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WO2018139477A1 - Nouvel agent thérapeutique pour l'anémie néphrogénique ciblant un récepteur d'érythropoïétine via no et la stimulation de la voie no - Google Patents

Nouvel agent thérapeutique pour l'anémie néphrogénique ciblant un récepteur d'érythropoïétine via no et la stimulation de la voie no Download PDF

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Publication number
WO2018139477A1
WO2018139477A1 PCT/JP2018/002088 JP2018002088W WO2018139477A1 WO 2018139477 A1 WO2018139477 A1 WO 2018139477A1 JP 2018002088 W JP2018002088 W JP 2018002088W WO 2018139477 A1 WO2018139477 A1 WO 2018139477A1
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nitrate
isosorbide
therapeutic agent
anemia
administration
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PCT/JP2018/002088
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English (en)
Japanese (ja)
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陽介 中山
三有紀 横路
圭 深水
昌一 山岸
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学校法人 久留米大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

Definitions

  • the present invention relates to a novel use in the clinical field of nitrate drugs, especially isosorbide nitrate. Specifically, the present invention relates to a therapeutic agent for renal anemia, which contains a nitrate drug such as isosorbide nitrate as an active ingredient.
  • Renal anemia is known to be the onset and progression factor of chronic kidney injury (CKD) and cardiovascular disease (CVD). These common risk factors for CKD and CVD interact and have attracted attention as cardiorenal linkage (CRS). Among these factors, it is speculated that vascular endothelial injury factor is an important factor in CRS. (Non-Patent Document 1). Asymmetric dimethylarginine (ADMA), which is produced by asymmetric methylation of arginine residues, is known as a vascular endothelial dysfunction factor.
  • ADMA Asymmetric dimethylarginine
  • Non-Patent Document 2 nitric oxide (vascular endothelium-derived vasorelaxant) Inhibits NO) synthase (NOS) activity, reduces NO production, causes vascular endothelial injury, and develops various diseases such as arteriosclerosis, hypertension, diabetes, and other cardiovascular and renal diseases It is known to be involved in development (Non-Patent Document 2). In recent years, the present inventors have clarified that the entire ADMA metabolic system exists in erythrocytes themselves based on previous studies that erythrocytes are rich in methylated proteins and free ADMA (Non-patent Document 3).
  • Non-Patent Document 4 Non-Patent Document 5
  • the accumulation of erythrocyte ADMA inhibits the anemia response mechanism in the body at the gene level using a renal failure model mouse, and in human chronic kidney injury (CKD) cases Reported that erythrocyte ADMA increased (Patent Document 1, FIG. 7).
  • CKD human chronic kidney injury
  • ESA erythropoietin
  • Patent Literature 2 As therapeutic agents for renal anemia other than ESA, those containing arginine as an active ingredient (Patent Literature 2, Patent Literature 3), and those using erythropoietin production promoter as a therapeutic agent for renal anemia (Patent Literature 4, Patent Literature) 5, Patent Document 6, Patent Document 7, Patent Document 8, Patent Document 9, Patent Document 10, Patent Document 11), containing a fraction extract extracted from deer rice cake as an active ingredient (Patent Document 12), bone marrow erythrocyte A progenitor cell differentiation promoter containing at least one selected from the group consisting of alanine, serine, glutamine, tyrosine and asparagine as an active ingredient (Patent Document 13), and an imidazolone derivative as an active ingredient (Patent) Reference 14) has been developed.
  • Patent Document 12 As therapeutic agents for renal anemia other than ESA, those containing arginine as an active ingredient (Patent Literature 2, Patent Literature 3), and those using erythropoiet
  • Nitrate drugs act as NO donors.
  • Nitric acid drugs such as nitroglycerin and isosorbide nitrate, can be structurally expressed as R-NO 2, and finally release NO to exert its effect.
  • the mechanism until nitric acid releases NO is as follows.
  • R-NO 2 that enters the blood is either (1) a reaction involving an enzyme (including aldehyde dehydrogenase) or (2) a reaction with a reducing substance in a living body (a thiol group). Involved in the substance possessed), it becomes R-SNO (nitrosothiol) form and moves from vascular endothelial cells to smooth muscle cells, releasing NO and exerting its action.
  • Nitrate medicine spreads the coronary arteries around the heart to increase blood flow and replenish oxygen to the heart, reducing systemic vascular resistance and reducing the burden on the heart. It is known to be effective for angina pectoris where sufficient oxygen cannot reach the muscles.
