JP2013014549A - Agent for alleviating side effect of anticancer agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a technique of effectively alleviating side effects caused by an anticancer agent, and more particularly, to provide an agent for alleviating the side effects of an anticancer agent and a drug for preventing and/or treating cancer.SOLUTION: This prevention discloses the agent for alleviating the side effects of an anticancer agent, containing as an active ingredient cilnidipine or a pharmaceutically acceptable salt thereof and a drug for preventing and/or treating cancer comprising a combination of cilnidipine or a pharmaceutically acceptable salt thereof and an anticancer agent.

Description

  The present invention relates to a side effect reducing agent for an anticancer agent using cilnidipine or a pharmaceutically acceptable salt thereof, and a preventive and / or therapeutic agent for cancer.

  Numerous researches and product developments have been conducted on drugs for preventing or treating cancer, and there are many drugs actually used in the medical field. The problems with currently used anti-cancer and immunotherapeutic agents such as anti-cancer and immunotherapeutic agents are the difficulty of allowing drugs to act specifically on cancer cells without affecting normal cells, and chemically synthesized substances This is to reduce the inherent toxicity of these drugs. As a result, drugs used for the prevention or treatment of cancer exhibit an anticancer effect and induce side effects, and the amount showing the effectiveness (minimum effective concentration) and the amount allowed for safety (minimum poisoning) The concentration) is very close to each other, or the minimum poisoning concentration may be lower than the minimum effective concentration, and sufficient effectiveness has not been obtained.

  Anticancer drugs are effective in the prevention and treatment of cancer, but for the reasons described above, for example, loss of appetite, general malaise, pain, dyspnea, skin symptoms, nausea, vomiting, diarrhea, fever, hair loss, olfactory loss Loss, hepatorenal dysfunction, interstitial pneumonia, organ failure associated with peripheral circulatory failure, and serious side effects such as myelosuppression. The recent trend in cancer treatment is to improve the quality of life (QOL) in addition to the long survival time of cancer patients, and how to reduce the side effects of anticancer drugs. It is an important issue. If the side effects of anticancer drugs can be reduced, cancer patients can be released not only from physical pain but also from mental pain.

  One type of anticancer drug is adriamycin, which belongs to an anthracycline-based anticancer drug. It is used in various cancers, but it is known that it causes various organ disorders such as renal dysfunction, cardiac dysfunction, and liver dysfunction. It has been. In order to avoid the occurrence of these side effects or to reduce the symptoms of side effects, for example, there are cases where it is possible to cope by reducing the dose of the anticancer agent per one time. However, if the dose of the anticancer agent is decreased, the anticancer effect is lowered, and as a result, the treatment period is prolonged. Furthermore, administration of an anticancer agent over a long period of time despite a low dose may result in an increase in the total dose as compared with normal administration, and the side effect symptoms may be worse than expected. Therefore, in order not to reduce the effect of the anticancer agent in this way, there is a strong demand for a drug that can reduce side effects without reducing the dose.

  On the other hand, cilnidipine is a kind of dihydropyridine calcium antagonist and is known to have both an L-type and an N-type calcium antagonistic action and a blood pressure lowering action. The antihypertensive effect of cilnidipine is characterized by a longer duration than other antihypertensive drugs. Utilizing this effect, cilnidipine has been reported to be useful for the treatment or prevention of cerebral infarction and cerebral hemorrhage in addition to the commonly used antihypertensive treatment (Patent Document 1). However, it is not known that cilnidipine has an effect of reducing the side effects of anticancer agents, and there has been no report on reducing side effects caused by adriamycin.

JP 2004-359675 A

  An object of the present invention is to effectively reduce the side effects of an anticancer agent, and specifically, to provide a side effect reducing agent for an anticancer agent and a preventive and / or therapeutic agent for cancer with reduced side effects. .

  As a result of intensive studies on the above problems, the present inventors have found that side effects of anticancer agents are significantly reduced by cilnidipine and have completed the present invention.

