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WO2016031949A1 - Remède pour l'insuffisance rénale chronique - Google Patents

Remède pour l'insuffisance rénale chronique Download PDF

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WO2016031949A1
WO2016031949A1 PCT/JP2015/074350 JP2015074350W WO2016031949A1 WO 2016031949 A1 WO2016031949 A1 WO 2016031949A1 JP 2015074350 W JP2015074350 W JP 2015074350W WO 2016031949 A1 WO2016031949 A1 WO 2016031949A1
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carbon atoms
alkyl
phenyl
hydrogen
carbons
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Japanese (ja)
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五十嵐　浩司
佳丈 高橋
智子 阪本
和幸 金子
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Toray Industries Inc
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Toray Industries Inc
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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
    • A61K31/33—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
    • A61K31/343—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 condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone

Definitions

  • the present invention relates to a therapeutic agent for chronic renal failure and a method for treating the same.
  • Patent Document 1 a report in a rat renal failure model in which nephritis produced by administering an antibody of glomerular basement membrane is used as a primary disease is known ( Patent Document 1).
  • renal function markers such as serum creatinine (SCre) and blood urea nitrogen (BUN), which are higher than normal values. It has been shown that, when the compound (I) is administered, increases in numerical values such as urinary protein excretion, SCre, and BUN, which increase with the progression of renal failure, are suppressed compared to the control group.
  • SCre serum creatinine
  • BUN blood urea nitrogen
  • Non-patent Document 1 the administration of beraprost sodium suppressed the decrease in renal function in conservative renal failure, which was indicated by a decrease in creatinine clearance and SCre reciprocal in patients with chronic renal failure.
  • Non-patent Document 1 an increase in patients with chronic renal failure has become a big problem not only in human medicine but also in veterinary medicine. Pets such as dogs and cats can now enjoy a more nutritious diet and more advanced veterinary services. As a result, pets, like humans, have a long life, and the number of animals suffering from aging-related diseases and chronic diseases that are difficult to treat is rapidly increasing. Chronic renal failure is seen in many types of pet animals, but cats develop chronic renal failure at a particularly high rate.
  • Chronic renal failure accounts for about 30% of all illnesses in cats over 15 years of age and is the leading cause of death for cats. Furthermore, when a patient cat is brought to a veterinary hospital, it is a very advanced chronic renal failure state, and there are very many cases of uremia.
  • a therapeutic agent for uremia containing a compound of the general formula (I) of the present application is effective in treating uremia associated with such chronic renal failure patients (Patent Document 2).
  • a suitable model for determining uremia, recovery of reduced appetite, improvement of activity, weight gain, etc. are achieved quickly without side effects, but these are only improvements in uremia symptoms, not necessarily kidneys It did not show an effect on the insufficiency state, ie, decrease in renal function. In other words, improvement of renal function and improvement of uremia have not been directly linked, leaving a problem in the treatment of chronic renal failure itself.
  • side effects such as diarrhea, vomiting, sedation, and increased heart rate may occur when a compound represented by the general formula (I) is administered at 30 ⁇ g / kg body weight or more.
  • the problem to be solved by the present invention is to provide a therapeutic agent and a treatment method for chronic renal failure in mammals including cats.
  • the present inventors have found that the optimal usage and dosage of a therapeutic agent for chronic renal failure comprising the compound represented by the general formula (I) of the present application as an active ingredient
  • the compound represented by the general formula (I) is administered at a dose of 55 ⁇ g per dose, or administered at 6 to 26.4 ⁇ g / kg per dose, preferably continuously administered for 30 days or more.
  • the present inventors have found that the increase in the numerical values of renal function markers such as SCre and BUN can be suppressed and maintained stably without causing harmful side effects, and the present invention has been completed. That is, the present invention 1.
