WO1999043324A1 - Agents prophylactiques ou remedes contre les troubles renaux d'origine medicamenteuse - Google Patents
Agents prophylactiques ou remedes contre les troubles renaux d'origine medicamenteuse Download PDFInfo
- Publication number
- WO1999043324A1 WO1999043324A1 PCT/JP1999/000916 JP9900916W WO9943324A1 WO 1999043324 A1 WO1999043324 A1 WO 1999043324A1 JP 9900916 W JP9900916 W JP 9900916W WO 9943324 A1 WO9943324 A1 WO 9943324A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- drug
- renal
- represent
- therapeutic agent
- formula
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention provides a compound of the formula
- R 1 and R 2 each represent a hydrogen atom or together form a single bond; and when R 1 and R 2 represent a hydrogen atom, R 3 represents one CH (OH ) CH (OH) CH 3 , — CH (OCOCHs) CH (OCOCHs) CH 3 , — CH 3 , represents one CH 2 OH or phenyl group, and R 1 and R 2 are linked together to form a single bond.
- R 3 represents —COCH (OH) CH 3 ]
- a pharmaceutically acceptable salt thereof as an active ingredient relates to a drug for preventing and / or treating pharmacological renal disorder.
- Drug-induced renal impairment clinically manifests primarily as nephrotic syndrome (proteinuria in mild cases) and impaired renal function.
- glomerular disorders such as membrane nephropathy caused by gold preparations lead to nephrotic syndrome
- tubular disorders caused by nephrotoxic substances such as cisplatin lead to acute renal failure.
- tubule transport function When tubule transport function is specifically impaired, it presents with clinical symptoms such as Fanconi syndrome, tubular acidosis, and renal diabetes insipidus.
- acute interstitial nephritis caused by methicillin etc. it appears as renal dysfunction.
- drug-induced renal impairment presents various clinical symptoms depending on the type of the drug or the site of the disorder (MedicalPractic evol. 14no. 8, 1997,. 1273).
- cyclosporin A is an immunosuppressant commonly used at the time of transplantation, It is highly nephrotoxic and its frequency of occurrence is more than 50%, although it depends on the blood concentration.
- the phenotypes of renal injury caused by cyclosporin A include acute renal failure, chronic renal failure, hemolytic uremic syndrome (hemolytic uricics yn drome), thrombus ft microangiopathy (thromb oticmicro an angiopat hy). ), Hypertension, electrolyte abnormalities (eg, hyperkemia, metabolic acidosis, hypomagnesemia, etc.). Acute renal failure is difficult to differentiate from acute rejection and must be confirmed by renal biopsy.
- GFR glomerular filtration rate
- renin-Angi O tensin system the renin-Angi O tensin system
- sympathetic nervous system stimulation thromboxane A 2 production promoting, endothelin involvement
- endothelin involvement is considered.
- renal transplant patients often show chronic renal failure due to long-term administration of cyclosporine, but it is difficult to differentiate from chronic rejection, and in some cases, renal biopsy cannot be performed.
- the tissue changes caused by cyclosporine are mainly endothelial cell damage from the interlobar arteries to the imported arterioles, and mainly consist of renal sclerosis, interstitial cell infiltration and fibrosis.
- cyclosporine administration is often accompanied by hypomagnesemia, and extreme hypomagnesemia is also considered to be a cause of systemic convulsions caused by cyclosporine (Kurokawa Kiyoshi, Nephrology Pathophysiological Approach, Minamido Pp. 419-428, 1995).
- NO nitric oxide
- NO such as heme enzyme or SH enzyme groups throat reaction to not only control the metabolism, Super O dimethylsulfoxide (0 2 -) the first and active oxygen species, biological thiols, with such crosstalk Asukorubin acid physiological Demonstrates function and pathological activity.
- heme enzyme or SH enzyme groups throat reaction to not only control the metabolism, Super O dimethylsulfoxide (0 2 -) the first and active oxygen species, biological thiols, with such crosstalk Asukorubin acid physiological Demonstrates function and pathological activity.
- SH enzyme groups throat reaction to not only control the metabolism
- Super O dimethylsulfoxide (0 2 -) the first and active oxygen species
- biological thiols with such crosstalk Asukorubin acid physiological Demonstrates function and pathological activity.
- the molecular entity in vivo remains unknown.
- NO which has various actions, is produced when L-arginine is oxidized and Nc -hydroxyl-L-arginine is converted to L-citrulline.
- NOS NO synthase
- the NOS gene contains, as a coenzyme, in addition to the binding site of calmodulin (CaM), flavin, and NADPH, the compound of the formula (I) which is the active ingredient of the present invention contains It was found that there was a binding site for _L-erythro 5,6,7,8-tetrahydropiopterin (hereinafter referred to as "BH4"). Furthermore, it has been suggested that BH4 is actually involved in the control of NOS function.
- BH4 _L-erythro 5,6,7,8-tetrahydropiopterin
- the purpose of preventing or treating drug-induced renal injury is not only to prevent or treat renal injury, but to enable the use of drugs that cause renal injury, prolong the life of patients, and enhance It's about making life.
- drug-induced renal failure the administration of drugs must be discontinued in the case of acute renal failure to restore renal function, and dialysis or kidney transplantation must be relied on for chronic renal failure. No improvement of the disease or condition is expected.
- treatment for drug-induced renal injury has not yet been established, and there is no therapeutic drug as well as its preventive drug. Therefore, there is a need for a drug that fully satisfies all of the requirements for side effects, long-term safety, and improvement in quality of life (QAL).
- the compound of formula (I), which is an active ingredient of the therapeutic agent of the present invention, is a known compound, and is known for use as a therapeutic agent for malignant hyperphenylalaninemia, depression, Parkinson's disease, and other therapeutic agents. .
- the present invention improves the circulation dynamics and organ function by controlling endothelial cell function, suppresses the progress of various complications, and enhances the quality of daily life of patients with drug-induced renal injury. It is intended to provide a therapeutic agent.
- the present inventors have prepared a cyclosporin-induced nephropathy rat as a model of drug-induced nephropathy, and found an abnormality in the function of NS in the model rat. In addition, it was confirmed that the Ns activity level was enhanced and the BH4 level was also enhanced in the cyclosporine nephropathy rat. As a result of various studies, surprisingly, administration of BH4 restores endothelial cell function and normalizes N ⁇ S function, resulting in an extremely physiologically excellent renal protective effect. This led to the completion of the present invention. That is, the present invention relates to the effective prevention or treatment of drug-induced nephropathy using a BH4 preparation.
- the present invention provides a compound of formula (I):
- R 1 and R 2 represent- ⁇ to represent a single bond
- R 3 — represents COCH (OH) CH 3 ]
- a pharmaceutically acceptable salt thereof as an active ingredient for preventing or treating drug-induced renal damage.
- drug-induced nephropathy broadly includes conditions in which a lesion has occurred in the kidney, and means those caused by drugs.
- Drug-induced kidney damage is clinically Nephrotic syndrome (proteinuria in mild cases) and impaired renal function.
- Drug-induced nephropathy in this specification broadly includes diseases caused by impaired renal function, diseases in which impaired renal function worsens symptoms, and diseases in which impaired renal function delays healing.
- