JPWO2012137645A1 - Preventive and / or therapeutic agent for allodynia caused by anticancer agents - Google Patents

Abstract

An object of the present invention is to provide a medicament effective for the prevention and / or treatment of allodynia caused by an anticancer agent. An agent for preventing and / or treating allodynia caused by an anticancer agent containing natural calcitonin or a calcitonin derivative as an active ingredient is provided. Further, a method for preventing and / or treating allodynia caused by an anticancer agent by administering natural calcitonin or a calcitonin derivative, and a natural type for producing an agent for preventing and / or treating allodynia caused by an anticancer agent The use of calcitonin or calcitonin derivatives is also contemplated. [Selection figure] None

Description

  The present invention relates to a medicament having a preventive and / or therapeutic effect on allodynia caused by an anticancer agent.

  In the treatment of cancer (malignant tumors), surgery, radiation therapy, and chemotherapy are appropriately used alone or in combination. Of these, anticancer agents (anti-neoplastic agents) used in cancer chemotherapy are inherently cytotoxic and cytotoxic, and have side effects caused by damaging not only cancer (malignant tumor) cells but also normal cells. Occurs.

  Side effects caused by anticancer agents include blood disorders, gastrointestinal disorders, and neurological disorders. Recently, however, problems of acute or chronic neurological disorders have been increasing. This is because the major side effects of new anticancer drugs that show significant anticancer effects are often neuropathy, the effects of multidrug therapy such as FOLFOX therapy, and the side effects of blood disorders and digestive disorders Is considered to be due to an improvement trend. At present, in order to cope with the neuropathy caused by this anticancer agent, it is necessary to reduce the amount of the anticancer agent or interrupt the cancer chemotherapy.

  In addition to the central nervous system, autonomic nervous system, and peripheral nervous system, neuropathy caused by anticancer agents is also observed in sensory organs such as taste. Peripheral neuropathy such as pain such as severe pain and burning pain, numbness of the extremities, hypersensitivity such as hypersensitivity to cold stimulation, sensory abnormalities such as sensory loss and numbness, sensory ataxia, muscle weakness Is frequently expressed, and cold allodynia and mechanical allodynia are particularly problematic as typical symptoms. Examples of anticancer agents that easily cause peripheral neuropathy include taxane drugs (paclitaxel, docetaxel), vinca alkaloid drugs (vincristine, vinblastine, vindesine, vinorelbine), and platinum preparations (oxaliplatin, cisplatin).

  At present, effective preventive and therapeutic methods have not been established for peripheral neuropathy caused by anticancer agents, particularly allodynia. Although the usefulness of calcium / magnesium intravenous administration and glutathione has been reported for peripheral neuropathy of oxaliplatin, it is mostly used because of the complexity of cancer chemotherapy and the need for large doses. Absent. In actual clinical settings, it is necessary to deal with peripheral neuropathy caused by anticancer drugs by combining physical therapy, complementary therapy such as massage and acupuncture, and drug therapy such as steroids, antidepressants, antiepileptic drugs, and opioids. However, the effectiveness of these therapies has not been proved, and there are many side effects in themselves (Non-patent Documents 1 and 2).

  On the other hand, natural calcitonin is a polypeptide consisting of 32 amino acids secreted from thyroid cells in mammals. Natural calcitonin or calcitonin derivatives act on osteoclasts to suppress bone resorption and reduce blood calcium levels, so they are known as therapeutic and / or prophylactic agents for hypercalcemia and osteoporosis. (Non-Patent Document 3) has been used in clinical practice. In addition, natural calcitonin or calcitonin derivatives have been reported to have analgesic action against certain types of pain such as low back pain associated with osteoporosis, neuropathic pain, bone metastatic cancer pain, and inflammatory pain. For example, it is known that continuous administration of elcatonin is effective for neuropathic pain (Patent Document 1).

International Publication WO2006 / 132261

NCI Cancer Bulletin, 2010, Feb. 23, Vol. 7, no. 4 Pharmacological Journal of Japan, 136, 275-279, 2010 Calcitonin-Basics and Clinical-, Life Sciences Publishing, 1998

  The problem to be solved by the present invention is to provide a medicament for the prevention and / or treatment of allodynia which is effective against allodynia caused by an anticancer agent.

  In order to cope with neuropathy caused by an anticancer agent, the present inventors are forced to reduce the amount of the anticancer agent or interrupt the administration of the anticancer agent, and an effective prevention method and treatment method for the neuropathy caused by the anticancer agent. It is important to recognize the current situation that has not yet been established as a problem, and to provide a drug for effectively preventing and / or treating neuropathy caused by anticancer drugs, especially allodynia caused by anticancer drugs. I thought it was a difficult task. Since allodynia caused by anticancer drugs makes daily life difficult and is one of the biggest causes of cancer treatment discontinuation, solving allodynia problems caused by anticancer drugs improves the quality of life of patients Not only because of the continuation of cancer treatment, but because it was considered important in cancer treatment.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have surprisingly found that calcitonins, particularly erkatonin and salmon calcitonin, which are one of them, are excellent prevention against allodynia caused by anticancer agents. And it discovered that it showed a therapeutic effect, and came to complete this invention. To date, there has been no report or suggestion that calcitonin can prevent and / or treat neuropathy caused by anticancer drugs, and allodynia caused by anticancer drugs. In addition, elcatonin has been reported to be effective in improving cooling sensation (Takashi Nagai et al., Journal of East Japan Disaster Reduction, Vol. 18, 493-497, 2006). (Cold sense), which is clearly distinguished from allodynia. Furthermore, Patent Document 1 discloses that continuous administration of elcatonin is effective for neuropathic pain, and allodynia is also mentioned. However, it has not been confirmed that allodynia was actually effective, and there is no disclosure or suggestion about allodynia caused by anticancer agents.
Moreover, it is known that the neuropathic pain of patent document 1 and the allodynia caused by the anticancer agent of the present invention are clearly different diseases. For example, it has been suggested that allodynia that occurs in the definitive mononeuropathy model of Patent Document 1 develops through the activation of spinal microglia, but the same classification model as the model used in the present invention. In peripheral neuropathy models caused by administration of paclitaxel, oxaliplatin, or vincristine, it has been suggested that allodynia develops without any microglia activation in the spinal cord (FY Zheng et al. Neuroscience 176 (2011) 447-454), neuropathic pain of Patent Document 1 and allodynia caused by the anticancer agent of the present invention are considered to be completely different onset mechanisms. That is, allodynia caused by the neuropathic pain of Patent Document 1 and the anticancer agent of the present invention is a clearly different disease.
On the other hand, it has been reported that human calcitonin has no effect on cold allodynia in strangulated mononeuropathy model and arthritis model (S. Perrot et al., Pain, 52, 1993, p41-47). . Among them, it was quite surprising that the present inventors found that elcatonin, a kind of cartonin, has a preventive and / or therapeutic effect on allodynia caused by an anticancer agent.

  That is. Examples of the present invention include the following.

[1] A medicament for the prevention and / or treatment of allodynia caused by an anticancer agent, which comprises natural calcitonin or a calcitonin derivative as an active ingredient.

[2] The medicament according to [1] above, wherein the calcitonin derivative is elcatonin.

[3] The medicament according to [1] above, wherein the natural calcitonin is salmon calcitonin.