  • R 1 is (A) COOR 2 , where R 2 is 1) hydrogen or a pharmacologically acceptable cation, 2) straight-chain alkyl having 1 to 12 carbons or branched alkyl having 3 to 14 carbons 3) —Z—R 3 , where Z is a valence bond, or straight-chain or branched alkylene represented by C t H 2t in it, t is an integer of 1 to 6, R 3 is a substituted cycloalkyl cycloalkyl or carbon atoms which is substituted one to three pieces of R 4 3-12 3-12 carbon atoms, R 4 Is hydrogen or alkyl of 1 to 5 carbon atoms, 4) — (CH 2 CH 2 O) n CH 3 , where n is an integer from 1 to 5, 5) -Z-Ar 1 , where Z is as defined above, Ar 1 is phenyl, ⁇ -naphthyl, ⁇ -naphthyl, 2-pyridyl, 3-
  • R represents —SO 2 R 10
  • the other R 9 is not —SO 2 R 10
  • (D) —CH 2 OTHP THP is a tetrahydropyranyl group
  • R 1 is (A) COOR 2 , where R 2 is 1) hydrogen or a pharmacologically acceptable cation, 2) straight-chain alkyl having 1 to 12 carbons or branched alkyl having 3 to 14 carbons 3) —Z—R 3 , where Z is a valence bond, or straight-chain or branched alkylene represented by C t H 2t in it, t is an integer of 1 to 6, R 3 is a substituted cycloalkyl cycloalkyl or carbon atoms which is substituted one to three pieces of R 4 3-12 3-12 carbon atoms, R 4 Is hydrogen or alkyl of 1 to 5 carbon atoms, 4) — (CH 2 CH 2 O) n CH 3 , where n is an integer from 1 to 5, 5) -Z-Ar 1 , where Z is as defined above, Ar 1 is phenyl, ⁇ -naphthyl, ⁇ -naphthyl, 2-pyridyl, 3-
  • R represents —SO 2 R 10
  • the other R 9 is not —SO 2 R 10
  • (D) —CH 2 OTHP THP is a tetrahydropyranyl group
  • E represents hydrogen or —OR 18 , wherein R 18 is acyl having 1 to 12 carbons, aroyl having 1 to 15 carbons or R 2 (wherein R 2 is as defined above),
  • General formula (I) represents d-form, l-form or dl-form]
  • a therapeutic agent for chronic renal failure comprising administering 6 to 26.4 ⁇ g / kg of a compound represented by the following: 3.
  • R 1 is COOR 2 , where R 2 is hydrogen or a pharmacologically acceptable cation, A is — (CH 2 ) m —, where m is an integer from 1 to 3, Y is hydrogen, B is —X—C (R 11 ) (R 12 ) OR 13 , wherein R 11 and R 13 are hydrogen; X is —CH ⁇ CH—, R 12 is —C u H 2u —C ⁇ C—R 17 , wherein u is an integer of 1 to 7, C u H 2u is a linear or branched alkylene, R 17 is a linear alkyl having 1 to 6 carbon atoms, The therapeutic agent for chronic renal failure according to 1 or 2, wherein E is hydrogen or -OR 2 (wherein R 2 is as defined above), 4).
  • R 1 is COOR 2 , where R 2 is hydrogen or sodium ion, A is — (CH 2 ) m —, where m is 3, Y is hydrogen, B is —X—C (R 11 ) (R 12 ) OR 13 , wherein R 11 and R 13 are hydrogen; X is —CH ⁇ CH—, R 12 is —C u H 2u —C ⁇ C—R 17 , where u is 2, C u H 2u is branched alkylene, R 17 is methyl, E is -OH,
  • the therapeutic agent for chronic renal failure according to 1 or 2, wherein the compound represented by the general formula (I) is beraprost sodium, 6).
  • R 1 is (A) COOR 2 , where R 2 is 1) hydrogen or a pharmacologically acceptable cation, 2) straight-chain alkyl having 1 to 12 carbons or branched alkyl having 3 to 14 carbons 3) —Z—R 3 , where Z is a valence bond, or straight-chain or branched alkylene represented by C t H 2t in it, t is an integer of 1 to 6, R 3 is a substituted cycloalkyl cycloalkyl or carbon atoms which is substituted one to three pieces of R 4 3-12 3-12 carbon atoms, R 4 Is hydrogen or alkyl of 1 to 5 carbon atoms, 4) — (CH 2 CH 2 O) n CH 3 , where n is an integer from 1 to 5, 5) -Z-Ar 1 , where Z is as defined above, Ar 1 is phenyl, ⁇ -naphthyl, ⁇ -naphthyl, 2-pyridyl, 3-
  • R represents —SO 2 R 10
  • the other R 9 is not —SO 2 R 10
  • (D) —CH 2 OTHP THP is a tetrahydropyranyl group
  • E represents hydrogen or —OR 18 , wherein R 18 is acyl having 1 to 12 carbons, aroyl having 1 to 15 carbons or R 2 (wherein R 2 is as defined above),
  • General formula (I) represents d-form, l-form or dl-form] A compound represented by It is.
