WO2007081061A1

WO2007081061A1 - Therapeutic agent for neurogenic pain

Info

Publication number: WO2007081061A1
Application number: PCT/JP2007/050850
Authority: WO
Inventors: Tsutomu Tanabe
Original assignee: Japan Science And Technology Agency; National University Corporation Tokyo Medical And Dental University
Priority date: 2006-01-16
Filing date: 2007-01-15
Publication date: 2007-07-19
Also published as: JP4428481B2; JP2007186477A

Abstract

Disclosed is a neurogenic pain therapeutic agent having an excellent therapeutic effect on neurogenic pain which is one of intractable diseases. More specifically, disclosed are: a therapeutic agent for neurogenic pain, which comprises a compound having an inhibitory activity on Na/K ATPase (Na pump) (e.g., ouabain, digoxin and digitoxin) as an active ingredient; a pharmaceutical composition for treatment of neurogenic pain, which comprises a compound having an inhibitory activity on Na/K ATPase (Na pump) and a pharmaceutically acceptable carrier; and others.

Description

Specification

Neuropathic pain treatment

Technical field

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. Background art

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. Examples of 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.

As analgesics that have been used in conventional pharmacotherapy, central ovoid receptor agonists represented by morphine, nonsteroidal anti-inflammatory agents (NSAIDS) represented by indomethacin, and the like are known. However, these analgesics are generally less effective against neuropathic pain, and analgesics (especially narcotic analgesics) that are effective for normal nociceptive pain are known to be particularly ineffective. ing. 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. .

Various factors are thought to be intricately related to the development of neuropathic pain. So far, 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. As an external preparation, 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.

-On the other hand, 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 theory that digitalis cardiotonic action is based on the inhibition of Na / K ATPase (Na pump) has been described in many pharmacological textbooks, but there are many unclear points so far. Proof was not made. Recently, a group of Prof. KenPhilipson from the University of California showed that this exchanger is indispensable for the inotropic action of ouabain based on the analysis using knockout mouse of Na / Ca exchanger. Reveals the mechanism of action (Reuter H et al. Circ

Res.2002; 90: 305-308 Patent Document 1]). In addition, the presence of vavine-like substances in living organisms has been reported one after another, and their blood concentration is regulated by the intake of salt, etc., and only Na / K ATPase (Na pump) activity is regulated. In addition, it was also revealed that it exhibits a hormone-like action (Eur JBiochem. 2002; 269: 2440-2448, Ann NY Acad Sci. 2003; 986: 685-693).

With regard to the action of wabine (G-strophantin), I!], For example, in JP-A-8-99894 (Patent Document 1), 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

As described above, there are currently no known drugs effective for the treatment of neuropathic pain, and development of such drugs is desired. Under such circumstances, 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.

(1) A therapeutic agent for neuropathic pain comprising, as an active ingredient, a compound having an inhibitory action on Na / K ATP as (Na pump).

(2) The therapeutic agent for neuropathic pain according to the above (1), wherein the compound having an Na / K ATP as (Na pump) inhibitory action is ouabain, digoxin, digitoxin or a pharmaceutically acceptable salt thereof.

(3) The therapeutic agent for neuropathic pain according to the above (2), wherein the compound having an inhibitory action on Na / K ATP as (Na pump) is ouabain or a pharmaceutically acceptable salt thereof.

(4) 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).

(5) 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. (6) 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).

(7) Use of a compound having an inhibitory effect on Na / K ATP as (Na pump) for the manufacture of a therapeutic agent for neuropathic pain.

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. Brief Description of Drawings

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. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

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.

Various compounds having an inhibitory effect on Na / K ATPase (Na pump) are known, but there have been no reports on the pain suppression effect of these compounds alone or in combination in a neuropathic pain model. Surprisingly, the present inventors have found for the first time that these compounds alone have a therapeutic effect on neuropathic pain. In the present specification, 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. For example, Kelly RA, Smith TW. In: Goodman & Lri 丄 man's the pharmaco-ogical basis of therapeutics. 9th ed. New York: McGraw-Hill; 1996. p.809— It can be confirmed by 38.

As used herein, 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. Further, the term “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 α)-3- [(6-Deoxy-H-L-mannopyranosyl) oxy.

S]-1,5,11,14,19-Pentahydroxycarda-20 (22) -Enolide. The inhibitory action of uabain and its Na / K ATP as (Na pump) has been described in various literatures (Reuter H et al. Circ

Res.2002; 90: 305-308; Kelly RA, Smith TW. In: Goodman & Gilman's the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1996. p.809-38 etc.).

Digoxin is (3 β, 5 β, 12 β) ~ 3- [(0-2, 6 -dideoxy- β-D- _r hexapyranosyl- (1 → 4) -0-2, 6 -dideoxy- β -Ό-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

β) -3-[(0-2, 6 -dideoxy-/ 3- D-hexobilanosyl- (1 → 4)-^ 2, 6 -dideoxy- β-D-r hexobiranosyl- (1 → 4) -2, 6-dideoxy-β-ϋ-rib hexopyranosyl) oxy]-14-hydroxycarda-20 (22) -enolide.