That is, the present invention relates to the following.
[1] An anticancer agent side effect reducing agent comprising cilnidipine or a pharmaceutically acceptable salt thereof as an active ingredient.
[2] The agent according to [1], wherein the anticancer agent is an anticancer antibiotic.
[3] The agent according to [2], wherein the anticancer antibiotic is an anthracycline anticancer agent.
[4] The agent according to [3], wherein the anthracycline anticancer agent is adriamycin.
[5] The agent according to any one of [1] to [4], wherein the side effect is organ damage.
[6] The agent according to [5], wherein the organ disorder is renal dysfunction and / or cardiac dysfunction.
[7] A prophylactic and / or therapeutic agent for cancer comprising a combination of cilnidipine or a pharmaceutically acceptable salt thereof and an anticancer agent.
[8] The prophylactic and / or therapeutic agent according to [7], wherein the anticancer agent is an anticancer antibiotic.
[9] The prophylactic and / or therapeutic agent according to [8], wherein the anticancer antibiotic is an anthracycline anticancer agent.
[10] The prophylactic and / or therapeutic agent according to [9], wherein the anthracycline anticancer agent is adriamycin.

  According to the present invention, by using cilnidipine or a pharmaceutically acceptable salt thereof, side effects caused by an anticancer agent (particularly, adriamycin) can be effectively reduced. Further, according to the present invention, by using a combination of cilnidipine or a pharmaceutically acceptable salt thereof and an anticancer agent, a preventive and / or therapeutic agent for cancer with reduced side effects can be provided. Since cilnidipine or a pharmaceutically acceptable salt thereof in the present invention reduces the side effects caused by an anticancer agent, it can suppress a decrease in the dose of the anticancer agent when used in combination. By reducing the side effects of anticancer drugs, 1) reduction of QOL in cancer patients, 2) improvement of life prognosis due to side effects, 3) continuation of anticancer drug treatment, 4) increase of anticancer drugs, etc., prevention of cancer And / or the therapeutic effect can be improved.

FIG. 1 is a graph showing measured amounts of albumin, protein and NAG in rat urine at 4 weeks after administration of cilnidipine. The horizontal axis shows albumin, protein and NAG which are measurement items. The vertical axis represents the measurement amount (%) of various items. FIG. 2 is a graph showing measured values of the left ventricular ejection fraction and left ventricular diameter shortening rate of the rat heart at 4 weeks after administration of cilnidipine. The horizontal axis shows the left ventricular ejection fraction and the left ventricular diameter shortening rate, which are measurement items. A vertical axis | shaft shows the measured value (%) of various items. FIG. 3 is a graph showing changes in blood pressure of various rats over 4 weeks after administration of cilnidipine. The white diamonds indicate the blood pressure measurement values of the normal control group, the black diamonds indicate the non-treatment group, and the black circles indicate the cilnidipine administration group. The horizontal axis indicates the administration period (weeks), and the vertical axis indicates the blood pressure measurement value (mmHg).

(1) Anticancer agent side effect reducing agent The present invention provides an anticancer agent side effect reducing agent (hereinafter also simply referred to as a side effect reducing agent) containing cilnidipine or a pharmaceutically acceptable salt thereof as an active ingredient. Silnidipine or a pharmaceutically acceptable salt thereof has an action of reducing side effects caused by administration of an anticancer drug in various mammals such as humans, monkeys, mice, rats, rabbits, pigs, dogs, horses, cows, and the like. An agent containing cilnidipine or a pharmaceutically acceptable salt thereof as an active ingredient is useful as a side effect reducing agent for anticancer agents.

  Silnidipine used as an active ingredient is a compound known as an L / N-type calcium antagonist that inhibits both L-type and N-type calcium channels. Specifically, the following structural formula:

(±) -2-methoxyethyl 3-phenyl-2- (E) propenyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxy Rate. The cilnidipine in the present invention includes optical isomers based on the above structural formula, and any of them can be produced using a known production method (Japanese Patent Publication No. 3-14307, Japanese Patent Publication No. 6-43397, etc.) See). It is also commercially available.