  • the compound represented by the general formula (I) of the present invention is administered at 55 ⁇ g per dose, or administered at 6 to 26.4 ⁇ g / kg at a time, preferably twice a day for 30 days or more.
  • a time preferably twice a day for 30 days or more.
  • the time courses of body weight and general condition (activity, appetite, dehydration) when 55 ⁇ g or 20 ⁇ g per dose of BPS was orally administered to a cat with chronic renal failure twice daily for 180 days are shown.
  • the general state was scored from 0 to 4 in advance according to a predetermined standard, and was judged by a veterinarian.
  • the horizontal axis of each figure shows the number of days after administration. In the 20 ⁇ g group, almost no improvement was observed, but in the 55 ⁇ g group, all items improved. Especially in terms of activity and appetite, significant improvement in symptoms is observed in the 55 ⁇ g group.
  • Renal function (BUN, SCre, phosphorus / calcium ratio (P / Ca), blood indoxyl) when 55 ⁇ g or 20 ⁇ g of BPS is orally administered to a cat with chronic renal failure twice daily for 180 days (Sulfuric acid, blood phenol).
  • the horizontal axis of each figure shows the number of days after administration.
  • BUN, SCre, P / Ca, indoxyl sulfate, and phenol are all increased, but the increase in the 55 ⁇ g group is suppressed as compared to the 20 ⁇ g group, and the suppression is maintained.
  • BUN, SCre, and P / Ca in the 20 ⁇ g group showed a large increase from 150 to 180 days after administration, whereas BUN and P / Ca on the 180 day administration increased significantly in the 20 ⁇ g group.
  • Renal function urine specific gravity, urinary protein / creatinine (UPC), urinary N-acetyl- ⁇
  • UPC urinary protein / creatinine
  • NAG urinary N-acetyl- ⁇
  • TGF- ⁇ urinary transforming growth factor ⁇
  • a significant decrease in body weight is observed in the placebo group, and a significant deterioration in activity is observed in the general state, while a maintenance of weight, a significant improvement in activity, and a significant improvement in appetite are observed in the 55 ⁇ g group.
  • Renal function (BUN, SCre, P / Ca) in a clinical study (double-blind comparative study) in which 55 ⁇ g of BPS per administration or placebo tablet was administered twice a day for 180 days in a chronic renal failure cat , UPC).
  • the placebo group there is a significant deterioration tendency in each item, but in the 55 ⁇ g group, the increase is suppressed and stably maintained.
  • R 1 is preferably COOH, COONa or COOMe, particularly preferably COONa, As A, — (CH 2 ) 2 —, — (CH 2 ) 3 —, —CH ⁇ CH—, —O—CH 2 — is preferable, and — (CH 2 ) 3 ) — is particularly preferable.
  • Y is particularly preferably hydrogen
  • B is represented by —X—C (R 11 ) (R 12 ) OR 13 , where R 11 and R 13 are particularly preferably hydrogen, and X is preferably —CH ⁇ CH—, particularly trans —CH ⁇ CH— is preferred
  • R 12 includes hexyl, pentyl, 1-methylpropyl, 2-chlorophenyl, propyloxymethyl, cyclohexyl, 4-hexyn-2-yl, 2-methyl-4-hexyne-2 -Yl is preferred, especially 4-hexyn-2-yl
  • E is particularly preferably —OH.
  • Preferable specific compounds of the compound represented by the general formula (I) include 16-methyl-18,18,19,19-tetradehydro-5,6,7-trinor-4,8-inter-m- phenylene PGI 2 (common name beraprost), 16-methyl -18,18,19,19- Tetoradehidoro -5,6,7- trinor-4,8-inter -m- phenylene PGI 2 sodium salt (sodium rac- ( 1R, 2R, 3aS, 8bS) -2,3,3a, 8b-tetrahydro-2-hydroxy [(E)-(3S, 4RS) -3-hydroxy-4-methyl-1-en-6-]-1H -Cyclopenta [b] [1] benzofuran-5-butanoate: generic name beraprost sodium) Among them preferably a beraprost sodium. However, these are merely specific examples and are not limited thereto.