  • Nitric oxide (NO) plays an important role in maintaining blood vessel homeostasis, and it is widely known that this failure is deeply involved in the development of arteriosclerosis.
  • NO is produced from NOS using L-arginine as a substrate.
  • causes of NO production deficiency and reduced biological activity include deficiency of L-arginine, a substrate for NO, decreased expression of NOS, deficiency of coenzyme tetrahydrobioptein (BH4) essential for retention of NOS dimer (this NOS uncoupling occurs due to deficiency of coenzyme, reactive oxygen species (ROS) are produced instead of NO from NOS, NO inactivation by ROS, peroxynitrite which is a powerful radical (ONOO-) generation, competitive inhibition by methylated arginine such as ADMA, and the like.
  • NO is produced by vascular endothelial cells, not vascular smooth muscle cells.
  • the actions of NO in vascular smooth muscle are (1) activation of guanylate cyclase and (2) direct release of Ca-dependent K channels.
  • the pathway of (1) consists of (a) activation of guanylate cyclase (binding to the heme moiety) to generate cGMP from GTP, (b) cGMP activates myosin light chain dephosphorylating enzyme, and (c) myosin light Dephosphorylation from the chain, (d) weakening of myosin-actin cross-linking, (e) smooth muscle relaxation, and (f) vasodilation mechanism.
  • the pathway (2) consists of (a) activation of Ca-dependent K channel, (b) K + outflow, (c) membrane hyperpolarization, (d) potential dependence of smooth muscle cells.
  • Sexual Ca 2+ channel activity is reduced, (e) intracellular Ca 2+ concentration in smooth muscle is reduced, muscle is relaxed, and (f) is due to the mechanism of vasodilation.
  • JP2016-114606 Table 2005/089743 Chart 2006/115274 Table 2004/052859 JP2011-037841 JP2011-153105 JP2012-082181 JP2012-144571 Chart 2013/054755 JP2015-003933 JP2016-040321 JP 07-025774 JP2008-105954 JP2011-231022
  • ESA is the only effective therapeutic agent for renal anemia, and medication to ESA-resistant patients, soaring medical costs, and physical burden on patients have been problems. Under such circumstances, a novel therapeutic agent for renal anemia has been desired.
  • the present inventors have already shown that the accumulation of erythrocyte ADMA inhibits the anemia response mechanism in the body at the gene level, and the erythrocyte ADMA actually increases in human chronic kidney injury (CKD) cases using a renal failure model mouse. I found. This time, the present inventors focused on vasodilator factor NO produced by L-arginine as a substrate by endothelial NO synthase (eNOS), which acts oppositely to ADMA in vascular endothelial function, and is related to renal anemia. Verified.
  • eNOS endothelial NO synthase
  • ADMA competes with NO produced by nitric oxide synthase (NOS), and as a result of NOS inhibition by ADMA, NO concentration, which is a regulator of vascular endothelial function, decreases in CKD patients.
  • NOS nitric oxide synthase
  • isosorbide nitrate (trade name: nitrol), which is a NO-releasing agent, was administered to a renal failure model mouse that had been nephrectomized on 5/6.
  • EPO receptor expression was improved, Hb was improved without an ESA administration, and anemia was eliminated.
  • the present invention includes the following.
  • a pharmaceutical composition comprising a nitrate drug and a pharmacologically acceptable carrier.
  • a therapeutic agent for renal anemia containing a therapeutically effective amount of nitrate.
  • the therapeutic drug according to (4), wherein the nitrate drug is selected from the group consisting of nitroglycerin, isosorbide nitrate and isosorbide mononitrate.
  • the therapeutic agent for renal anemia containing the therapeutically effective amount of the nitrate drug of the present invention is a novel therapeutic agent for renal anemia in ESA-resistant patients for which there has been no therapeutic method so far. It can be offered as a treatment option for patients other than ESA resistant patients. Patients can choose treatments that take into account their side effects depending on their physical symptoms, eliminating the patient's economic and physical burden.
  • FIG. 1 is a graph showing that anemia is markedly improved by administration of a NO donor in a CKD model mouse.
  • the numbers in FIG. 1 indicate the mean ⁇ SD. Mann-Whitney U test, * P ⁇ 0.05 vs sham, +0.05 vs 5 / 6Nx
  • FIG. 2 is a diagram showing that hemoglobin concentration was remarkably improved by administration of NO donor in CKD model mice.
  • FIG. 3 shows that gene expression of Epo receptor in hematopoietic tissue (spleen) was improved by administration of NO donor in CKD model mice.