  Silnidipine can be converted to a pharmaceutically acceptable salt, hydrate or solvate thereof as required. The pharmaceutically acceptable salt is not particularly limited, but for example, a salt with an inorganic acid (hydrochloride, hydrobromide, phosphate, nitrate, sulfate, etc.) or a salt with an organic acid (acetic acid) Salt, succinate, maleate, fumarate, malate, tartrate, lactate, citrate, etc.).

  Hereinafter, cilnidipine or a pharmaceutically acceptable salt thereof may be simply referred to as cilnidipine.

  In the present specification, “reducing” the side effect of an anticancer agent means that the adverse effect on the living body caused by the administration of the anticancer agent is directed toward normalization. Not only “improvement” and “treatment” of once-occurring side effects, but also “prevention” of “prevention of side effects” is included in the prevention or suppression before side effects occur.

Side effects of anticancer agents are generally recognized in the art, such as loss of appetite, general malaise, pain, dyspnea, skin symptoms, nausea, vomiting, diarrhea, fever, hair loss, olfaction Physical disorders such as loss, organ damage (eg, renal dysfunction, cardiac dysfunction, liver dysfunction), interstitial pneumonia, organ failure associated with peripheral circulatory failure, and bone marrow suppression. In addition, mental distress such as anxiety, agitation, loss of interest, dullness, insomnia, alienation, fear, adjustment disorder, depression, delirium, etc. associated with these physical disorders are also regarded as side effects of anticancer drugs. Can be tricked.
In particular, the present invention is suitable for reducing organ damage, preferably renal dysfunction and / or cardiac dysfunction.

  The anticancer agent is not particularly limited as long as it is a compound that acts directly or indirectly on cancer cells and contributes to inhibition of proliferation or metastasis of cancer cells, killing of cancer cells, or inhibition of development of cancer cells, for example, anticancer antibiotics. Substances, platinum preparations, alkylating agents, antimetabolites, plant alkaloids, molecular target therapeutic agents, hormonal agents and the like.

  Anticancer antibiotics (antitumor antibiotics) refer to antibiotics belonging to anticancer agents (DNA-damaging anticancer agents) that suppress the growth of cancer cells by causing damage to DNA or RNA associated with cancer cells. Although it does not specifically limit as an anticancer antibiotic, For example, anthracycline anticancer agents, such as adriamycin, epidoxorubicin, epirubicin, daunorubicin, aclarubicin, pirarubicin, amrubicin, idarubicin; mitomycin C, bleomycin, peplomycin, chromomycin A3, actino Mycin D, dinostatin stimamarer and the like.

  Platinum preparations are the bases of DNA, guanine and adenine that bind to the N-7 position at two chlorine atom sites, form crosslinks in the DNA strand, and inhibit DNA synthesis to proliferate cancer cells. It refers to an anticancer agent that exerts an inhibitory effect. The platinum preparation is not particularly limited, and examples thereof include cisplatin, carboplatin, nedaplatin, oxaliplatin and the like.

  An alkylating agent refers to an anticancer agent that exerts an effect of inhibiting the growth of cancer cells by cleaving by alkylating DNA. Examples of the alkylating agent include, but are not limited to, nitrogen mustards such as nitrogen mustard, nitrogen mustard N-oxide, chlorambucil, ifosfamide, cyclophosphamide and melphalan; ethyleneimines such as carbocone and thiotepa Sulfonic acid esters such as busulfan and improsulfan tosylate; nitrosoureas such as nimustine, ranimustine, dacarbazine and procarbazine, and temozolomide.