  • the compound represented by the general formula (I), particularly beraprost sodium is stable for a long period of time and has high bioavailability by oral administration. For this reason, in patients with renal diseases, particularly patients with chronic kidney diseases, since long-term administration is required, it can be particularly preferably used.
  • the compounds represented by the above general formula (I) used in the present invention are known, for example, Japanese Patent Publication No. 1-53672, Japanese Patent Publication No. 7-5582, Japanese Patent Publication No. 3-7275, Japanese Patent Publication No. 6-62599. It can manufacture by the well-known method described in gazette gazette etc.
  • the compounds represented by the general formula (I) of the present invention can be used alone or in combination of two or more.
  • chronic renal failure means that the number of functioning nephrons decreases, the excretion of nitrogen metabolites becomes insufficient, and the abnormal functional state of the kidney, which cannot maintain the homeostasis of the internal environment of the living body, lasts for a long time. That means. Specifically, it can be referred to as a state or syndrome in which the numerical values of renal function markers such as SCre and BUN in blood show a continuous increase.
  • Examples of the primary diseases of chronic renal failure include kidney stones, urinary tract obstruction, diabetic nephropathy, acute glomerulonephritis and chronic glomerulonephritis, nephrotic syndrome, polycystic kidney disease, nephropathy due to infection, lupus nephritis, Examples include interstitial nephritis, acute tubulointerstitial nephritis, chronic tubulointerstitial nephritis, cirrhosis, hepatic edema, and congestive heart failure.
  • chronic glomerulonephritis microglomerular change nephritis, focal / segmental glomerulonephritis, diffuse glomerulonephritis, mesangial proliferative glomerulonephritis, diffuse endoproliferative nephritis, crescent-forming nephritis It is also effective for uremic diseases with diffuse sclerosing glomerulonephritis and IgA nephropathy as primary diseases.
  • the patient for whom the therapeutic agent in the present invention is effective is not particularly limited, and may be any mammal determined to be chronic renal failure according to the above definition, but is preferably a cat, dog or person.
  • beraprost sodium contained in the general formula (I) of the present invention is administered as a therapeutic agent to a cat suffering from chronic renal failure, an increase in numerical values of renal function markers such as SCre and BUN is suppressed.
  • the therapeutic agent of the present invention has a remarkable effect on cats because no side effects such as diarrhea and vomiting occurred during the long-term administration period, and clinical symptoms of uremia were improved. It can be said that it shows.
  • the dose of the compound represented by the general formula (I), which is an active ingredient of the therapeutic agent of the present invention is 55 ⁇ g per time or 6 to 26.4 ⁇ g / kg per time.
  • This dose is preferably administered twice a day and may be administered continuously for 30 days or longer, preferably 60 days or longer, more preferably 120 days or longer, and even more preferably 180 days, but is not limited thereto. It is not something.
  • side effects such as diarrhea, vomiting, sedation, and increased heart rate may occur when the compound represented by formula (I) is administered in excess of 30 ⁇ g / kg body weight (patent) From the literature 2), it is preferable to avoid administration of a certain dose or more.
  • Various dosage forms can be used as the dosage form of the pharmaceutical composition of the present invention.
  • tablets, powders, fine granules, granules, solutions, syrups, capsules, pills. Can be a spray.
  • the molded product can be film-coated, sugar-coated, or capsule-filled.
  • Preferable examples include tablets, powders, fine granules, granules, liquids, syrups, and capsules.
  • it may be administered parenterally in the form of a bactericidal solution, or other solutes such as sodium chloride or glucose sufficient to make the solution isotonic can be used.
  • the therapeutic and prophylactic agents of the present invention can be used as various injections and suppositories in addition to the above preparations.
  • it is possible to individually control release such as slow release and delayed release.
  • the drug can be provided with a sustained release function by an existing method, and a wide range of administration methods can be applied parenterally such as an implantable sustained release pump (eg, Alzamini pump).
  • an implantable sustained release pump eg, Alzamini pump
  • renal diseases are chronic diseases that require long-term treatment
  • the therapeutic agent of the present invention can be added in advance to a prescription meal for patients with renal diseases under the guidance of a doctor or veterinarian.
  • it can be orally administered in conjunction with, or simultaneously with, an existing activated carbon preparation for uremic treatment.
  • the therapeutic agent of the present invention when the therapeutic agent of the present invention is given for a certain period of time in advance, it is possible to switch the activated carbon preparation from the therapeutic agent of the present invention almost simultaneously.