[4] The medicament according to any one of [1] to [3], wherein the allodynia is cold allodynia.

[5] The medicament according to any one of [1] to [3], wherein the allodynia is mechanical allodynia.

[6] The medicament according to any one of [1] to [5] above, wherein the anticancer agent is one or more selected from the group consisting of taxane drugs and platinum preparations.

[6-2] The medicament according to [6] above, wherein the taxane drug is one or more selected from the group consisting of paclitaxel and docetaxel.

[7] The medicament according to [6], wherein the anticancer agent is paclitaxel.

[7-2] The medicament according to [6] above, wherein the platinum preparation is at least one selected from the group consisting of oxaliplatin, cisplatin, carboplatin, and nedaplatin.

[8] The medicament according to [6], wherein the anticancer agent is oxaliplatin.

[9] The medicament according to any one of [1] to [5] above, wherein the anticancer agent is administered by FOLFOX therapy or FOLFIRI therapy.

[10] The medicament according to any one of [1] to [9], wherein the natural calcitonin or calcitonin derivative is administered intermittently.

  In addition, when the item number to be cited is shown as a range as in [1] to [9] and a term having a branch number such as [6-2] is arranged in the range, [6] -2] means that a term having a branch number such as is also cited. The same applies to the following.

[10-2] The medicament according to any one of [1] to [9] above, wherein the intermittent administration is once a week.

[10-3] The medicament according to any one of [1] to [9], wherein the intermittent administration is daily administration.

[10-4] The medicament according to any one of [1] to [9] above, wherein the natural calcitonin or calcitonin derivative is administered once a week.

[10-5] The medicament according to any one of [1] to [9], wherein the natural calcitonin or calcitonin derivative is administered daily.

[11] Ovarian cancer, non-small cell cancer, breast cancer, gastric cancer, endometrial cancer, head and neck cancer, esophageal cancer, leukemia, malignant lymphoma, childhood tumor, multiple myeloma, malignant astrocytoma, glioma, chorionic Disease, germ cell tumor, lung cancer, testicular tumor, bladder cancer, renal pelvis tumor, urethral tumor, prostate cancer, cervical cancer, neuroblastoma, small cell lung cancer, osteosarcoma, malignant pleural mesothelioma, malignant bone tumor, and The medicament according to any one of [1] to [10-5] above, which is administered to a cancer patient suffering from one or more types of cancer selected from the group consisting of colorectal cancer.

[12] A medicament for the prevention and / or treatment of allodynia caused by an anticancer agent, comprising natural calcitonin or a calcitonin derivative as an active ingredient, which is administered in combination with an anticancer agent.

[12-2] The medicament according to [12], wherein the anticancer agent is a taxane drug or a platinum preparation.

[12-3] The medicament according to [12] above, wherein the anticancer agent is paclitaxel.

[12-4] The medicament according to [12] above, wherein the anticancer agent is oxaliplatin.

[13] A method for preventing and / or treating allodynia caused by an anticancer agent, comprising the step of administering natural calcitonin or a calcitonin derivative to a mammal.

[13-2] The method described in [13] above, which has the characteristics described in [1] to [12-4] above.

[14] Use of natural calcitonin or a calcitonin derivative for producing a medicament for the prevention and / or treatment of allodynia caused by an anticancer agent.

[14-2] Use according to [14] above, which has the characteristics described in [1] to [12-4] above.

  According to the present invention, it becomes possible to effectively prevent and / or treat allodynia caused by an anticancer agent. Until now, in order to cope with allodynia caused by anticancer drugs, it has been necessary to reduce the weight of anticancer drugs or interrupt cancer chemotherapy, but the present invention makes it possible to continue appropriate cancer chemotherapy, It is possible to contribute to quality improvement.

FIG. 1 shows the results of examining the therapeutic effect and sustained effect of elcatonin on mechanical allodynia caused by oxaliplatin administration in the von Frey test. *: Comparison by t-test with no correspondence between measured values in control group and OX administration group P <0.05, #: t-test with no correspondence in measured values between OX administration group and OX and test drug administration group Comparison by P <0.05 FIG. 2 shows the results of examining the preventive effect of elcatonin against mechanical allodynia caused by oxaliplatin administration in the von Frey test. FIG. 3 shows a schematic diagram of a cooling sensation threshold analysis device used in the Cold plate test. FIG. 4 shows the results of examining the therapeutic effect and sustained effect of elcatonin on cold allodynia caused by oxaliplatin administration in a cold stimulation test. *: Comparison by t-test with no correspondence between measured values of control group and OX administration group P <0.05, #: t-test with no correspondence between measured values of OX administration group and OX and test drug administration group Comparison by P <0.05 FIG. 5 shows the results of examining the preventive effect of elcatonin against cold allodynia caused by oxaliplatin administration in the von Frey test. FIG. 6 shows the results of examining the therapeutic effect and sustained effect of elcatonin on mechanical allodynia caused by paclitaxel administration in the von Frey test. *: Comparison by t-test with no correspondence between measured values of control group and PTX administration group P <0.05, #: t-test with no correspondence between measured values of PTX administration group, PTX and test drug administration group Comparison by P <0.05 FIG. 7 shows the results of examining the therapeutic effect and sustained effect of elcatonin on cold allodynia caused by paclitaxel administration in a cold stimulation test. *: Comparison by t-test with no correspondence between measured values of control group and PTX administration group P <0.05, #: t-test with no correspondence between measured values of PTX administration group, PTX and test drug administration group Comparison by P <0.05 FIG. 8 shows the results of examining the therapeutic effect and duration of effect of salmon calcitonin on mechanical allodynia caused by oxaliplatin administration in the von Frey test. *: Comparison by t-test with no correspondence between measured values in control group and OX administration group P <0.05, #: t-test with no correspondence in measured values between OX administration group and OX and test drug administration group Comparison by P <0.05 FIG. 9 shows the results of examining the therapeutic effect and continuous effect of salmon calcitonin on cold allodynia caused by oxaliplatin administration in a cold stimulation test. *: Comparison by t-test with no correspondence between measured values of control group and OX administration group P <0.05, #: t-test with no correspondence between measured values of OX administration group and OX and test drug administration group Comparison by P <0.05 FIG. 10 shows the results of examining the onset time of the therapeutic effect of elcatonin on cold allodynia caused by oxaliplatin administration in a cold stimulation test.

  Hereinafter, a mode for carrying out the present invention (hereinafter sometimes abbreviated as “the present embodiment”) will be specifically described.

  Examples of calcitonin useful as an active ingredient of a prophylactic and / or therapeutic agent for allodynia caused by the anticancer agent of the present embodiment include various natural calcitonin or calcitonin derivatives.

  Natural calcitonin is a polypeptide that is present in C cells in the thyroid gland in mammals and in the post-gland gland in other animals, and is considered to be one of the calcium metabolism regulating hormones. Specific examples of natural calcitonin include chicken calcitonin, eel calcitonin, human calcitonin, salmon calcitonin, or porcine calcitonin, and eel calcitonin or salmon calcitonin (Helv. Chim. Acta (1969), 52 (7) 1789-95), and eel calcitonin is more preferred. As another aspect, salmon calcitonin may be more preferable.