  • FIG. 4 is a diagram showing that the expression of iron utilization-related genes in hematopoietic tissues was not changed by NO donor administration in CKD model mice.
  • FIG. 5 is a graph showing that the hepcidin expression in the liver was not significant but decreased by about 10% by administration of NO donor in CKD model mice.
  • FIG. 6 is a graph showing that anemia improvement by NO donor administration in CKD model mice is not due to Epo enhancement in the kidney.
  • FIG. 7 is a view showing erythropoietin receptor inhibition through erythropoietin receptor expression inhibition by erythropoietin signal and ADMA accumulation.
  • nitrate drugs which have been used as therapeutic drugs for heart diseases, are effective for the treatment of renal anemia.
  • NO nitrate drugs
  • Nitric acid drugs such as nitroglycerin and isosorbide nitrate, can be structurally expressed as R-NO 2, and finally release NO to exert its effect.
  • Nitric acid drugs include nitroglycerin (trade name: nitropen, nitroderm TTS, myocol spray), isosorbide nitrate (trade name: nitrol, Flandre), isosorbide mononitrate (trade name: itolol), and so on. And isosorbide mononitrate are preferred.
  • Nitroglycerin is almost lost due to the first-pass effect of the liver, and cannot be administered orally. Nitroglycerin itself has a half-life of 5 minutes, and a metabolite with a single NO 2 group has a half-life of 40 minutes. Nitroglycerin is basically used under the tongue.
  • Isosorbide nitrate is also called “isosorbide dinitrate” and is represented by the following formula. Isosorbide nitrate has a longer half-life than nitroglycerin and is more effective than nitroglycerin if the same amount. However, since it is strongly affected by the first-pass effect on the liver, it cannot be used with oral administration at present. Isosorbide nitrate has a half-life of 1 hour. When the NO 2 group at position 2 is removed, it becomes isosorbide mononitrate and the half-life is extended to 2 to 4 hours.
  • Isosorbide mononitrate (chemical name: 1,4: 3,6-Dianhydro-D-glucitol 5-nitrate) is represented by the following formula. Isosorbide mononitrate has good absorbability from the intestinal tract and is not easily affected by the first pass through the liver, so its bioavailability is almost 100%. Among the nitrate drugs, isosorbide nitrate has been marketed in a number of preparations such as tablets, sprays, and patches (tapes). Isosorbide mononitrate is a substance produced by metabolism of isosorbide nitrate, and a product obtained by formulating this metabolite as a drug is isosorbide mononitrate (trade name: Aitrol). Isosorbide mononitrate is superior in that it is less susceptible to liver metabolism than isosorbide nitrate.
  • Isosorbide mononitrate exhibits a dose-dependent vasorelaxation effect in the isolated thoracic aorta and abdominal vena cava in rabbits, increasing cGMP content in vascular tissue.
  • Such a vasorelaxant action is highly selective for venous blood vessels, and an increase in cGMP content is more pronounced in veins than in arteries.
  • Isosorbide mononitrate reduces cardiac preload by reducing venous return due to venous vasodilatation in anesthetized dogs, and afterload by reducing total peripheral vascular resistance Let Furthermore, the coronary blood flow is increased in a dose-dependent manner without directly affecting the myocardial contractile force.
  • isosorbide mononitrate When isosorbide mononitrate is orally administered to an anaesthetized dog, it exhibits a dose-dependent pulse pressure reducing action and has a high bioavailability. There is a positive correlation between plasma isosorbide mononitrate concentration and the effect of reducing pulse pressure.
  • the therapeutic agent of the present invention can be further mixed with sugars such as mannitol, glucose and lactose, salts such as sodium phosphate and sodium phosphate as additives as necessary.
  • sugars such as mannitol, glucose and lactose, salts such as sodium phosphate and sodium phosphate as additives as necessary.
  • nitrate drug that is an active ingredient
  • sublingual administration is preferred when the nitrate drug is nitroglycerin.
  • a pharmaceutical composition for parenteral administration comprises a solution of the nitrate drug of the present invention dissolved in a generally acceptable carrier, preferably an aqueous carrier.
  • a generally acceptable carrier preferably an aqueous carrier.
  • aqueous carriers can be used, all of which are known in the art, for example, water, buffered water, saline, glycine, and the like. These solutions are sterile and generally free of particulate matter.
  • These pharmaceutical compositions can be sterilized by ordinary well-known sterilization methods.