  • the compound represented by the general formula (I) when switching from the activated carbon preparation to the therapeutic agent of the present invention, the compound represented by the general formula (I) may be adsorbed on the activated carbon, which may affect the drug efficacy. Is desirable.
  • Example 1 Preparation of beraprost sodium tablets
  • the drugs administered to cats in the examples and comparative examples of the present invention were both 20 ⁇ g / tablet using beraprost sodium (BPS) as the compound represented by the general formula (I)
  • Film-coated tablets of 40 ⁇ g / tablet, 55 ⁇ g / tablet and 150 ⁇ g / tablet were prepared by the following method.
  • the base powder lactose, starch
  • stirring granulation was performed while adding a solution of BPS and binder (hypromellose) prepared in advance.
  • Lubricant magnesium stearate
  • a rotary tableting machine using a 6mm, 8R tool. Obtained.
  • the obtained uncoated tablet was put into a coating apparatus, and coating was performed while spraying a previously prepared coating solution (polyethylene glycol, hypromellose), and then carnauba wax was added to obtain a film-coated tablet.
  • Example 2 Administration of 55 ⁇ g beraprost sodium for 180 days to cats with chronic renal failure (FIGS. 1, 2 and 3)
  • the cat suffering from chronic renal failure used in the test had an SCre of 1.6 mg / dL to 5.0 mg / dL and a total serum thyroxine (T 4 ) of 0.9 ⁇ g / dL to 0.9 ⁇ g / dL before the start of the test.
  • T 4 total serum thyroxine
  • acute renal failure acute exacerbation of chronic renal failure
  • chronic heart failure New York Heart Association classification: class II, III or IV
  • diabetes hyperadrenocorticism
  • urinary tract infection Feline leukemia virus infection, feline immunodeficiency virus infection, feline infectious peritonitis, malignant tumor, markedly decreased liver function, pregnancy, and cats with obvious bleeding tendency were excluded.
  • the BPS was administered orally after the meal in the morning and evening, once a day, once a day for the BPS tablet prepared in Example 1. Drugs requiring withdrawal before the study were prohibited during the study period and infusion was prohibited. We also decided not to start or change the diet throughout the study.
  • Body temperature and body weight were measured at 0, 30, 60, 90, 120, 150, and 180 days after administration 2 weeks before the test, and the general condition (activity, appetite, dehydration) was preliminarily 0-4 according to the following criteria. Was scored and judged by the veterinarian.
  • Activity is 0: active, 1: normal, 2: mildly decreased, 3: moderately decreased, 4: severely decreased, appetite is 0: enhanced, 1: normal, 2: 1 daily diet is about 1/4 Decreased, 3: 1 daily food consumption reduced by more than 1/2, weekly one day not eaten, 4: non-eaten day more than 2-3 days a week, dehydration less than 0: 5% 1: 5% (slight skin elasticity, mucosal dryness), 2: 7-8% (apparent reduction in skin elasticity, capillary refill time (CRT) 2-3 seconds, ocular Slight depression, limb sensation, 3: 10-12% (disappearance of skin elasticity, CRT 3 seconds or longer, marked eyeball depression, shock, involuntary muscle spasm, skin sensation), 4: 12-15 % (Obvious shock state, moribund state).
  • CTR capillary refill time
  • hematologic tests red blood cell count (RBC), white blood cell count (WBC), blood cell volume ratio (PCV), 0, 30, 60, 90, 120, 150, 180 days
  • Hemoglobin (Hb)) blood biochemical tests (total protein (TP), albumin (Alb), globulin (Glob), alanine aminotransferase (ALT), aspartate transferase (AST), alkaline phosphatase (ALP), total cholesterol (Tcho), total bilirubin (Tbil), glucose (Glu), BUN, SCre, sodium (Na), potassium (K), chlor (Cl), calcium (Ca), phosphorus (P)) were measured.
  • blood indoxyl sulfate and blood phenol test HPLC method was performed as an index of uremic toxin at 0, 90 and 180 days after administration 2 weeks before the test.