Wabain, digoxin and digitoxin, Merck Index ^{(TheMerck Index, 13 th Edition (} 2001)) first 235 pages, fifth 5 page 7 and the fifth 5 6 Pejiniso respectively, the compound name, chemical structure, Physicochemical properties and related main literature are described. The ^{digoxin, The pharmacological basis of therapeutics 10 th} Edition, Japanese edition (Hirokawa Shoten, 2003 Issued) of McGraw Hill 1 1 6 5 page also mechanism of action such as has been described in relation to digitoxin. Of these compounds, wabine is particularly preferred. In the present specification, 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.).

Therefore, 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. Examples of 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. Examples of 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. Examples of such 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.

Examples of preparations suitable for oral administration include powders, tablets, capsules, fine granules, granules, solutions or syrups. For oral administration, 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. In addition, 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.

Examples of preparations suitable for parenteral administration include injections and suppositories. In the case of parenteral administration, 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. Furthermore, 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

Hereinafter, the present invention will be described more specifically based on examples, but the present invention is not limited to these examples.

(Experimental materials used and general experimental methods)

(1) Model animals

As an experimental animal, a pain hypersensitivity model prepared by completely ligating the L5 / L6 spinal nerve to a 6-week-old male rat was used.

(2) Grouping

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.

(3) Preparation of test substance For the 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.

(4) Administration method

The 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. Example 1

(Uabine · mechanical stimulation method)

Use male rats (279. 0 to 338, 2g) of pain hypersensitivity model per group, maximum pressure: 15.0 g, maximum pressure before and after 30-, 60- and 90-minute administration of ouabain Time to reach: The pain threshold of the left footpad was measured using a stimulator set at 20 seconds. The results are shown in Fig. 1.

As shown in Fig. 1, in the control group administered with 0.5 w / v% strength aqueous solution of lupoxymethylcellulose sodium (CMC—Na), 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. Thus, administration of wabain significantly increased the pain threshold and confirmed the analgesic effect in neuropathic pain. In the above-mentioned pain hypersensitivity model, allodynia (alodynia) that feels a tactile stimulus that is not usually felt as pain occurs and the pain threshold decreases significantly, but intraperitoneal administration of vavine increases the pain threshold in a dose-dependent manner. And improved pain sensitivity. However, since the muscle relaxation were observed in the administration of mechanical irritation test 10 mg / kg, the thermal stimulation test was conducted with the highest dose as a 3 mg / k _g. Example 2 (Uabine · Thermal stimulation method)

(Thermal stimulation method)

A group of 5 male rats (308.3 to 379.9 g) of hypersensitivity pain group. The pain threshold of the left footpad 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.

As 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. In the case of administration, the maximum threshold after administration is 9.0 seconds, (b) In the case of lmg / kg administration, the maximum threshold value after administration is 9.5 seconds, (c) In the case of 3 mg / kg administration, The maximum threshold was 9.7 seconds. Thus, 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.

(Discussion)

From the above examples, it has been clarified that a 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. Industrial applicability

As described above, a therapeutic agent for neuropathic pain containing a compound having an inhibitory effect on Na / KATPase (Na pump) 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.

Claims

The scope of the claims

1. A therapeutic agent for neuropathic pain comprising, as an active ingredient, a compound having an inhibitory action on Na / K ATP as (N a pump).

2. The therapeutic agent for neuropathic pain according to claim 1, wherein the compound having Na / K ATP as (N a pump) inhibitory action is ouabain, digoxin, digitoxin or a pharmaceutically acceptable salt thereof.

3. The therapeutic agent for neuropathic pain according to claim 2, wherein the compound having an inhibitory action on Na / K ATP as (N a pump) is ouabain or a pharmaceutically acceptable salt thereof.

4. Neuropathic pain is postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, cancer pain, postoperative or posttraumatic prolonged pain, hyperalgesia, alodynia, post-thoracotomy pain, CRP S, multiple Claims 1 to 3 above, wherein the pain is one or more symptoms selected from pain due to sclerosis, AI DS, thalamic pain, paraplegia due to spinal cord disorder, non-sensory pain, and neuropathic pain in phantom limb pain. The therapeutic agent for neuropathic pain according to any one of the above.

5. A pharmaceutical composition for treating neuropathic pain comprising a compound having an inhibitory action on Na / K ATP as (N a pump) and a pharmaceutically acceptable carrier.

6. A method of treating neuropathic pain by administering an effective amount of a compound having an inhibitory action to Na / K ATP a s e (N a pump) to a mammal.

7. Use of a compound having an inhibitory effect on Na / K ATP as (N a pump) for the manufacture of a therapeutic agent for neuropathic pain.