  An antimetabolite is a substance that has a chemical structure similar to that of a nucleic acid material when cancer cells divide or proliferate, thereby preventing DNA synthesis and inhibiting cancer cell metabolism. It refers to an anticancer drug that suppresses. Although it does not specifically limit as an antimetabolite, For example, pyrimidine antimetabolites, such as 5-fluorouracil (5FU), tegafur, carmofur, doxyfluridine, floxuridine, cytarabine, enocitabine, gemcitabine; mercaptopurine, thioguanine, fludarabine phosphate And purine antimetabolites such as thioinosine; antifolate antimetabolites such as methotrexate, trimethoprim and pyrimethacin.

  Plant alkaloids include vinca alkaloids that inhibit the formation of microtubules that affect cancer cell division, taxanes that cause abnormal microtubule formation and inhibit the division of cancer cells, and DNA cleavage and reactivation during cell division. Examples include topoisomerase inhibitors that kill topoisomerase by inhibiting topoisomerase acting on binding. Examples of vinca alkaloids include vinblastine, vincristine, vindesine, vinorelbine, and the like. Examples of taxanes include docetaxel and paclitaxel. Examples of topoisomerase inhibitors include irinotecan, nogitecan, etoposide, sobuzoxane and the like.

  The molecular target therapeutic agent refers to an anticancer agent having an activity of targeting a molecule involved in cancer cell growth and killing the cancer cell by inhibiting the molecule. The molecular target therapeutic agent is not particularly limited, and examples thereof include imatinib, gefitinib, erlotinib, vandetanib, sunitinib, sorafenib, rituximab, cetuximab, infliximab, trastuzumab, bevacizumab and the like.

  Hormonal agents refer to anticancer agents that act on hormones involved in the division or proliferation of cancer cells. Although it does not specifically limit as a hormonal agent, For example, anastrozole, exemestane, ethinyl estradiol, chlormadinone, goserelin, tamoxifen, bicalutamide, flutamide, bretonisolone, leuprorelin, letrozole etc. are mentioned.

The side effect reducing agent of the present invention is particularly useful for reducing the side effects of anticancer antibiotics among the above anticancer agents. The anticancer antibiotic is preferably an anthracycline anticancer agent. Examples of anticancer agents belonging to the anthracycline anticancer agent are as described above, and common side effects include cardiac dysfunction and renal dysfunction.
Examples of renal dysfunction include renal failure caused by glomerular damage or tubular damage. Examples of cardiac dysfunction include myocardial injury, specifically heart failure caused by myocardial injury and the like.

  In particular, the side effect reducing agent of the present invention is effective in reducing side effects caused by adriamycin (also known as doxorubicin) among the above-mentioned anthracycline anticancer agents. It should be noted that the anticancer agents disclosed herein, including adriamycin, can be included as the same as long as there is a description that matches in a commonly used name such as a common name or a common name, and is further commonly used. The salt (for example, doxorubicin hydrochloride etc.) can also be included as the same thing.

  Further, the side effect reducing agent of the present invention can be administered as a medicine.

  When the side effect reducing agent of the present invention is administered as a pharmaceutical, the administration form may be either oral administration or parenteral administration, and the dosage form is, for example, a powder, granule, capsule, as long as it is an oral administration agent. Solid agents such as tablets and chewable agents; liquid agents such as solutions and syrups; and parenteral agents such as injections, infusions, and nasal / pulmonary sprays It is done. The side effect-reducing agent of the present invention can be formulated into drugs of these dosage forms by a usual method.

  From the viewpoint of reducing the burden on the patient, the side effect reducing agent of the present invention is preferably administered orally to the subject. A tablet is preferable as the dosage form for oral administration. On the other hand, for subjects who are difficult to administer orally, the agent of the present invention can be administered as an infusion solution by intravenous or arterial administration.

  Further, the side effect reducing agent of the present invention is an appropriate pharmaceutically acceptable carrier, for example, an excipient, a binder, a lubricant, a solvent, a disintegrant, a solubilizing agent, if necessary in the preparation. A suspending agent, an emulsifier, an isotonic agent, a stabilizer, a soothing agent, an antiseptic, an antioxidant, a corrigent, a coloring agent, and the like can be blended into a preparation.