  • composition of the present invention contains generally used additives such as stabilizers (arginine, polysorbate 80, macrogol 4000, etc.), excipients (mannitol, sorbitol, sucrose), etc., and sterile filtration, dispensing.
  • stabilizers arginine, polysorbate 80, macrogol 4000, etc.
  • excipients mannitol, sorbitol, sucrose
  • sterile filtration, dispensing sterile filtration, dispensing.
  • the preparation can be prepared by treatment with freeze-drying or the like and can be administered as an injection or transmucosally (nasally, orally, sublingually).
  • the therapeutically effective dose of nitrate in the present invention varies depending on the severity of the disease state, age, weight, etc. of the subject and is ultimately determined at the discretion of the doctor, but is usually 160 ⁇ g / kg to 160,000 ⁇ / A single dose of kg / day, preferably 1,600 ⁇ g / kg to 16,000 ⁇ g / kg / day may be administered.
  • Those skilled in the art will be able to use standard pharmacological methods to determine the required treatment regimen depending on the particular disease and the severity of the condition to be treated.
  • CKD model mice C57BL6 mice were used as wild type, and CKD models were prepared by 5/6 nephrectomy. Half-nephrectomy was performed at 7 weeks of age and 2/6 nephrectomy at 8 weeks of age to create a 5/6 nephrectomy model. This model has already been established as a chronic renal failure model and exhibits erythropoietin-resistant renal anemia after 12 weeks. Control diet (CE-2) was mixed with isosorbide nitrate (ISDN), and 0.16% NO diet was orally administered.
  • CE-2 Control diet
  • ISDN isosorbide nitrate
  • Wild type + control diet, CKD mouse + control diet, CKD mouse + NO diet started at 8 weeks of age, administered for 12 weeks, and BUN, creatinine, red blood cell count, and Hb were compared at 20 weeks of age. During the study, mice consumed 3.35g on average per day.
  • FIG. 1 As is apparent from FIG. 1, anemia was markedly improved by administration of isosorbide nitrate, which is a NO donor.
  • mice Improvement of hemoglobin concentration by NO donor administration in CKD model mice
  • IDN isosorbide nitrate
  • CE-2 control diet
  • 0.16% NO diet was orally administered.
  • Wild type + control diet, CKD mouse + control diet, CKD mouse + NO diet started at 8 weeks of age and administered for 12 weeks, and hemoglobin concentrations were compared at 20 weeks of age. During the study, mice consumed 3.35g on average per day.
  • the primers and probes used for analysis of the mouse erythropoietin receptor (Epor), transferrin receptor (Tfrc-1), erythroferon (Fam132b) and hepcidin (Hamp) genes were Mm_Epor_SG, Mm_Tfrc_1_SG, Mm_Fam132b_1_SG and Mm_Hamp_1, respectively. Qiagen, Venlo, Netherlands). Hypoxanthine guanine phosphoribosyltransferase (Hprt) (Mm_Hprt_1_SG) was used as an endogenous control (Qiagen, Venlo, The Netherlands).
  • PCR cycling conditions were as follows: initial denaturation step at 95 ° C for 15 minutes followed by denaturation (94 ° C for 15 seconds), annealing (60 ° C for 30 seconds) and extension (72 ° C for 30 seconds) 45 cycles.
  • the relative amount of target gene mRNA was normalized to Hprt by the delta-delta CT method.
  • the primers and probes used for analysis of the mouse erythropoietin receptor (Epor), transferrin receptor (Tfrc-1), erythroferon (Fam132b) and hepcidin (Hamp) genes were Mm_Epor_SG, Mm_Tfrc_1_SG, Mm_Fam132b_1_SG and Mm_Hamp_1, respectively. Qiagen, Venlo, Netherlands). Hypoxanthine guanine phosphoribosyltransferase (Hprt) (Mm_Hprt_1_SG) was used as an endogenous control (Qiagen, Venlo, The Netherlands).
  • PCR cycling conditions were as follows: initial denaturation step at 95 ° C for 15 minutes followed by denaturation (94 ° C for 15 seconds), annealing (60 ° C for 30 seconds) and extension (72 ° C for 30 seconds) 45 cycles.
  • the relative amount of target gene mRNA was normalized to Hprt by the delta-delta CT method.
  • FIG. 4 shows the results for transferrin receptor-1
  • FIG. 4 (b) shows the results for erythroferon.
  • hepcidin in liver in CKD model mice The same mice as in Example 1 were used, sacrificed at 20 weeks of age, and the spleen and liver were stored frozen at -80 degrees. RT-PCR was performed using the QuantiTect SYBRGreen PCR kit (Qiagen, Venlo, The Netherlands) according to the supplier's recommendations.
