WO2007081061A1 - Agent therapeutique utilise contre les douleurs neurogenes - Google Patents

Agent therapeutique utilise contre les douleurs neurogenes Download PDF

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Publication number
WO2007081061A1
WO2007081061A1 PCT/JP2007/050850 JP2007050850W WO2007081061A1 WO 2007081061 A1 WO2007081061 A1 WO 2007081061A1 JP 2007050850 W JP2007050850 W JP 2007050850W WO 2007081061 A1 WO2007081061 A1 WO 2007081061A1
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WO
WIPO (PCT)
Prior art keywords
pain
neuropathic pain
pump
therapeutic agent
compound
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PCT/JP2007/050850
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English (en)
Japanese (ja)
Inventor
Tsutomu Tanabe
Original Assignee
Japan Science And Technology Agency
National University Corporation Tokyo Medical And Dental University
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Publication date
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Publication of WO2007081061A1 publication Critical patent/WO2007081061A1/fr

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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
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a therapeutic agent for neuropathic pain having an excellent pain suppressing effect on neuropathic pain, a method for treating neuropathic pain using such a therapeutic agent, and the like.
  • Neuropathic pain is pain caused by damage or dysfunction of the peripheral nervous system or central nervous system, and is refractory pain in which ovoid receptor agonists such as morphine do not sufficiently respond.
  • diseases with neuropathic pain include post-herpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, prolonged pain after surgery and trauma, and other diseases that present with symptoms of hyperalgesia. Can do.
  • central ovoid receptor agonists represented by morphine
  • nonsteroidal anti-inflammatory agents represented by indomethacin
  • these analgesics are generally less effective against neuropathic pain
  • analgesics especially narcotic analgesics
  • Inadequate analgesic effect of narcotic analgesics on neuropathic pain is a major feature of neuropathic pain, and in some cases, this feature is used to diagnose neuropathic pain. .
  • neuropathic pain has been treated by neurosurgery such as nerve block, spinal epidural electrostimulation, tricyclic antidepressants, intrathecal administration of drugs such as baclofen, etc. It has been known. However, these treatments have problems that are not effective enough or have side effects.
  • capsaicin cream is effective for postherpetic neuralgia and pain syndrome after mastectomy by desensitizing pain substance substance P released from nerve terminals and reducing pain. There is also a report. Problem with burning pain caused by kabusaicin There are problems in terms of usability and safety. Thus, neuropathic pain is an intractable disease, and no effective treatment has yet been established.
  • ouabain G-stout fantin
  • a compound that has Na / K ATPase (Na pump) inhibitory activity has been used as a cardiotonic agent for the treatment of heart failure. It is a plant active substance isolated from the eastern eastern tree. Along with digoxin, digitoxin, etc., it is one of a group of digitalis called cardiac glycosides and can be said to be a representative of it.
  • Digitalis is a cardiovascular treatment that has been used for a long time. Digitalis was first known to be effective in treating edema as an English folk remedy. This compound has since been used empirically for the treatment of heart failure over many years, and is now in clinical use.
  • the digitalis group (particularly wabine) is used as an inhibitor of inflammatory site force in secretion. It is described as being effective in treating various diseases caused by secretion or production of cytokines such as IL-6, IL-18, MCAF, G-CSF, and GM-1 CSF. Also, in Japanese translation of Japanese translation of Hei 10-502673 (Patent Document 2), The use of digitalis as a potentiator for the application of continuous local anesthesia is described. Disclosure of the invention
  • an object of the present invention is to provide a novel neuropathic pain therapeutic agent that exhibits an excellent effect on intractable pain called neuropathic pain.
  • the present inventors have conducted research based on an original idea that solves the above-mentioned problems, and in the intractable neuropathic pain model, a compound having an inhibitory action on Na / K ATPase (Na pump) is high. It has been found that it has an analgesic effect, and the present invention has been completed. That is, the present invention provides the following therapeutic agent for neuropathic pain, a pharmaceutical composition for treating neuropathic pain, a method for treating neuropathic pain, and the like.
  • a therapeutic agent for neuropathic pain comprising, as an active ingredient, a compound having an inhibitory action on Na / K ATP as (Na pump).