  Examples of excipients include sugars such as lactose, glucose and D-mannitol, organic excipients such as starches and celluloses such as crystalline cellulose, and inorganic excipients such as calcium carbonate and kaolin. As a lubricant, pregelatinized starch, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, D-mannitol, trehalose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc. Are stearic acid, fatty acid salts such as stearate, talc, silicates, etc., as solvent, purified water, physiological saline, etc., as disintegrant, low substituted hydroxypropylcellulose, chemically modified Cellulose and de Pungs, etc. include polyethylene glycol, propylene glycol, trehalose, benzyl benzoate, ethanol, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, etc. as suspending agents or emulsifiers. Sodium sulfate, gum arabic, gelatin, lecithin, glyceryl monostearate, polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose sodium and other celluloses, polysorbates, polyoxyethylene hydrogenated castor oil, etc. , Potassium chloride, saccharides, glycerin, urea, etc., as stabilizer, polyethylene glycol, sodium dextran sulfate, other amino acids, etc., as soothing agent, glucose, Calcium gluconate, procaine hydrochloride, etc., as preservatives, paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc., as antioxidants, sulfite, ascorbic acid, etc. Examples of the flavoring agent include sweeteners and fragrances commonly used in the pharmaceutical and food fields, and examples of the coloring agent include colorants commonly used in the pharmaceutical and food fields.

  The dose of the side effect reducing agent of the present invention varies depending on the type of anticancer agent, the age, weight, disease state, administration method, etc. of the subject, and usually considers the clinical dose of the active ingredient cilnidipine or a pharmaceutically acceptable salt thereof. And can be set as appropriate. For example, the daily dose per adult is 0.0001 to 1000 mg, preferably 0.001 to 100 mg, particularly preferably 0.01 to 50 mg of the active ingredient is orally administered in one or several divided doses, or adult 1 As a daily dose per person, 0.0000001 to 100 mg, preferably 0.000001 to 50 mg, particularly preferably 0.0001 to 20 mg can be parenterally administered once a day to several times, or 1 hour per day To 24 hours and can be administered intravenously.

(2) Preventive and / or therapeutic agent for cancer As described above, cilnidipine or a pharmaceutically acceptable salt thereof can reduce side effects caused by an anticancer agent. Therefore, the present invention can provide a preventive and / or therapeutic agent for cancer, which has reduced side effects, including cilnidipine or a pharmaceutically acceptable salt thereof and an anticancer agent. Furthermore, the present invention is based on the action of reducing the side effects of anticancer agents possessed by cilnidipine or a pharmaceutically acceptable salt thereof, and includes reducing the side effects including the combined use of cilnidipine or a pharmaceutically acceptable salt thereof and an anticancer agent. It is possible to provide a method for preventing and / or treating cancer.

The cilnidipine used in the present invention is as described in the above section (1) Anticancer agent side effect reducing agent, and the anticancer agent used in combination therewith is not particularly limited, and the above (1) Anticancer agent side effect reducing agent section. Examples similar to those enumerated above. Further, two or more kinds of anticancer agents may be used in combination.
The anticancer agent used in combination is preferably an anthracycline anticancer agent, particularly preferably adriamycin.