  Examples of calcitonin derivatives include peptide analogs of natural calcitonin. Specific examples include compounds in which the 1,7-position disulfide bond is chemically modified based on the structure of the above-mentioned natural calcitonin. More specifically, [ASU1-7] chicken calcitonin or [ASU1-7] Eel calcitonin (chemical name 1-butyric acid-7- (L-2-aminobutyric acid) -26-L-aspartic acid-27-L-valine described in JP-B-53-41677) 29-L-alanine calcitonin (hereinafter sometimes abbreviated as “elcatonin”) and the like are preferable examples, and [ASU1-7] eel calcitonin (elcatonin) is particularly preferable. As calcitonin useful as an active ingredient of the preventive and / or therapeutic agent for allodynia caused by the anticancer agent in the present embodiment, elcatonin or salmon calcitonin is particularly preferable, and elcatonin is most preferable. In another embodiment, salmon calcitonin is most preferable.

  These natural calcitonin or calcitonin derivatives have extremely low toxicity. For example, elcatonin can be lethal to mice and rats by intravenous, intramuscular, subcutaneous, or oral routes of 13500 or 7400 units / kg (body weight). No toxicity was observed.

  The “cancer chemotherapy” in the present invention means a method for treating cancer using an anticancer agent.

  The “anticancer agent” in the present embodiment is a drug having an anticancer activity and is not particularly limited as long as it exhibits allodynia symptoms upon administration. For example, an anticancer agent that inhibits metabolism of nucleic acid ( Platinum preparations, etc.), anticancer agents that inhibit microtubule polymerization (vinca alkaloids), anticancer agents that inhibit microtubule depolymerization (taxanes), anticancer agents that have hormone antagonism (antiestrogens, etc.), intracellular signals Anticancer agents that inhibit transmission (proteosome inhibitors, etc.), anticancer agents that act on molecular targets specific to malignant tumors (tyrosine kinase inhibitors, antibody preparations, etc.), or anticancer agents that have nonspecific immunostimulatory action (streptococcal preparations, etc.) And an anticancer agent that inhibits nucleic acid metabolism or an anticancer agent that inhibits microtubule polymerization or depolymerization. For example, the anticancer agent includes one or more anticancer agents selected from the group consisting of taxane drugs and platinum preparations. Taxane drugs or platinum preparations are preferable, and taxane drugs are more preferable. Moreover, a platinum formulation may be preferable as another aspect.

  Examples of the taxane-based preparation include paclitaxel, docetaxel, tamoxifen, and the like. One or more types selected from the group consisting of paclitaxel and docetaxel are preferable, and paclitaxel is more preferable.

  Examples of the platinum preparation include oxaliplatin, cisplatin, carboplatin, nedaplatin and the like. One or more kinds selected from the group consisting of oxaliplatin, cisplatin, carboplatin, and nedaplatin are preferable, and oxaliplatin is preferable.

  The allodynia caused by the anticancer drug to be prevented and / or treated by the pharmaceutical of the present embodiment is not limited to single agent therapy using a single type of anticancer drug, but a combination of a plurality of drugs having different action mechanisms Allodynia caused by multiple-drug combination therapy is also included. Multi-drug combination therapy includes FOLFOX therapy or FOLFIRI (forphyri) therapy, and FOLFOX therapy is preferred. In another embodiment, FOLFIRI therapy may be preferable.

  FOLFOX therapy is one type of cancer chemotherapy performed in combination with oxaliplatin, fluorouracil and levofolinate. FOLFOX therapy is classified into, for example, FOLFOX2, FOLFOX3, FOLFOX4, FOLFOX6, mFOLFOX6, FOLFOX7, mFOLFOX7, etc., depending on the administration method.

  FOLFIRI therapy is one type of cancer chemotherapy performed in combination with irinotecan, fluorouracil, levofolinate or leucovorin.

  Anticancer agents that inhibit nucleic acid metabolism include, for example, alkylating agents (eg, cyclophosphamide, nimustine), antitumor antibiotics (eg, doxorubicin, mitomycin C, preomycin), topoisomerase inhibitors (eg, irinotecan). , Etoposide), platinum preparations (eg, cisplatin, carboplatin, oxaliplatin), pyrimidine metabolism inhibitors (eg, mercaptopurine, fludarabine), or folate synthesis inhibitors (eg, methotrexate). Of these, platinum preparations are preferred, and oxaliplatin is more preferred from the viewpoint that it is an anticancer agent most likely to cause allodynia and a method for treating allodynia is strongly desired.

  Anticancer agents that inhibit microtubule polymerization or depolymerization include vinca alkaloids (eg, vincristine, vinblastine), taxanes (eg, paclitaxel, docetaxel, tamoxifen), or antiandrogens (eg, flucmid). . Of these, taxanes are preferred, and paclitaxel is more preferred.

  Examples of the anti-cancer agent having a hormone antagonistic action include an anti-estrogen agent (for example, tamoxifen) or an anti-androgen agent (for example, flutamide).

  Examples of the anticancer agent that inhibits intracellular signal transduction include a proteosome inhibitor (for example, bortezomib).

  Anticancer agents that act on molecular targets specific for malignant tumors include, for example, BCR / ABL tyrosine kinase inhibitors (eg, imatinib), EGFR tyrosine kinase inhibitors (eg, gefitinib), antibody formulations (eg, rituximab, trastuzumab, tocilizumab ) Or arsenic preparations.

  Examples of the anticancer agent having a non-specific immunostimulatory action include a streptococcal preparation and a polysaccharide polysaccharide preparation.

“Allodynia caused by anticancer agent” in the present embodiment means allodynia (sometimes referred to as allodynia) caused by administration of the anticancer agent as exemplified above. Allodynia means a symptom in which a stimulus that does not usually cause pain (for example, light contact, pressure, or mild low-temperature stimulus) is felt as pain. The allodynia caused by anticancer agents includes acute allodynia that appears immediately after administration of the anticancer agent and chronic allodynia that appears late with the continuation of anticancer agent treatment. Included in allodynia caused by anticancer drugs. Acute allodynia is characteristic of oxaliplatin. As a method for evaluating allodynia caused by an anticancer agent, any method generally known as a method for evaluating the degree of pain may be used. For example, VAS (Visual analog scale), NRS (Numerical rating) scale), ENS (Eastern Cooperative Group neuropathy scale), WHO classification scale for neuropathy-symbols, and the like. In addition, allodynia caused by an anticancer drug may be evaluated as one of the symptoms of peripheral neuropathy caused by the anticancer drug. As an evaluation standard for peripheral neuropathy, DEB-NTC (Debiopharm: neurological symptom-sensory toxicity standard), CTCAE (Common Terminology Criteria for Advanced Events), or the like is used.
For example, in DEB-NTC, peripheral neuropathy can be evaluated by the following four grades.
Grade 0: No abnormality Grade 1: Peripheral nerve symptom manifestation; However, disappearance in less than 7 days Grade 2: Peripheral nerve symptom persisting for 7 days or more. However, there is no motor dysfunction.
Grade3: Painful abnormal sensation, peripheral nerve symptoms, or motor dysfunction that interferes with daily life.
In CTCAE v3.0 (neuropathy: sensory), peripheral neuropathy can also be evaluated by the following 4-grade Grade.
Grade 1: no symptoms; deep tendon reflex loss or sensory abnormalities (including aching) but no motor dysfunction.
Grade 2: Although there is a motor dysfunction due to a sensory change or a sensory abnormality (including pain), there is no problem in daily life.
Grade 3: Perceptual changes or abnormalities that hinder daily life.
Grade 4: Inactivity In this embodiment, “allodynia caused by an anticancer drug” may be referred to as “allodynia due to cancer chemotherapy”.