  • Neuropathic pain includes postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, cancer pain, postoperative or posttraumatic prolonged pain, hyperalgesia, alodiure, post-thoracotomy pain, CRP S, frequent occurrence (1) to (1) above, which is one or more symptoms selected from pain caused by multiple sclerosis, AI DS, thalamic pain, paraplegic pain due to spinal cord disorder, non-sensory pain and phantom limb pain The therapeutic agent for neuropathic pain according to any one of 3).
  • a pharmaceutical composition for treating neuropathic pain comprising a compound having an inhibitory action on Na / K ATPase (Na pump) and a pharmaceutically acceptable carrier.
  • a method of treating neuropathic pain by administering to a mammal an effective amount of a compound having an inhibitory effect on Na / K ATPase (Na pump).
  • the therapeutic agent for neuropathic pain of the present invention exhibits symptoms such as postherpetic neuralgia, trigeminal neuralgia, glycouria neuralgia, cancer pain, postoperative or posttraumatic prolonged pain, hyperalgesia, alodynia, etc. It is effective for the treatment of neuropathic pain.
  • FIG. 1 is a diagram showing the experimental results of Example 1, in which ouabain was intraperitoneally administered to rats with hypersensitivity and the change in pain threshold value due to mechanical stimulation was shown.
  • FIG. 2 is a diagram showing the experimental results of Example 2, in which ouabain was intraperitoneally administered to a rat with hypersensitivity, and the change in pain threshold with respect to thermal stimulation was shown.
  • the present invention relates to a therapeutic agent for neuropathic pain comprising a compound having a Na / K ATPase (Na pump) inhibitory action as an active ingredient, a compound having a Na / K ATPase (Na pump) inhibitory action, and a pharmaceutical composition.
  • Composition for the treatment of neuropathic pain comprising a pharmaceutically acceptable carrier, a method for treating neuropathic pain using a compound having an inhibitory action on Na / K ATPase (Na pump), Na / KATPase (Na pump)
  • the present invention provides a therapeutic agent for neuropathic pain containing a mixture of compounds having an inhibitory action as an active ingredient.
  • the “compound having Na / K ATPase (Na pump) inhibitory action” means a substance having an action of inhibiting or suppressing Na / K ATPase (Na pump) activity.
  • Na / K ATPase (Na pump) is present in the cell membrane of all animal cells, and “Na / K ATPase (Na pump) activity” uses the energy obtained by hydrolysis of ATP. This is the activity of transporting sodium ions out of cells and potassium ions into cells, forming and maintaining a concentration gradient of sodium ions and potassium ions inside and outside the cells.
  • Na / K ATPase (Na pump) inhibitory activity can be measured by the method described in J. Kyte et al. Biochemistry 1987; 26: 8350-8360.
  • Inhibition of Na a / K ATPase (Na pump) by digitalis such as uvain increases intracellular sodium ion concentration, and suppresses or reverses the forward conversion of Na / Ca exchanger (calcium ion excretion).
  • (Influx of calcium ions) increases intracellular calcium ion concentration by promoting cardiotonic effects.
  • Kelly RA Smith TW. In: Goodman & Lri ⁇ man's the pharmaco-ogical basis of therapeutics. 9th ed. New York: McGraw-Hill; 1996. p.809— It can be confirmed by 38.
  • the term “treatment” generally means amelioration of symptoms in humans and non-human mammals.
  • the term “improvement” refers to, for example, the case where the degree of the disease is reduced or not worsened compared to the case where the therapeutic agent of the present invention is not administered, and also includes the meaning of prevention.
  • pharmaceutical composition means a composition containing an active ingredient useful in the present invention (such as ouabain, digoxin, digitoxin) and an additive such as a carrier used in the preparation of a medicine.
  • Examples of the compound having Na / K ATPase (Na pump) inhibitory activity used in the present invention include uvaine, digoxin, digitoxin, and pharmaceutically acceptable salts thereof. All of these compounds are known. For example, uabain, digoxin and digitoxin are registered as CAS numbers 63 0-6 0-4, 208 30-7 5-5 and 7 1-6 3-6, respectively.
  • Wapain is a type of cardiac glycoside obtained from the seeds or bark of Coleoptera.
  • Uavine is a compound called G-strophanthin, also known as (1 j3, 3 jS, 5 j3, 11 ⁇ )-3- [(6-Deoxy-H-L-mannopyranosyl) oxy.
  • Digoxin is (3 ⁇ , 5 ⁇ , 12 ⁇ ) ⁇ 3- [(0-2, 6 -dideoxy- ⁇ -D- _r hexapyranosyl- (1 ⁇ 4) -0-2, 6 -dideoxy- ⁇ - ⁇ -1 ba ⁇ hexopyranosyl- (1 ⁇ 4) -2,6 -dideoxy-; 8-D -rj'A hexopyranosyl) oxy]-12, 14 -dihydroxy carda-20 (22) -enolide It has the compound name. Digitoxin is (3,5
  • the term “comprising a compound having an inhibitory action on Na / KATPase (Na pump)” means that a compound having an inhibitory action on Na / KATPase (Na pump) In all acceptable forms (eg, its salts, esters, amides, hydrated or solvated forms, racemic mixtures, optically pure forms, etc.).
  • the compound as an active ingredient used in the present invention may be a free form or a pharmaceutically acceptable salt.