Applicable cancers include those for which anticancer drugs are effectively administered. Specifically, breast cancer (eg, invasive ductal cancer, non-invasive ductal cancer, inflammatory breast cancer, etc.), prostate cancer (Eg, hormone-dependent prostate cancer, hormone-independent prostate cancer, etc.), pancreatic cancer (eg, pancreatic duct cancer, etc.), stomach cancer (eg, papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma, etc.), lung cancer (eg, Non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, etc.), colon cancer (eg, gastrointestinal stromal tumor, etc.), rectal cancer (eg, gastrointestinal stromal tumor, etc.), colon cancer (eg, familial colon) Cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor, etc.), small intestine cancer (eg, non-Hodgkin lymphoma, gastrointestinal stromal tumor, etc.), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (eg, nasopharynx) Cancer, oropharyngeal cancer, hypopharyngeal cancer, etc.), salivary gland cancer, brain tumor (eg, pineal astrocytoma, ciliary astrocytoma, diffuse astrocytoma, regression) Astrocytoma, etc.), schwannoma, liver cancer (eg, primary liver cancer, extrahepatic bile duct cancer, etc.), kidney cancer (eg, renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), gallbladder cancer, Bile duct cancer, pancreatic cancer, liver cancer, endometrial cancer, cervical cancer, ovarian cancer (eg epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low grade tumor, etc.), bladder cancer, Urethral cancer, skin cancer (eg, intraocular (eye) melanoma, Merkel cell carcinoma, etc.), hemangioma, malignant lymphoma (reticulosarcoma, lymphosarcoma, Hodgkin's disease), malignant melanoma, thyroid cancer (eg, thyroid marrow) ), Parathyroid cancer, nasal cavity cancer, sinus cancer, bone tumor (eg, osteosarcoma, Ewing tumor, uterine sarcoma, soft tissue sarcoma, etc.), angiofibroma, retinal sarcoma, penile cancer, testicular tumor, child Solid cancer (eg, Wilms tumor, childhood renal tumor, etc.), Kaposi sarcoma, Kaposi sarcoma caused by AIDS, maxillary sinus tumor, fibrotic tissue Spherical tumor, leiomyosarcoma, rhabdomyosarcoma, leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia, etc.), and the like.
Preferably, malignant lymphoma (reticulosarcoma / lymphosarcoma / Hodgkin's disease), lung cancer, stomach cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, liver cancer, colon cancer, rectal cancer, breast cancer, osteosarcoma and the like.

  The preventive and / or therapeutic agent and the preventive and / or therapeutic method of the present invention are characterized in that side effects of the administered anticancer agent are reduced. Here, examples of the side effect of the anticancer agent include those listed in the above section (1) Anticancer agent side effect reducing agent. Particularly, as the anticancer agent, an anticancer antibiotic (preferably an anthracycline anticancer agent, more preferably When adriamycin) is used in combination with cilnidipine, the side effects to be reduced are renal dysfunction (preferably, renal failure due to glomerular or tubular damage) and / or cardiac dysfunction (preferably myocardial dysfunction). Due to heart failure).

  The administration of cilnidipine and anticancer agent in the present invention may be either oral administration or parenteral administration, and the dosage form thereof is a solid preparation such as powder, granule, capsule, tablet, chewable agent, etc. Agents: Solutions such as solutions, syrups, and the like, and parenteral agents include injections, infusions, nasal / pulmonary sprays, and the like. Any of these can be formulated into pharmaceuticals of these dosage forms by ordinary methods. Each preparation is prepared according to the necessity of the preparation, as appropriate pharmaceutically acceptable carrier, for example, excipient, binder, lubricant, solvent, disintegrant, solubilizer, suspending agent, emulsifier. , Tonicity agents, stabilizers, soothing agents, preservatives, antioxidants, flavoring agents, coloring agents and the like may be incorporated. Specific examples of the various carriers are the same as described above.

  The dose of cilnidipine or anticancer agent in the present invention is the type of anticancer agent to be used, the age, weight, disease state, administration method (administration form, administration route, etc.) of the subject, target effect and its extent (eg, side effect reduction action). Depending on the clinical dose of cilnidipine or an anticancer agent, it can be appropriately set and increased or decreased as appropriate.

  In the present invention, cilnidipine and an anticancer agent are used in combination. In the present specification, “combination” means administration (use) of cilnidipine before, during (simultaneously) or after administration of an anticancer agent. As long as both cilnidipine and an anticancer drug are used and cilnidipine can reduce the side effects of the anticancer drug, their dosage forms are not limited.

  Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating cilnidipine and an anticancer agent, and (2) two preparations obtained by separately formulating cilnidipine and an anticancer agent. Simultaneous administration by the same administration route, (3) administration of two formulations obtained by separately formulating cilnidipine and an anticancer agent, with a time difference in the same administration route, and (4) cilnidipine and the anticancer agent separately Simultaneous administration of two preparations obtained by formulation into different administration routes, (5) Administration of two preparations obtained by separately formulating cilnidipine and an anticancer agent at different administration routes with a time difference (For example, administration of cilnidipine first and then anticancer agent or vice versa). In the present invention, cilnidipine is preferably formulated separately from cilnidipine and an anticancer agent from the viewpoint of reducing the side effects of the anticancer agent, and administered after a time difference, and in particular, after administering the anticancer agent, cilnidipine is then administered. The order of doing is preferred. Silnidipine may be administered after confirming that side effects have occurred after administration of the anticancer drug, or may be administered before side effects occur.

  When cilnidipine and an anticancer agent are used as a single preparation, the administration frequency and administration period of the preparation are appropriately set based on the administration subject, symptoms, administration route, dosage form, type of anticancer agent, and the like. Usually, from the viewpoint of cancer treatment, it is administered at a frequency of 1-2 times / day for 1 day to 28 days, preferably at a frequency of 1-2 times / day for 1 day to 14 days.

  When cilnidipine or a pharmaceutically acceptable salt thereof and an anticancer agent are different preparations, the administration frequency and administration period of each preparation are based on the subject of administration, symptoms, administration route, dosage form, type of anticancer agent, etc. Is set as appropriate. The frequency of administration may be the same or different. Usually, from the viewpoint of cancer treatment, cilnidipine is administered at a frequency of 1-2 times / day for 7 days to 28 days, preferably at a frequency of 1-2 times / day for 14 days to 28 days, and the anticancer agent is 1 It is administered at a frequency of ˜2 times / day for 1 day to 10 days, preferably at a frequency of 1 time / day for 1 day to 7 days. In addition, an administration suspension period may be provided for administration of the anticancer agent. The administration suspension period is, for example, 1 to 28 days, preferably 7 to 14 days. The administration period and the administration suspension period are combined into one course, and this can be repeated over one course to several courses.

  When cilnidipine and an anticancer agent are administered separately as different preparations, the preparation containing cilnidipine and the preparation containing the anticancer agent may be administered at the same time, but the preparation containing the anticancer agent is administered first. Thereafter, a preparation containing cilnidipine may be administered, or a preparation containing cilnidipine may be administered first, followed by administration of a preparation containing an anticancer agent. Preferably, the formulation containing anticancer agent is administered first, and then the formulation containing cilnidipine is administered. In the case of administration with a time difference, the time difference varies depending on the dosage form, administration method, type of anticancer agent, etc. For example, when a preparation containing an anticancer agent is administered first, it is usually 1 after administration of the preparation containing the anticancer agent. Examples include a method of administering a preparation containing cilnidipine within 1 to 28 days, preferably within 1 to 14 days, more preferably within 1 to 7 days. Conversely, when a preparation containing cilnidipine is administered first, the preparation containing an anticancer drug is usually administered within 1 to 84 days, preferably within 1 to 28 days after administration of the preparation containing cilnidipine. The method of doing is mentioned.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, these are merely examples and do not limit the scope of the present invention.

1. Effect on renal dysfunction
Adriamycin 1.5 mg / kg was administered to the 12-week-old male SHR / Izm (spontaneously hypertensive rat, Sankyo Lab Service Co., Ltd.) 3 times a week via the tail vein. In the normal control group, physiological saline was administered instead of adriamycin.
After 3 administrations of adriamycin, rats are divided into no treatment group and cilnidipine group using blood pressure, body weight and urinary albumin excretion as indicators, 0.5% hypromellose is used for no treatment group, and cilnidipine 10 mg / kg is used for cilnidipine group. It was orally administered every day for 4 weeks. Four weeks after administration, urine was collected for 24 hours, and urine albumin, protein, and NAG (N-acetylglucosaminidase) were measured. In addition, albumin uses ELISA method (Nephrat, manufactured by Exocell), protein uses BCA method (Pierce BCA Protein Assay Kit, manufactured by Pierce), and NAG uses enzyme method (N-assay L NAG Nittobo, manufactured by Nittobo Medical). Measured. In the normal control group, physiological saline was administered three times, and hypromellose was orally administered for 4 weeks every day, and the measurement was performed in the same manner.