  Allodynia is defined by the International Society of Pain as “pain caused by stimuli that do not normally cause pain”. In the present embodiment, allodynia is not particularly limited as long as it is a symptom in which a stimulus that does not usually cause pain is felt as pain, and examples thereof include mechanical allodynia or cold allodynia. Symptoms are preferred. In another embodiment, mechanical allodynia may be preferable.

  Mechanical allodynia includes symptoms in which a tactile stimulus that does not usually cause pain is felt as pain. For example, symptoms such as fastening buttons on a shirt, taking out coins in a wallet, walking, etc. become difficult.

  Cold allodynia includes symptoms in which a cold stimulus that does not usually cause pain is felt as pain. For example, there are symptoms such as cooking and washing with water, having a cup with water, and making it difficult to perform daily operations such as going out in winter.

  In the present embodiment, the natural calcitonin or calcitonin derivative can be administered before the anticancer agent is administered (prophylactic administration), or can be administered after the anticancer agent is administered (therapeutic administration). It is preferable to administer after administering an anticancer agent. Moreover, as another aspect, it may be preferable to administer before administering an anticancer agent. Furthermore, natural calcitonin or a calcitonin derivative and an anticancer agent can be administered simultaneously.

  When natural calcitonin or a calcitonin derivative is administered before administration of an anticancer agent, the number of hours before administration of the anticancer agent is not particularly limited as long as the effect of preventing allodynia can be exhibited. Preferably, after 9 days before administration of the anticancer agent, more preferably after 7 days, more preferably after 5 days, particularly preferably after 3 days, most preferably after 1 day. As another aspect, 12 hours or more are most preferable.

  When administering natural calcitonin or a calcitonin derivative after administering an anticancer agent, how many hours after administration of the anticancer agent to administer the natural calcitonin or calcitonin derivative is not particularly limited as long as it can exert the effect of treating allodynia, It is preferably before 8 days after administration of the anticancer agent, more preferably before 6 days, more preferably before 4 days, particularly preferably before 2 days, most preferably before 6 hours. As another aspect, 1 hour or less is most preferable.

  In producing the medicament in the present embodiment, it is preferable to add a pharmaceutically acceptable carrier to the natural calcitonin or calcitonin derivative, which is an active ingredient, if necessary, to obtain a pharmaceutical composition.

  Natural calcitonin can be synthesized by a conventional method on the basis of known structural information (Satoshi Orimo, Tatsuo Suda, Ikuo Yamamoto, Naoyuki Takahashi, Calcitonin-Basics and Clinical-, Life Science Publishing, 1998), and especially salmon calcitonin. Can be purchased from Taiyo Pharmaceutical Co., Ltd. as salmon calcitonin IM 10 international unit “Taiyo”. In addition, calcitonin derivatives can be synthesized based on known structural information (Satoshi Orimo, Tatsuo Suda, Ikuo Yamamoto, Naoyuki Takahashi, Calcitonin-Basic and Clinical, Life Science Publishing, 1998). Co., Ltd.) can be purchased as 40 units of ercitonin injection.

  In preparing a pharmaceutical composition, it is preferable to select a pharmaceutically acceptable carrier so that there is no interaction that substantially reduces the pharmaceutical efficacy of natural calcitonin or calcitonin derivatives under normal use conditions. . The pharmaceutically acceptable carrier preferably has sufficiently high purity and sufficiently low toxicity to such an extent that there is no safety problem when administered to a patient. The pharmaceutically acceptable carrier is not particularly limited as long as it is generally recognized as a carrier that can be used for pharmaceuticals or can be recognized in the future. For example, saccharides such as lactose, glucose, and sucrose, corn starch , Starch such as potato starch, cellulose derivatives such as cellulose and sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, powdered tragacanth, gelatin, talc, stearic acid, magnesium stearate, peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, theobroma Vegetable oils such as oil, polyols such as propylene glycol, glycerin, sorbitol, mannitol, polyethylene glycol, buffers such as agar, alginic acid, isotonic solution, phosphate buffer, lauryl sulfate Wetting agents and lubricants, colorants such as thorium, flavoring agents, preservatives, stabilizers, antioxidants, preservatives, and the like antimicrobial agents.

  The pharmaceutical drug form in the present embodiment is not particularly limited as long as it is practically administrable and has an effect as a drug. For example, injections, rectal absorbents, vaginal absorbents, nasal drops Absorbents, transdermal absorbents, pulmonary absorbents, buccal absorbents, orally administered agents, and the like are preferable. Injectable agents, nasal absorbent agents, pulmonary absorbent agents, or orally administered agents are preferable, and injectable agents are particularly preferable. preferable. Moreover, as another aspect, a transdermal absorbent is preferable, a nasal absorbent is preferable, a pulmonary absorbent is preferable, and an oral administration agent may be preferable.

  The injection as a medicament in the present embodiment is preferably used for intramuscular administration or intravenous administration. When the medicament in the present embodiment is administered as a rectal or vaginal absorbent, it is generally used in the form of a suppository. When the medicament in the present embodiment is administered as a nasal absorbent or a transdermal absorbent, it is used in the form of a preparation to which an appropriate absorption enhancer is added. Further, when the medicament in the present embodiment is administered as a pulmonary absorbent, it is used in the form of an aerosol composition containing an appropriate dispersant or water and a propellant. When the medicament in the present embodiment is administered as an intraoral absorbent, an appropriate absorption enhancer is added and used, for example, in the form of a sublingual tablet. Moreover, when administering the pharmaceutical in this Embodiment as an oral administration agent, it is used with the forms for oral use, such as a ribosome formulation and a microcapsule formulation.

  When prescribing the medicine in this embodiment as an injection, for example, elcatonin is dissolved in distilled water for injection in which appropriate amounts of buffer, tonicity agent and pH regulator are dissolved, and sterilized through a sterilization filter. It can be prepared by dispensing into ampoules. For rectal and vaginal absorbents, for example, elcatonin can be used in distilled water or an oily solvent by appropriately selecting an absorption enhancer such as sodium bectinate or sodium alginate and a hypertonic agent such as sodium chloride or glucose. It is prepared as a rectal / vaginal injection suppository or suppository by dissolving or dispersing (see British Patent Nos. 20092002 and 2095994).

  The nasal absorbent as a medicament in the present embodiment is prepared as a solution or powder obtained by adding an absorption promoter such as glucuronic acid, succinic acid, and tartaric acid, which are water-soluble organic acids, to, for example, elcatonin (Japanese Patent Application Laid-Open (JP-A)) JP 63-243033, JP 63-316737, JP 1-230530, JP 2-000111, JP 2-104531). Further, for example, a nasal absorbent can be obtained by appropriately adding an emulsion to elcatonin (Japanese Patent Application Laid-Open No. 4-99729).

  In the case of prescribing the medicament in the present embodiment as a transdermal absorption agent, for example, a method for promoting absorption from the skin by adding an absorption accelerator such as Azone to salmon calcitonin has been reported ( The second annual meeting of the Pharmacological Society of Japan, p57-58), and the method of iontophoresis (Ann.NY Acad. Sci., 507, 32, 1988) of natural calcitonin or calcitonin derivatives. A transdermal absorbent may be obtained.