  • Such “salts” include acid salts and base salts.
  • acid salts include hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, and citrate.
  • Salt acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, dulconate, saccharide, benzoate, methanesulfonate, ethanesulfonate, benzenesulfone Acid salt, p-toluenesulfonic acid salt, 1, 1 ′ monomethylene monobis (2-hydroxy-3-naphthoic acid) salt, and the like.
  • the base salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as strong salt and magnesium salt, water-soluble amine addition salts such as ammonium salt and N-methyl darcamamine salt, Examples include lower alcohol salts, salts derived from other bases of pharmaceutically acceptable organic amines.
  • the therapeutic agent for neuropathic pain and the thread composition of the present invention are effective for the treatment of neuropathic pain.
  • neuropathic pain include, for example, postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, cancer pain, postoperative or posttraumatic prolonged pain, hyperalgesia, alodynia, postthoracotomy pain , CRPS, pain due to multiple sclerosis, AIDS, thalamic pain, paraplegic pain due to spinal cord disorder, non-sensory pain, neuropathic pain in phantom limb pain, etc.
  • the therapeutic agent for neuropathic pain of the present invention is particularly effective for the treatment of hyperalgesia and alodinia.
  • the administration form of the therapeutic agent for neuropathic pain of the present invention is not particularly limited, and can be administered orally or parenterally.
  • the active ingredient of the therapeutic agent for neuropathic pain of the present invention may be formulated singly or in combination, but it is pharmaceutically acceptable. It can also be provided in the form of a preparation by blending body or preparation additives. In this case, the active ingredient of the present invention can be contained, for example, in an amount of 0.1 to 99.9% by weight.
  • Examples of pharmaceutically acceptable carriers or additives include excipients, disintegrating agents, disintegrating aids, binders, lubricants, coating agents, dyes, diluents, solubilizers, solubilizing aids. , Tonicity agents, pH adjusting agents, stabilizers, etc. can be used.
  • preparations suitable for oral administration include powders, tablets, capsules, fine granules, granules, solutions or syrups.
  • various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate, dalysin are added to starch, preferably corn, starch or tapio, It can be used with various disintegrating agents such as alginic acid and certain kainate double salts, and granulating binders such as polybulurpyrrolidone, sucrose, gelatin, gum arabic.
  • disintegrating agents such as alginic acid and certain kainate double salts
  • granulating binders such as polybulurpyrrolidone, sucrose, gelatin, gum arabic.
  • lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often very effective for tablet formation.
  • the same kind of solid composition can also be used by filling gelatin capsules.
  • suitable substances in this connection include latatoose or lactose as well as high molecular weight polyethylene glycols. If you want an aqueous suspension and / or elixir for oral administration, use the active ingredient in combination with various sweeteners or flavors, colorants or dyes, and if necessary, use emulsifiers and Z or suspending agents. It can be used with water, ethanol, propylene glycol, glycerin, etc., and diluents that combine them.
  • preparations suitable for parenteral administration include injections and suppositories.
  • the active ingredient of the present invention can be dissolved in either sesame oil or peanut oil, or a solution dissolved in an aqueous propylene glycol solution can be used.
  • the aqueous solution should be buffered as appropriate (preferably pH 8 or higher), and the liquid diluent must first be made isotonic.
  • Such aqueous solutions are suitable for intravenous injection and oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection. The manufacture of all these solutions under aseptic conditions is easily accomplished with standard pharmaceutical techniques well known to those skilled in the art. You can.
  • the active ingredient of the present invention can be administered locally such as on the skin. In this case, topical administration in the form of creams, jellies, pastes, ointments is desirable according to standard pharmaceutical practice.
  • the dose of the therapeutic agent for neuropathic pain of the present invention is not particularly limited, and is appropriately administered according to various conditions such as the type of pain, the age and symptoms of the patient, the administration route, the purpose of treatment, and the presence or absence of a concomitant drug. It is possible to select the amount.
  • the dose of the therapeutic agent for neuropathic pain of the present invention is, for example, about 50 to 2500 mg, preferably 90 to 900 mg per day for an adult (for example, body weight 6 O kg).
