPLC, ammonium sulfate precipitation, ultrafiltration, etc. are used in an appropriate combination.
  • Antibodies to neurotrophin can be prepared by polyclonal and monoclonal methods known per se. The specific antibody can be used for immunochemical quantification such as an antibody column or ELISA. Reports on the regeneration and refining of neurotrophins are given below.
  • any of an injection, an oral preparation, a liquid preparation, and a lyophilized product can be used, and an injection preparation for subcutaneous intramuscular administration is particularly preferable.
  • stabilizers, buffers and carriers known in the art can be used.
  • plasma-derived proteins such as albumin, amino acids such as glycine, and sugars such as mannitol can be used.
  • a surfactant such as Tween 80 or a disinfectant for long-term storage may be added to prevent aggregation. If long-term efficacy is required, use a known protein Formulations can also be made using release preparation carriers (polylactic acid-polyglycolic acid copolymer, collagen, silicon, etc.).
  • the therapeutic agent for tactile dysfunction of the present invention is usually administered intravenously, subcutaneously, or intramuscularly at 0.5 / X g to 5 O mg per kilogram of an adult.
  • the frequency of administration may be adjusted according to the dose, administration route and patient's symptoms, but may be administered once to three times a month, generally 1 to 7 times a week for several weeks. Treatment is given. This treatment promotes the recovery of skin tactile sensation. It can be used in combination with other neuropathic agents such as steroids, vitamin B12, carbamazepine, and cabsaicin.
  • the animals were male Wistar rats (170-210 g : NRC Haruna), and the adjuvant was “Complete Freund's Adjuvant” (Sigma).
  • the adjuvant was injected subcutaneously into the plantar of the right hind limb under ether narcotics in a conventional manner.
  • An adjuvant-induced hyperalgesia model was created (J. of Neuroscience, vol. 16, p. 2716-2723 (1996)).
  • BDNF l / g Five hours after the adjuvant injection, BDNF l / g was locally injected subcutaneously into the dorsal side of the foot in the above modeler, and the effect on tenderness was examined. As a result, as shown in FIG. 1, adjuvant injection was performed in the von Frev hairs method.
  • BDNF 1 / ig was locally injected subcutaneously into the ipsilateral dorsum of the foot, and the effect on tactile sensation was examined.
  • tactile sensation a newly developed method using a paint brush was used.
  • the rat was held so that it hung in a hollow state with the right hind limb extended, and the foot was bent with a soft paint brush to observe the reaction of bending the foot. This was performed 10 times, and the number of reactions was expressed as frequency (%).
  • the recovery was significantly accelerated and returned to about 82% after 24 hours.
  • a typical aqueous preparation for subcutaneous administration containing BDNF can be produced as follows.
  • the therapeutic agent for tactile dysfunction of the present invention can ameliorate skin dysesthesia impaired by various causes, in particular, impairment of tactile sensation.

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  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Neurosurgery (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Psychology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention porte sur de nouveaux remèdes contre les défaillances tactiles, qui contiennent, en tant que principe actif, des neurotrophines telles que BNDF. Ces remèdes sont utiles dans le traitement de la dysesthésie cutanée (notamment l'anesthésie et l'hypoesthésie tactiles) induite par divers troubles du système nerveux périphérique/central causées par une carence vitaminique, un empoisonnement, des maladies inflammatoires, une infection virale, le diabète, un traitement par des agents anticancéreux, un traumatisme, des stimulations physiques dans le milieu de travail, etc., un trouble psychophysiologique, etc.
PCT/JP1999/006821 1998-12-08 1999-12-06 Remedes contre les defaillances tactiles Ceased WO2000033864A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP10348327A JP2000169389A (ja) 1998-12-08 1998-12-08 触覚異常治療剤
JP10/348327 1998-12-08

Publications (1)

Publication Number Publication Date
WO2000033864A1 true WO2000033864A1 (fr) 2000-06-15

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PCT/JP1999/006821 Ceased WO2000033864A1 (fr) 1998-12-08 1999-12-06 Remedes contre les defaillances tactiles

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5453361A (en) * 1989-08-30 1995-09-26 Regeneron Pharmaceuticals, Inc. Method for producing biologically active human brain derived neurotrophic factor
WO1996033273A1 (fr) * 1995-04-21 1996-10-24 The Speywood Laboratory Limited Derives de la toxine botulinique capables de modifier les fonctions des afferents peripheriques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5453361A (en) * 1989-08-30 1995-09-26 Regeneron Pharmaceuticals, Inc. Method for producing biologically active human brain derived neurotrophic factor
WO1996033273A1 (fr) * 1995-04-21 1996-10-24 The Speywood Laboratory Limited Derives de la toxine botulinique capables de modifier les fonctions des afferents peripheriques

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ALBERS K.M. ET AL.: "Cutaneous overexpression of NT-3 increases sensory and sympathetic neuron number and enhances touch dome and hair follicle innervation", J. CELL BIOL., 1996, pages 487 - 497, XP002926896 *
JOHNSON JR., E.M. ET AL.: "Central nervous system and peri-pheral nerve growth factor provide tropic support critical to mature sensory neuronal survival", NATURE, vol. 314, no. 25, 1985, pages 751 - 752, XP002926897 *
SHOEI FURUKAWA ET AL.: "Shinkei seicho inshi (NGF)-shinkeikei to menekikei wo tsunagu saitokain bunshi-", SHINKEI SEISHIN YAKURI, vol. 18, no. 12, 1996, pages 807 - 813, XP002955580 *
SNIDER W.D.: "How do you feel? Neurotrophins and mechano-transduction", NATURE NEUROSCIENCE, vol. 1, no. 1, May 1998 (1998-05-01), pages 5 - 6, XP002926895 *
YOSHIKO FURUKAWA ET AL.: "Neurotrophins no seikagaku", SEIKAGAKU, vol. 68, no. 1, 1996, pages 14 - 30, XP002955579 *

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