  When prescribing the medicine in this embodiment as a pulmonary absorbent, natural calcitonin or a calcitonin derivative is pulverized and pulverized with a dispersing agent such as Arlacel and Span 80 to obtain a homogeneous paste, and then the paste is cooled. A method of obtaining a transpulmonary absorbent by dispersing in a propellant such as Freon 11 or Freon 12 and filling a container equipped with a valve may be used (Japanese Patent Laid-Open No. 60-161924).

  Moreover, when prescribing the medicament in the present embodiment as an oral absorbent, for example, ascorbic acids, acidic amino acids, citric acids, unsaturated fatty acids, salicylic acids, etc. alone or in combination with natural calcitonin or calcitonin derivatives. Oral absorbents can be obtained by combining more than one kind and adding excipients such as glucose, flavoring agents such as menthol, etc. to make troches, sublingual tablets, powders, etc. 56-140924). Furthermore, for oral administration, natural calcitonin or a calcitonin derivative may be prepared by a method using a W / O / W emulsion (Endocrinol. Jpn., 23, 493, 1976), or a ribosome formulation method (Hormone). Res., 16, 249, 1982) natural calcitonin or calcitonin derivatives may be formulated.

  It is preferable that the medicine in this embodiment has high safety. Pharmaceutical safety can be confirmed by carcinogenicity tests, genotoxicity tests, toxicokinetics and pharmacokinetics, toxicity tests, reproductive and developmental toxicity tests, safety pharmacology tests, immunotoxicity tests, etc. (ICH guidelines).

  The medicament in the present embodiment is not particularly limited as long as the effect of prevention and / or treatment of allodynia caused by an anticancer agent is confirmed after administration of natural calcitonin or a calcitonin derivative, Examples are confirmed to be confirmed within 24 hours after administration of natural calcitonin or calcitonin derivative, and the effect is preferably confirmed within 12 hours, more preferably confirmed within 6 hours, and 3 hours. The effect is more preferably confirmed within 1 hour, particularly preferably when the effect is confirmed within 1 hour, and most preferably when the effect is confirmed within 30 minutes. As described above, the medicament in the present embodiment may be characterized in that the effect of prevention and / or treatment of allodynia caused by an anticancer agent is confirmed at an early stage.

  Moreover, although the pharmaceutical in this Embodiment can be prescribed as an intermittent administration formulation or a continuous administration formulation, it is preferable to formulate as an intermittent administration formulation.

  Intermittent administration refers to administration or release of a drug into the body at a certain time, not continuously, one or more times, preferably multiple times. For example, the intermittent administration may be once or twice a day, and preferably once a day. In addition, intermittent administration may be daily, 1-3 days per week, or 1-5 days per week, but preferably 1 day per week. In another embodiment, 5 days per week may be preferable. As yet another aspect, daily may be preferred.

  The intermittent administration may be once a day, once a week, three times a week, five times a week, or once every two weeks, but once a week. Is preferred. In another embodiment, five times a week may be preferable. Yet another aspect may be preferred daily. In some cases, administration once every two weeks is also preferable.

  Continuous administration means an administration method in which a drug is continuously released into the body for a certain period of time or longer, and any administration route may be used as long as it is systemic administration or local administration to peripheral tissues, for example, an infusion pump, Examples thereof include administration using a device such as an infusion pump or manual administration, and a sustained release preparation using a polymer that is degraded in vivo as a carrier.

  The natural calcitonin or calcitonin derivative contained in the medicament in the present embodiment as an active ingredient varies depending on the age, physique, sex, degree of symptoms, specific activity of the administered calcitonin derivative, drug form, etc. The effective dose of elcatonin used as an internal injection is 0.5 to 5000 units / human / day (weeks), preferably 0.7 to 1000 units / human / day (weeks), more preferably 1 to 400 units / person / day (weeks). With reference to these, it may be adjusted as appropriate according to the patient's condition and the pharmaceutical form of the present embodiment. The frequency of administration of natural calcitonin or calcitonin derivative may be 1 to 2 times a day, or may be daily or 1 to 3 times a week. The amount of the natural calcitonin or calcitonin derivative in the drug can be determined as appropriate. In short, it is sufficient that the calcitonin activity per administration is determined to be equivalent to 0.5 to 5000 units of the elcatonin injection. For example, as disclosed in “Calcif. Tissue Int., 46, 5-8, 1990”, when 200 units of a nasal absorbent of salmon calcitonin is administered to a human, the blood concentration after administration is 37 pg / mL. And approximately the same concentration as the highest blood concentration (Biol. Pharm. Bull., 18 (6), 900, 1995) when 20 units of elcatonin was administered intramuscularly, and the specific activity of salmon calcitonin (J. Bone Miner.Res.17,1478-1485,2002) and the specific activity of elcatonin (modern medical practice, 20 (12), 2217,1978), so the dose of nasal absorbent is administered by injection It can also be estimated at about 10 times the amount. In addition, as disclosed in, for example, “J. Bone Miner. Res. 17, 1478-1485, 2002”, the dose of an orally administered salmon calcitonin is determined based on the ratio of blood concentration to intravenous infusion. Orally because it is about 60 times the dose and about 1.5 times the dose required to obtain the maximum blood concentration equivalent to intravenous infusion by intramuscular administration of elcatonin (in-house data) The dose of the absorbent can be estimated to be about 40 times the dose of the injection. Thus, the dose of natural calcitonin or calcitonin derivative in various dosage forms can be set from the blood concentration. Further, an appropriate amount of natural calcitonin or a calcitonin derivative may be dissolved in a suitable infusion solution such as Solita T-3 and administered intravenously, for example, over 1 to several hours. In this case, the dose of the natural calcitonin or calcitonin derivative is preferably a dose that does not change the blood calcium concentration. For example, in rats, the dose is between 0.75 milliunit / kg / week and 75 units / kg / week. There are also preferred embodiments in which 75 units / kg / week to 400 units / kg / week is preferred, and this value can be set with reference to other animal species including humans.

  Although the patient who administers the medicine in this Embodiment will not be specifically limited if it is a patient who administers an anticancer agent, Specifically, a cancer patient is illustrated. Examples of cancer patients include ovarian cancer, non-small cell cancer, breast cancer, stomach cancer, endometrial cancer, head and neck cancer, esophageal cancer, leukemia, malignant lymphoma, childhood tumor, multiple myeloma, malignant astrocytoma, glioma Tumor, choriocarcinoma, germ cell tumor, lung cancer, testicular tumor, bladder cancer, renal pelvis tumor, urethral tumor, prostate cancer, cervical cancer, neuroblastoma, small cell lung cancer, osteosarcoma, malignant pleural mesothelioma, malignant Examples are cancer patients suffering from one or more types of cancer selected from the group consisting of bone tumors and colon cancer.

  The medicament in the present embodiment is one or more drugs selected from other drugs used as a method for treating peripheral neuropathy caused by an anticancer drug, such as steroids, antidepressants, antiepileptic drugs, opioids, and the like. Can be selected and administered as a combination or combination. It is also possible to administer natural calcitonin or a calcitonin derivative in combination with physical therapy, complementary therapy such as massage or acupuncture.