  • the dose when administered as an injection is, for example, about 10 to 500 mg, preferably 18 to 180 mg per day for an adult (for example, 60 kg body weight). These daily doses may be administered in two to four divided doses.
  • Example 1 Example 1
  • the mechanical stimulation test was measured using the Dynamic Planter Aesthesiometer (37400, Ugobasil), and the thermal stimulation test was measured using the plantar thermal stimulation device (Planter test 7370, Ugobasil) to measure the pain threshold of the model animal. Groups were grouped using Preclinical Package Version 5.0 (SAS Institute Japan) so that the pain threshold measured before administration on the experimental day was uniform. For mechanical stimulation, animals with a foot pain threshold of 8.0 g or more in the model animals were excluded from the study, and for heat stimulation, animals with a model foot pain threshold of 10 seconds or more were excluded from the study.
  • test substance powder the raw powder with an agate mortar opi pestle, and then gradually add 0.5 w / v% sodium carboxymethylcellulose (CMC—Na) as a medium to form a uniform suspension. Liquid. The concentration of the dosing solution was adjusted using a measuring flask with a measuring cylinder and a measuring flask, and all adjustments were made before use.
  • CMC—Na sodium carboxymethylcellulose
  • test substance is intended to confirm the direct action on the spinal cord, but it has been confirmed that it passes through the brain barrier. It was administered intraperitoneally at a volume of 5 ral / kg using a syringe barrel and needle.
  • the maximum pain threshold after administration was 6.2 g.
  • A In the case of 0.3 mg / kg, the maximum threshold after administration was 7.5 g,
  • B In the case of 3 mg / kg, the maximum threshold after administration was 11.8 g,
  • c In the case of 10 mg / kg administration, the maximum threshold after administration was 14. lg.
  • administration of wabain significantly increased the pain threshold and confirmed the analgesic effect in neuropathic pain.
  • a group of 5 male rats (308.3 to 379.9 g) of hypersensitivity pain group was measured using a plantar thermal stimulation device set at 45, before, and after 30, 60, and 90 minutes of dosing. The results are shown in Fig. 2.
  • the maximum pain threshold after administration was 7.9 seconds in the control group administered with physiological saline, whereas (a) 0.3 mg / kg in the group administered with vavine.
  • the maximum threshold after administration is 9.0 seconds
  • the maximum threshold value after administration is 9.5 seconds
  • the maximum threshold was 9.7 seconds.
  • the administration of vavine was not statistically significant, but there was a tendency for the pain threshold to rise even at doses of 0.3, lmg / kg and 3 mg / kg.
  • neuropathic pain therapeutic agent containing a compound having an inhibitory activity of Na / KATPase (Na pump) as an active ingredient is effective for the treatment of neuropathic pain.
  • a therapeutic agent for neuropathic pain containing a compound having an inhibitory effect on Na / KATPase improves symptoms of neuropathic pain caused by various causes Since it has an action, it can be used effectively in the treatment of neuropathic pain.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un agent thérapeutique utilisé contre les douleurs neurogènes, qui font partie des maladies incurables. L'invention concerne, plus spécifiquement, un agent thérapeutique utilisé contre les douleurs neurogènes, contenant un composé présentant une activité inhibitrice sur la Na/K ATPase (pompe Na) (par exemple, la ouabaïne, la digoxine et la digitoxine) comme ingrédient actif; une composition pharmaceutique de traitement des douleurs neurogènes, contenant un composé présentant une activité inhibitrice sur la Na/K ATPase (pompe Na) et un véhicule acceptable d'un point de vue pharmaceutique; et analogues.
PCT/JP2007/050850 2006-01-16 2007-01-15 Agent therapeutique utilise contre les douleurs neurogenes WO2007081061A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2006007889A JP4428481B2 (ja) 2006-01-16 2006-01-16 神経因性疼痛治療剤
JP2006-007889 2006-01-16

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009103932A1 (fr) * 2008-02-19 2009-08-27 Henderson Morley Plc Utilisation d’un glycoside cardiaque et/ou d’un diurétique pour le traitement de la douleur neuropathique

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011085307A1 (fr) * 2010-01-11 2011-07-14 Phoenix Biotechnology, Inc. Méthode de traitement d'affections neurologiques faisant appel à des glycosides cardiaques

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004521111A (ja) * 2001-01-25 2004-07-15 ユーロ−セルティーク，エス．エイ． 局所麻酔薬および使用法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004521111A (ja) * 2001-01-25 2004-07-15 ユーロ−セルティーク，エス．エイ． 局所麻酔薬および使用法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009103932A1 (fr) * 2008-02-19 2009-08-27 Henderson Morley Plc Utilisation d’un glycoside cardiaque et/ou d’un diurétique pour le traitement de la douleur neuropathique

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JP2007186477A (ja) 2007-07-26

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