  • the primers and probes used for analysis of the mouse erythropoietin receptor (Epor), transferrin receptor (Tfrc-1), erythroferon (Fam132b) and hepcidin (Hamp) genes were Mm_Epor_SG, Mm_Tfrc_1_SG, Mm_Fam132b_1_SG and Mm_Hamp_1, respectively. Qiagen, Venlo, Netherlands). Hypoxanthine guanine phosphoribosyltransferase (Hprt) (Mm_Hprt_1_SG) was used as an endogenous control (Qiagen, Venlo, The Netherlands).
  • PCR cycling conditions were as follows: initial denaturation step at 95 ° C for 15 minutes followed by denaturation (94 ° C for 15 seconds), annealing (60 ° C for 30 seconds) and extension (72 ° C for 30 seconds) 45 cycles.
  • the relative amount of target gene mRNA was normalized to Hprt by the delta-delta CT method.
  • hepcidin expression in the liver was not significant but decreased by about 10% by administration of isosorbide nitrate as a NO donor. This means that NO has no effect on hepcidin expression in the liver involved in iron metabolism, or has no hepcidin inhibitory effect through anti-inflammatory action.
  • the therapeutic agent for renal anemia containing the therapeutically effective amount of the nitrate drug of the present invention is a novel therapeutic agent for renal anemia in ESA-resistant patients for which there has been no therapeutic method so far. It can be offered as a treatment option for patients other than ESA resistant patients. Patients can choose treatments that take into account their side effects depending on their physical symptoms, eliminating the patient's economic and physical burden.

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Abstract

La présente invention concerne un nouvel agent thérapeutique pour l'anémie néphrogénique qui est également efficace pour des patients résistant à l'ESA. L'invention concerne une composition médicinale qui comprend un nitrate organique et un véhicule pharmacologiquement acceptable; et un agent thérapeutique pour l'anémie néphrogénique qui comprend une quantité thérapeutiquement efficace d'un nitrate organique. En tant que nitrate organique, le nitrate d'isosorbide ou le mononitrate d'isosorbide est préféré.
PCT/JP2018/002088 2017-01-30 2018-01-24 Nouvel agent thérapeutique pour l'anémie néphrogénique ciblant un récepteur d'érythropoïétine via no et la stimulation de la voie no WO2018139477A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63307818A (ja) * 1987-06-08 1988-12-15 Sekisui Chem Co Ltd 経皮吸収貼付剤
JPH059115A (ja) * 1991-08-31 1993-01-19 Nippon Kayaku Co Ltd ニトログリセリンを含有する感圧性粘着テープまた はシートの製造方法
WO2005089743A1 (fr) * 2004-03-19 2005-09-29 Ajinomoto Co., Inc. Agent thérapeutique pour l'anémie rénale
WO2006115274A1 (fr) * 2005-04-26 2006-11-02 Ajinomoto Co., Inc. Inducteur de differenciation des progeniteurs myeloerythroides
JP2016114606A (ja) * 2014-12-15 2016-06-23 学校法人 久留米大学 腎性貧血のバイオマーカーとしての赤血球ａｄｍａの使用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63307818A (ja) * 1987-06-08 1988-12-15 Sekisui Chem Co Ltd 経皮吸収貼付剤
JPH059115A (ja) * 1991-08-31 1993-01-19 Nippon Kayaku Co Ltd ニトログリセリンを含有する感圧性粘着テープまた はシートの製造方法
WO2005089743A1 (fr) * 2004-03-19 2005-09-29 Ajinomoto Co., Inc. Agent thérapeutique pour l'anémie rénale
WO2006115274A1 (fr) * 2005-04-26 2006-11-02 Ajinomoto Co., Inc. Inducteur de differenciation des progeniteurs myeloerythroides
JP2016114606A (ja) * 2014-12-15 2016-06-23 学校法人 久留米大学 腎性貧血のバイオマーカーとしての赤血球ａｄｍａの使用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Itorol Tablets 10mg, 20 mg Isosorbide Mononitrate Tablets", CLINICAL RESEARCH, July 2014 (2014-07-01) *
COKIC, BOJANA B. BELESLIN ET AL.: "Nitric oxide and hypoxia stimulate erythropoietin receptor via MAPK kinase in endothelial cells", MICROVASCULAR RESEARCH, vol. 92, March 2014 (2014-03-01), pages 34 - 40, XP055530795 *

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