  Further, according to the present invention, there is provided a medicament for the prevention and / or treatment of allodynia caused by an anticancer agent, which comprises natural calcitonin or a calcitonin derivative administered as a combination with an anticancer agent as an active ingredient. Provided. Preferred examples of the natural calcitonin or calcitonin derivative in the present embodiment include the above-mentioned natural calcitonin or calcitonin derivative. Moreover, as an anticancer agent in this Embodiment, the preferable example as said anticancer agent is mentioned. Furthermore, as the allodynia in this Embodiment, the preferable example as said allodynia is mentioned.

  In the present embodiment, “administered in combination with an anticancer agent” means that the natural calcitonin or calcitonin derivative is administered simultaneously with the anticancer agent, or the natural calcitonin or calcitonin derivative is administered before or after the anticancer agent administration. It is mentioned that. About how many hours before administration of the anticancer agent or after administration of the anticancer agent, natural calcitonin or a calcitonin derivative is administered as described above.

  The present invention also provides a medicament for the prevention and / or treatment of allodynia caused by an anticancer drug, which comprises natural calcitonin or a calcitonin derivative and an anticancer drug as active ingredients.

  Furthermore, a method for preventing and / or treating allodynia caused by an anticancer agent, which comprises the step of administering natural calcitonin or a calcitonin derivative to a mammal, is also included in the scope of the present invention.

  Furthermore, use of natural calcitonin or a calcitonin derivative for producing a medicament for the prevention and / or treatment of allodynia caused by an anticancer agent is also included in the scope of the present invention.

  Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto.

[Example 1] Effect of oxaliplatin on rat allodynia In order to confirm the effect of elcatonin (hereinafter sometimes abbreviated as ECT) on allodynia caused by an anticancer agent, when the anticancer agent oxaliplatin is administered to rats The effects of ECT on allodynia induced by mechanical stimulation and allodynia caused by low temperature stimulation were examined. ECT was subcutaneously administered to rats as a test drug, and the following tests (von Frey test and cold plate test) were performed.

  As elcatonin, ercitonin injection (40 units: Asahi Kasei Pharma Co., Ltd.) was used.

(1) Preparation of oxaliplatin administration-induced allodynia model rat 5-week-old SD male rats (150-200 g) were used as experimental animals, and oxaliplatin (hereinafter sometimes abbreviated as OX) was added to the rats at 6 mg / day. After a single dose of kg into the abdominal cavity, the therapeutic and sustained effects of ECT were confirmed. The control group was similarly administered with 5% glucose solution (5% TZ) used as a solvent for OX. Further, for the purpose of confirming the preventive effect of ECT, OX was administered again 16 days after the initial administration of OX and 9 days after the withdrawal of the test drug.

  Oxaliplatin was used for Elplat injection (100 mg: Yakult Co., Ltd.).

(2) Administration of test drug The experimental animals were divided into three groups: a control group, an OX administration group, OX, and a test drug administration group (OX + test drug administration group). In the OX + test drug administration group, ECT, which is the test drug, was administered subcutaneously (20 U / kg) once a day for 5 days from 3 days after OX administration. In the control group and the OX administration group, ECT solvent (0.1 mM sodium acetate buffer (pH 5.5) containing 0.02% BSA) was added at 0.1 ml / B. W. 100 g was administered in the same manner.

(3) Statistical processing Statistical processing of the results was performed by unsupported t-test (SAS system, version 8.2), and a risk rate of 5% or less was considered significant (* in the figure: from the control group) Comparison of measured values with OX administration group, P <0.05;# in the figure: comparison of measured values between OX administration group and OX and test drug administration group, P <0.05).

(4) von Frey test
The three groups of rats were subjected to mechanical stimulation alternately 5 times on the back of the left and right hind limbs using von Frey filaments having strengths of 1, 2 and 4 g. The number of avoidance actions (lifting the hind limbs, biting the hind limbs) was measured, and allodynia due to mechanical stimulation was observed. 30 minutes before OX administration, 3 days after OX administration and before test drug administration, 3 days after OX administration and 6 hours after test drug administration, 5 and 7 days after OX administration and before test drug administration, 10 days after OX administration and test 3 days after drug withdrawal, before OX re-administration (16 days after OX first administration), 9 days after study drug withdrawal, 6 days after OX re-administration (22 days after first administration of OX), and 15 days after study drug withdrawal Carried out.

  FIG. 1 shows an example of the results of the ECT therapeutic effect and sustained effect confirmation test (von Frey filament strength: 4 g). In the OX administration group, the number of avoidances was significantly increased compared to the control group. In the OX + test drug administration group, the number of avoidances was similar to that in the control group from 6 hours after administration of the test drug, and the increase in the number of avoidances was significantly improved as compared with the OX administration group. Moreover, in the OX + test drug administration group, it was observed that the improvement in the increase in the number of avoidances was maintained even after the administration of the test drug was completed. The test results carried out with the strength of von Frey filament: 1 and 2 g also showed the same tendency as in FIG.

  An example of the result of the ECT prevention effect confirmation test (intensity of von Frey filament: 4 g) is shown in FIG. After the first OX administration, the number of avoidances increased in the OX administration group compared to the control group, and the increase in the number of avoidances was suppressed in the OX + test drug administration group compared to the OX administration group. However, 16 days after OX administration, the difference was not observed between the OX administration group and the control group, and the increase in the number of avoidances by the OX + test drug administration group was not observed. When OX is re-administered at this point, the number of avoidance increases in the OX administration group 22 days after the first OX administration (6 days after the OX re-administration) compared to the control group, and in the OX + study drug administration group 15 days after the withdrawal of the study drug However, an increase in the number of avoidances was prevented from the OX administration group.

  From the above results, it was confirmed that elcatonin has an excellent preventive effect on OX mechanical allodynia and a therapeutic effect excellent in immediate effect and sustainability.

(5) Cold plate test
The cold sensation threshold analysis device (FIG. 3) used for the Cold plate test is composed of a Peltier element, a cold stimulator, and a thermistor. The surface temperature of the cold stimulator was controlled by a proportional / integral control (PI) temperature controller. Using the tip of the cold stimulator controlled at 8 ° C for the three groups of rats described above, avoidance behavior (raising the hind limbs and biting the hind limbs) when stimulating the back of the left and right hind limbs alternately 5 times each Latency was measured and allodynia caused by low-temperature stimulation was observed. Cut off time was 15 seconds. 30 minutes before OX administration, 3 days after OX administration and before test drug administration, 3 days after OX administration and 6 hours after test drug administration, 5 and 7 days after OX administration and before test drug administration, 10 days after OX administration and test 3 days after drug withdrawal, before OX re-administration (16 days after OX first administration), 9 days after study drug withdrawal, 6 days after OX re-administration (22 days after first administration of OX), and 15 days after study drug withdrawal Carried out.

  An example of the results of the ECT treatment effect and sustained effect confirmation test is shown in FIG. In the OX administration group, the avoidance latency was remarkably reduced as compared with the control group. The OX + test drug administration group showed an avoidance latency comparable to that of the control group 6 hours after administration of the test drug, and significantly reduced the avoidance latency compared to the OX administration group. Moreover, in the OX + test drug administration group, it was observed that the improvement in the decrease in avoidance latency was maintained even after the administration of the test drug was completed.