  • BUN, SCre, P / Ca and UPC used for evaluation of renal function were employed as markers for glomerular function. Both BUN and SCre are not excreted from the kidney due to a decrease in renal function, and the blood concentration is increased. P / Ca is increased in concentration due to a decrease in renal function and phosphorus is not excreted. The value increases because of a decrease, and the value of UPC increases due to an increase in protein in urine due to a decrease in renal function. Indoxyl sulfate and phenol were adopted as indicators of uremic toxins. It is known that indoxyl sulfate increases in blood concentration due to a decrease in renal function, and phenol accumulates in blood due to renal failure and uremia and increases in concentration.
  • Urine specific gravity and urinary NAG were used as tubule markers, and urinary TGF- ⁇ was used as a fibrosis and inflammation marker.
  • the specific gravity of urine is decreased due to decrease in urine concentration ability due to renal failure, and urinary NAG is increased when tubular epithelial cells are abnormal.
  • Urinary TGF- ⁇ is also known to increase due to renal failure.
  • BPS tablets for all cases administered BPS tablets, deaths, body temperature and weight, general condition (activity, appetite, dehydration), hematological examination, blood biochemical examination, urinalysis results, etc.
  • the causal relationship with the administration of BPS was verified for all the adverse events that occurred, and the safety was evaluated.
  • BPS 55 ⁇ g tablet once a day 55 ⁇ g / head
  • BPS twice a day 110 ⁇ g / head / day
  • BUN increased from an average of 28.63 mg / dL on the 0th day to 31.27 mg / dL on the 30th day in the 55 ⁇ g administration group, but variation was observed until the 150th day. It was 31.63 mg / dL on the 180th day.
  • the increase rate on the 180th day was 10.5%.
  • SCre slightly increased from 2.10 mg / dL on day 0 of administration to 2.32 mg / dL on day 180.
  • the increase rate on the 180th day was 11.0%.
  • P / Ca increased from an average of 0.50 on the 0th day to 0.53 on the 60th day, but decreased to 0.48 on the 90th day, followed by little fluctuation and 0.49 on the 180th day.
  • the blood indoxyl sulfate slightly increased from an average of 2.57 ⁇ g / mL on day 0 to 2.80 ⁇ g / mL on day 90, but decreased to 2.65 ⁇ g / mL on day 180.
  • Blood phenol decreased from an average of 0.030 ⁇ g / mL on day 0 to 0.010 ⁇ g / mL on day 90 and to 0.009 ⁇ g / mL on day 180.
  • the urine specific gravity increased from an average of 1.024 on the 0th day of administration every month to 1.027 on the 180th day.
  • UPC decreased from an average of 0.136 on day 0 to 0.060 on day 30 and increased to 0.149 on day 60, but decreased to 0.088 on day 90. Decreased to 0.070.
  • Urinary NAG decreased from an average of 4.38 on day 0 to 3.165 on day 30 and increased to 6.436 on day 90. It decreased to 3.933 on the 120th day, and then increased to 4.65 on the 180th day with little fluctuation.
  • Urinary TGF- ⁇ showed little variation from the average of 966.77 on day 0 to 942.738 on day 90, increased to 11.90.959 on day 120, but decreased to 9455.592 on day 150, 180 On day, it dropped to 668.23.
  • the BPS-55 ⁇ g administration group of this example is 8.6 to 21.2 ⁇ g / kg (17.2 to 42.4 ⁇ g / kg / day) in terms of the dose per body weight of cats, which improves clinical symptoms and renal function An effect was observed in suppressing the rise of the marker and maintaining stability.
  • Comparative Example 1 Administration of 20 ⁇ g of beraprost sodium for 180 days to cats with chronic renal failure (FIGS. 1, 2, and 3) The test method followed the method described in Example 2. About 10 chronic cases of chronic renal failure cats that satisfy the above selection criteria and excluding excluded subjects, BPS 20 ⁇ g tablet once a day (20 ⁇ g / head) orally twice a day (40 ⁇ g / head / day) , Continued for 180 days and compared with the test results of Example 2.
  • BUN decreased from an average of 44.90 mg / dL on day 0 to 38.60 mg / dL on day 30, but 40.1 mg / dL on day 60. It increased to dL and did not change until day 150, but increased to 49.40 mg / dL on day 180.
  • the increase rate on the 180th day was 16.1%.
  • SCre was little changed from 2.58 mg / dL on day 0 to 2.65 mg / dL from day 150 to 150 days, but increased to 3.14 mg / dL on day 180.
  • the increase rate on the 180th day was 21.7%.
  • P / Ca averaged from 0.54 on the 0th day to 0.56 from the 150th day to 0.56, but increased to 0.64 on the 180th day.
  • p 0.0396
  • the blood indoxyl sulfate level changed from an average of 4.80 ⁇ g / mL on day 0 to 4.70 ⁇ g / mL on day 90, but increased to 10.33 ⁇ g / mL on day 180.
  • Blood phenol increased from an average of 0.008 ⁇ g / mL on day 0 to 0.030 ⁇ g / mL on day 90 and to 0.046 ⁇ g / mL on day 180.
  • the urine specific gravity of the 20 ⁇ g administration group increased from an average of 1.021 on the 0th day to 1.023 by the 120th day, but then decreased and returned to 1.021 on the 180th day.
  • UPC decreased from an average of 0.135 on day 0 to 0.103 on day 90 and increased to 0.128 on day 120. It decreased to 0.086 on the 150th day but increased to 0.160 on the 180th day.
  • Urinary NAG increased from an average of 7.555 on the 0th day to 9.751 on the 90th day, but decreased from 120th day to 2.697 on the 180th day.
  • Urinary TGF- ⁇ increased monthly from an average of 391.69 on day 0 of administration, increased to 121.284 on day 150, and decreased to 880.37 on day 180.
  • the BPS administered in this comparative example was 3.8 to 11.1 ⁇ g / kg (7.6 to 22.2 ⁇ g / kg / day) in terms of the dose per weight of the cat.
  • the dose was highly effective.
  • Example 3 Clinical study in cats with chronic renal failure (double-blind comparative study of placebo administration group and BPS 55 ⁇ g administration group, administration for 180 days, FIG. 5)
  • the chronic renal failure cat used in the study was from the middle stage II to the middle stage III of the International Renal Society Society (IRIS) excluding the acute exacerbation period, with an SCre value of 2.0 to 4.0 mg / dL and a UPC of 1.
  • IRIS International Renal Society Society
  • urine specific gravity is 1.008 to 1.030
  • T4 is 0.9 to 3.8 ⁇ g / dL
  • the BPS tablet used in the clinical trial was a tablet containing 55 ⁇ g of BPS prepared by the same method as in Example 1, whereas the placebo tablet was prepared by the same method as in Example 1 except that it did not contain BPS. BPS-free tablets.
  • BPS and placebo tablets were orally administered once a day, twice a day, after morning and evening meals.
  • administration of diuretics, cardiotonic agents, spherical adsorbed charcoal and activated carbon, blood products, iodine contrast media, prostaglandin products, corticosteroids, non-steroidal anti-inflammatory drugs is prohibited, and use of antihypertensive drugs Dose change and new administration were not allowed. In principle, infusion is prohibited, and dietary treatment is not newly started or changed.
  • body temperature and body weight were measured on days 0, 30, 60, 90, 120, 150, and 180, and the general condition was judged based on a score of 0 to 4 set in advance.
  • the score criterion is the same as that described in the second embodiment.
  • Hematology tests (RBC, WBC, PCV, Hb, TP, Alb, Glob, ALT, AST, 2 weeks before the test, 1 week before the test, 0, 30, 60, 90, 120, 150, 180 days)
  • the urine test was performed for urine occult blood, urine bacteria, urine specific gravity, UPC, and NAG at 0, 30, 60, 90, 120, 150, and 180 days two weeks before the test.
  • the BPS administered to the BPS-55 ⁇ g administration group of this example is 6.0 to 26.4 ⁇ g / kg (12.0 to 52.9 ⁇ g / kg / day) in terms of the dose per body weight. At approximately the same dose as above, it was highly effective in improving the general condition of cats with chronic renal failure and suppressing and stabilizing the increase in renal function markers.
  • Example 4 Safety study with healthy cats 3-6 year old cats with no abnormalities in clinical and blood tests at doses of BPS 0, 10, 30, 70, 100 ⁇ g / kg twice a day, Orally administered for 7 consecutive days. In each administration group, 4 males and 4 females were used, and a total of 8 were used and 0 ⁇ g / kg (control group) was used. Clinical symptoms, blood (RBC, WBC, PCV, Hb, Plat) and blood biochemistry (AST, ALT, TP, BUN, SCre, Na, K, Cl, Ca, IP), blood pressure and heart rate during the administration period was measured. The analysis of the test values was performed by using Stat View J-4.5 (Abacus Concepts) with a paired t-test with a significant difference of less than 5% on both sides.