  The measurement results of albumin, protein and NAG are shown in FIG. The urinary parameters in the untreated group were significantly higher in urinary albumin excretion, urinary protein excretion, and urinary NAG excretion than the normal control group. In contrast, the urinary parameters in the cilnidipine group were all significantly lower than those in the untreated group. Thus, cilnidipine decreased the amount of urinary albumin and protein excreted, and further decreased the amount of urinary NAG excretion. It was suggested.

2. Effect on cardiac dysfunction Cardiac function was evaluated at the same time as the measurement in 1 above for rats in the normal control group, no treatment group and cilnidipine group treated in 1 above. The evaluation of cardiac function was performed by using an ultrasound diagnostic imaging device (Xario SSA-660, manufactured by Toshiba Medical Supplies) to determine the left ventricular diameter shortening rate (FS) and left ventricular ejection fraction (EF) by echocardiography under anesthesia. Measured and performed. In addition, in order to examine the blood pressure transition of each group of rats in the above treatment 1, the tail cuff method (BP-98A, softron) was used at the time of administration of cilnidipine or hypromellose (0 week), and at 1 week and 4 weeks after administration. Was used to measure blood pressure.

  The result of cardiac function evaluation is shown in FIG. 2, and the result of blood pressure transition is shown in FIG. Regarding cardiac function evaluation, the left ventricular diameter shortening rate (FS) and left ventricular ejection fraction (EF) in the untreated group were significantly lower than those in the normal control group, whereas in the cilnidipine group, FS and All EFs were significantly higher than the untreated group, and almost no decrease was observed compared to the normal control group. Thus, it was suggested that cilnidipine suppresses the decrease in cardiac contractile function caused by adriamycin.

  From the results of 1 and 2 above, it was found that cilnidipine suppresses the progression of organ damage (particularly renal dysfunction and / or cardiac dysfunction), which is a side effect of adriamycin.

  ADVANTAGE OF THE INVENTION According to this invention, the side effect which an anticancer agent causes can be reduced effectively, and the agent and pharmaceutical useful for the prevention and / or treatment of human cancer can be provided. By reducing the side effects of the anticancer agent according to the present invention, it becomes possible to reduce the QOL reduction of cancer patients, improve the life prognosis reduction due to the side effects, continue the anticancer agent treatment, increase the anticancer agent, and the like.

Claims (10)

  A side effect reducing agent for an anticancer agent, comprising cilnidipine or a pharmaceutically acceptable salt thereof as an active ingredient.   The agent according to claim 1, wherein the anticancer agent is an anticancer antibiotic.   The agent according to claim 2, wherein the anticancer antibiotic is an anthracycline anticancer agent.   The agent according to claim 3, wherein the anthracycline anticancer agent is adriamycin.   The agent according to any one of claims 1 to 4, wherein the side effect is organ damage.   The agent according to claim 5, wherein the organ disorder is renal dysfunction and / or cardiac dysfunction.   A preventive and / or therapeutic agent for cancer comprising a combination of cilnidipine or a pharmaceutically acceptable salt thereof and an anticancer agent.   The prophylactic and / or therapeutic agent according to claim 7, wherein the anticancer agent is an anticancer antibiotic.   The prophylactic and / or therapeutic agent according to claim 8, wherein the anticancer antibiotic is an anthracycline anticancer agent. The prophylactic and / or therapeutic agent according to claim 9, wherein the anthracycline anticancer agent is adriamycin.

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