  An example of the result of the ECT prevention effect confirmation test is shown in FIG. Sixteen days after the first OX administration, there was almost no difference in the number of avoidances between the control group, the OX administration group, and the OX + test drug administration group. When OX is re-administered at this point, the avoidance latency is lower in the OX administration group than in the control group 22 days after the first OX administration (6 days after OX re-administration), and in the OX + study drug administration group, the test drug is withdrawn 15 Even after day, a decrease in avoidance latency was prevented from the OX administration group.

  From the above results, it was confirmed that elcatonin has an excellent preventive effect on OX cold allodynia and a therapeutic effect excellent in immediate effect and sustainability.

[Example 2] Action of paclitaxel on rat allodynia Similar to Example 1, mechanical stimulation generated when anticancer drug paclitaxel was administered to rats in order to confirm the effect of elcatonin on allodynia caused by anticancer drug. The effect of ECT on allodynia caused by stagnation and allodynia caused by cold stimulation was examined. ECT was subcutaneously administered to rats as a test drug, and the following tests were conducted.

  As elcatonin, ercitonin injection (40S: Asahi Kasei Pharma Co., Ltd.) was used.

(1) Preparation of paclitaxel administration-induced allodynia model rat As in Example 1, 5-week-old male SD rats (150 to 200 g) were used as experimental animals, and the rats were abbreviated as paclitaxel (hereinafter, PTX). 2 mg / kg was administered intraperitoneally. The administration was carried out four times every other day (days 1, 3, 5, 7). The control group was similarly administered with a PTX solvent, that is, 0.5 mL of a solution prepared by mixing Cremophor EL and ethanol in a 1: 1 ratio diluted to 1.5 mL with physiological saline.

  As paclitaxel, paclitaxel (100 mg: LKT Laboratories, Inc.) was used.

(2) Administration of test drug As in Example 1, the experimental animals were grouped into 3 groups: a control group, a PTX administration group, PTX and a test drug administration group (PTX + test drug administration group). In the PTX + test drug administration group, ECT, which is the test drug, was subcutaneously administered once a day for 5 days (20 U / kg) from 15 days after PTX administration. The ECT solvent was similarly administered to the control group and the PTX administration group.

(3) Statistical processing Statistical processing of the results was performed by unsupported t-test (SAS system, version 8.2), and a risk rate of 5% or less was considered significant (* in the figure: from the control group) Comparison of measurement values with PTX administration group, P <0.05;# in the figure: comparison of measurement values between PTX administration group, PTX and test drug administration group, P <0.05).
(4) von Frey test
As in Example 1, the three groups of rats were mechanically stimulated 5 times alternately on the back of the left and right hind limbs using 4 g strength von Frey filament. The number of avoidance actions was measured and allodynia due to mechanical stimulation was observed. 5 hours before PTX administration, 1 hour after PTX administration, 2, 3, 5, 6, 7, 9, 11, 13 days after PTX administration, 15 days after PTX administration and before administration of test drug, 15 days after administration of PTX and test drug 6 hours after administration, 17 and 19 days after administration of PTX, before administration of test drug, 22 days after administration of PTX, 3 days after administration, 26 days after administration of PTX, 7 days after administration, 29 days after administration of PTX, and 10 days after administration A measurement test was performed later.

  The test result (strength of von Frey filament: 4 g) is shown in FIG. The number of avoidances was significantly increased in the PTX administration group compared to the control group. In the PTX + test drug administration group, the number of avoidances was similar to that in the control group from 6 hours after administration of the test drug, and the increase in the number of avoidances was significantly improved compared to the PTX administration group. Moreover, in the PTX + test drug administration group, it was observed that the improvement in the increase in the number of avoidances was maintained even after the administration of the test drug was terminated.

  From the above results, it was confirmed that elcatonin has a therapeutic effect excellent in immediate effect and sustainability for mechanical allodynia caused by PTX.

(5) Cold plate test
As in Example 1, when the three groups of rats were stimulated alternately 5 times on the back of the left and right hind limbs using the tip of the cold stimulation unit controlled at 8 ° C. of the cold sensation threshold analysis device The latency of avoidance behavior was measured and allodynia caused by low-temperature stimulation was observed. Cut off time was 15 seconds. 5 hours before PTX administration, 1 hour after PTX administration, 2, 3, 5, 7, 9, 11 days after PTX administration, 15 days after PTX administration and before administration of test drug, 15 days after administration of PTX and 6 hours after administration of test drug , 17 and 19 days after PTX administration and before test drug administration, 22 days after PTX administration and 3 days after drug withdrawal, 26 days after PTX administration and 7 days after drug withdrawal, 29 days after PTX administration and 10 days after drug withdrawal Carried out.

  An example of the test result is shown in FIG. In the PTX administration group, the avoidance latency was remarkably reduced as compared with the control group. The PTX + test drug administration group showed avoidance latency comparable to that of the control group from 6 hours after administration of the test drug, and significantly reduced the avoidance latency compared to the PTX administration group. Moreover, in the PTX + test drug administration group, it was observed that the improvement in the decrease in avoidance latency was maintained even after the administration of the test drug was completed. From the above results, it was confirmed that elcatonin has a therapeutic effect excellent in immediate effect and sustainability for cold allodynia caused by PTX.

[Example 3] Action of salmon calcitonin on rat allodynia caused by oxaliplatin To confirm the effect of salmon calcitonin (hereinafter abbreviated as sCT) on allodynia caused by an anticancer agent in the same manner as in Example 1. The effect of sCT on allodynia induced by mechanical stimulation and allodynia caused by low-temperature stimulation was examined when oxaliplatin, an anticancer drug, was administered to rats. sCT was subcutaneously administered to rats as a test drug, and the following tests (von Frey test and cold plate test) were performed.

  As salmon calcitonin, THYROCALCITONIN SALMON, SYNTHETIC (SIGMA T3660) was used.

(1) Preparation of oxaliplatin administration-induced allodynia model rat A 5-week-old SD male rat (150-200 g) was used as an experimental animal, and oxaliplatin (OX) was 6 mg / kg in the rat, once in the abdominal cavity. After administration, the therapeutic and sustained effects of sCT were confirmed. The control group was similarly administered with 5% glucose solution (5% TZ) used as a solvent for OX.

  Oxaliplatin was used for Elplat injection (100 mg: Yakult Co., Ltd.).

(2) Administration of test drug The experimental animals were divided into three groups: a control group, an OX administration group, OX, and a test drug administration group (OX + test drug administration group). In the OX + test drug administration group, sCT, which is the test drug, was administered subcutaneously (20 U / kg) once a day for 5 days from 3 days after OX administration. In the control group and the OX administration group, sCT solvent (containing 0.9% benzyl alcohol, 1% gelatin, 0.9% physiological saline (pH 4.0)) was added at 0.1 ml / B. W. 100 g was administered in the same manner.

(3) Statistical processing Statistical processing of the results was performed by unsupported t-test (SAS system, version 8.2), and a risk rate of 5% or less was considered significant (* in the figure: from the control group) Comparison of measured values with OX administration group, P <0.05;# in the figure: comparison of measured values between OX administration group and OX and test drug administration group, P <0.05).