  • BUN tended to decrease with the administration of BPS
  • SCre showed a significant decrease when administered with 30 to 100 ⁇ g / kg.
  • AST showed a tendency to decrease with administration of 30 ⁇ g / kg or more
  • ALT also showed a tendency to decrease with administration of BPS, particularly in the 70 ⁇ g / kg group.
  • blood pressure and heart rate no significant change was observed due to repeated administration, and therefore the average value for 7 days was analyzed as an individual value. Both systolic blood pressure and diastolic blood pressure tended to decrease with administration of BPS, but no statistically significant difference was observed.
  • the heart rate increased in a dose-dependent manner, and a significant difference from the control group was observed in the administration group of 30 ⁇ g / kg or more.
  • Comparative Example 2 Verification of the effect of dose and administration period per body weight of cats with chronic renal failure About the effect when BPS was orally administered twice a day to cats with chronic renal failure Table 2 shows the results of comparison and verification in the case of conversion to the per unit and the administration period.
  • BPS When BPS is administered at a dose of 6.0 to 26.4 ⁇ g / kg body weight for 180 days continuously [Example 2 (Test E), Example 3 (Test D)], 180 days after administration
  • the rate of increase / decrease in BUN in the eyes is 5.3-10.5%
  • the rate of increase / decrease in SCre is 2.9-11.0%. Therefore, it is suggested that BPS has a dose-dependent effect on chronic renal failure.
  • the same dose was administered for a short period of 56 days, clinical symptoms improved, but the renal function markers all remained high or increased. There seems to be a tendency to show higher effects.

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Abstract

L'invention concerne un remède pour l'insuffisance rénale chronique de mammifères, tels que les chats, et une méthode de traitement correspondante. Par administration orale d'un composé représenté par la formule (I) en une quantité de 55 µg par dose, ou de 6 à 26,4 µg/kg par dose, de préférence deux fois par jour en continu pendant 30 jours ou plus, il est possible d'inhiber et de stabiliser des augmentations des marqueurs de la fonction rénale tels que BUN et SCre, ce qui permet d'améliorer une insuffisance rénale chronique.
PCT/JP2015/074350 2014-08-28 2015-08-28 Remède pour l'insuffisance rénale chronique Ceased WO2016031949A1 (fr)

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Publication number Priority date Publication date Assignee Title
JPWO2021132302A1 (fr) * 2019-12-23 2021-07-01
WO2022265031A1 (fr) 2021-06-16 2022-12-22 東レ株式会社 Procédé de traitement d'un félin atteint d'une néphropathie chronique

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Publication number Priority date Publication date Assignee Title
JP3743289B2 (ja) * 1999-05-10 2006-02-08 東レ株式会社 腎不全治療薬

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3743289B2 (ja) * 1999-05-10 2006-02-08 東レ株式会社 腎不全治療薬

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Neko no Mansei Jinfuzen ni Taisuru Beraprost Natrium no Chiryo Koka ni Tsuite no Kento", ANNUAL MEETING OF JAPANESE SOCIETY OF CLINICAL VETERINARY MEDICINE PROCEEDING, vol. 26 th, no. 3, 2005, pages 72 - 76 *

Cited By (8)

* Cited by examiner, † Cited by third party
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JPWO2021132302A1 (fr) * 2019-12-23 2021-07-01
WO2021132302A1 (fr) * 2019-12-23 2021-07-01 東レ株式会社 Médicament de prévention du décès par séance de dialyse ou par maladie rénale
WO2022265031A1 (fr) 2021-06-16 2022-12-22 東レ株式会社 Procédé de traitement d'un félin atteint d'une néphropathie chronique
JPWO2022265031A1 (fr) * 2021-06-16 2022-12-22
JP7318818B2 (ja) 2021-06-16 2023-08-01 東レ株式会社 慢性腎臓病のネコの治療方法
CN117396197A (zh) * 2021-06-16 2024-01-12 东丽株式会社 慢性肾脏病的猫的治疗方法
KR20240021749A (ko) 2021-06-16 2024-02-19 도레이 카부시키가이샤 만성 신장병의 고양이의 치료 방법
US12097177B2 (en) 2021-06-16 2024-09-24 Toray Industries, Inc. Therapeutic method for cat with chronic kidney disease

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