(4) von Frey test
For the above three groups of rats, mechanical stimulation was applied alternately 5 times to the back of the left and right hind limbs using 4 g strength von Frey filament. The number of avoidance actions (lifting the hind limbs, biting the hind limbs) was measured, and allodynia due to mechanical stimulation was observed. 30 minutes before OX administration, 3 days after OX administration and before test drug administration, 3 days after OX administration and 6 hours after test drug administration, 5 and 7 days after OX administration and before test drug administration, 10 days after OX administration and test A measurement test was conducted 3 days after the drug withdrawal.

  FIG. 8 shows an example of the results of the sCT treatment effect and sustained effect confirmation test (intensity of von Frey filament: 4 g). The number of avoidances increased in the OX administration group compared to the control group. In the OX + test drug administration group, the number of avoidances was similar to that in the control group from 6 hours after administration of the test drug, and the increase in the number of avoidances was significantly improved compared to the OX administration group 5 days after the OX administration. Moreover, in the OX + test drug administration group, it was observed that the improvement in the increase in the number of avoidances was maintained even after the administration of the test drug was completed.

  From the above results, salmon calcitonin was confirmed to have an immediate and long-lasting therapeutic effect on mechanical allodynia due to OX as well as elcatonin, and the strength of the effect was comparable to that of elcatonin. Met.

(5) Cold plate test
As in Example 1, when the three groups of rats were stimulated alternately 5 times on the back of the left and right hind limbs using the tip of the cold stimulation unit controlled at 8 ° C. of the cold sensation threshold analysis device The latency of avoidance behavior was measured and allodynia caused by low-temperature stimulation was observed. Cut off time was 15 seconds. 30 minutes before OX administration, 3 days after OX administration and before test drug administration, 3 days after OX administration and 6 hours after test drug administration, 5 and 7 days after OX administration and before test drug administration, 10 days after OX administration and test A measurement test was conducted 3 days after the drug withdrawal.

  An example of the results of the sCT treatment effect and sustained effect confirmation test is shown in FIG. In the OX administration group, the avoidance latency was remarkably reduced as compared with the control group. The OX + test drug administration group showed an improvement in avoidance latency from 6 hours after administration of the test drug, and after 5 days from OX administration, the decrease in avoidance latency was significantly improved as compared to the OX administration group. Moreover, in the OX + test drug administration group, it was observed that the improvement in the decrease in avoidance latency was maintained even after the administration of the test drug was completed.

  From the above results, salmon calcitonin has been confirmed to have an immediate and long-lasting therapeutic effect similar to elcatonin for cold allodynia due to OX, and the intensity of the effect is similar to that of elcatonin. there were.

[Example 4] Examination of pharmacological effect time of calcitonin for allodynia caused by anticancer drug Occurs of oxaliplatin, an anticancer drug, are administered to rats in order to examine the time of calcitonin effect on allodynia caused by anticancer drug. The effect of ECT on allodynia caused by cold stimulation was examined. ECT was administered to rats as a test drug once subcutaneously, and the following test (cold plate test) was performed.

  As elcatonin, ercitonin injection (40S: Asahi Kasei Pharma Co., Ltd.) was used.

(1) Preparation of oxaliplatin administration-induced allodynia model rat A 5-week-old SD male rat (150-200 g) was used as an experimental animal, and oxaliplatin (OX) was 6 mg / kg in the rat, once in the abdominal cavity. After administration, the ECT treatment effect onset time was examined. The control group was similarly administered with 5% glucose solution (5% TZ) used as a solvent for OX.

  Oxaliplatin was used for Elplat injection (100 mg: Yakult Co., Ltd.).

(2) Administration of test drug As in Example 1, experimental animals were grouped into 3 groups: a control group, an OX administration group, OX, and a test drug administration group (OX + test drug administration group). In the OX + test drug administration group, ECT, which is the test drug, was administered once subcutaneously (20 U / kg) from 3 days after OX administration. ECT solvent was subcutaneously administered to the control group and the OX administration group.

(3) Cold plate test
As in Example 1, when the three groups of rats were stimulated alternately 5 times on the back of the left and right hind limbs using the tip of the cold stimulation unit controlled at 8 ° C. of the cold sensation threshold analysis device The latency of avoidance behavior was measured and allodynia caused by low-temperature stimulation was observed. Cut off time was 15 seconds. Measurement tests were performed 30 minutes before OX administration, 3 days after OX administration and before administration of test drug, 3 days after OX administration and 30, 60, 120, 240, 360 minutes after administration of test drug.

  An example of the result of the ECT therapeutic effect onset confirmation test is shown in FIG. In the OX administration group, the avoidance latency was remarkably reduced as compared with the control group. In the OX + test drug administration group, the decrease in avoidance latency was improved 30 minutes after administration of the test drug, and the avoidance latency comparable to that of the control group was exhibited 240 minutes after administration of the test drug.

  From the above results, it was confirmed that calcitonin has a therapeutic effect excellent in immediate effect for allodynia caused by OX.

  The natural calcitonin or calcitonin derivative of the present invention has been shown to be extremely effective in the prevention and / or treatment of allodynia caused by anticancer agents. Elcatonin, a commercially available calcitonin derivative, has been used for many years and has been recognized as a very safe drug. Thus, the natural calcitonin or calcitonin derivative of the present invention can be used in the pharmaceutical industry field as providing a pharmaceutical product of the use.

Claims (14)

A medicament for the prevention and / or treatment of allodynia caused by an anticancer agent, which comprises natural calcitonin or a calcitonin derivative as an active ingredient. The medicament according to claim 1, wherein the calcitonin derivative is elcatonin. The medicine according to claim 1, wherein the natural calcitonin is salmon calcitonin. The medicine according to any one of claims 1 to 3, wherein the allodynia is cold allodynia. The medicament according to any one of claims 1 to 3, wherein the allodynia is mechanical allodynia. The medicament according to any one of claims 1 to 5, wherein the anticancer agent is one or more selected from the group consisting of taxane drugs and platinum preparations. The medicament according to claim 6, wherein the anticancer agent is paclitaxel. The medicament according to claim 6, wherein the anticancer agent is oxaliplatin. The medicament according to any one of claims 1 to 5, wherein the anticancer agent is administered by FOLFOX therapy or FOLFIRI therapy. The pharmaceutical according to any one of claims 1 to 9, wherein natural calcitonin or a calcitonin derivative is intermittently administered. Ovarian cancer, non-small cell cancer, breast cancer, stomach cancer, endometrial cancer, head and neck cancer, esophageal cancer, leukemia, malignant lymphoma, childhood tumor, multiple myeloma, malignant astrocytoma, glioma, choriocarcinoma, embryo From cell tumor, lung cancer, testicular tumor, bladder cancer, renal pelvis tumor, urethral tumor, prostate cancer, cervical cancer, neuroblastoma, small cell lung cancer, osteosarcoma, malignant pleural mesothelioma, malignant bone tumor, and colon cancer The medicament according to any one of claims 1 to 10, which is administered to a cancer patient suffering from one or more types of cancer selected from the group consisting of: A medicament for preventing and / or treating allodynia caused by an anticancer agent, comprising natural calcitonin or a calcitonin derivative as an active ingredient, which is administered in combination with an anticancer agent. A method for the prevention and / or treatment of allodynia caused by an anticancer agent, which comprises the step of administering a natural calcitonin or a calcitonin derivative to a mammal. Use of natural calcitonin or a calcitonin derivative for producing a medicament for the prevention and / or treatment of allodynia caused by an anticancer agent.

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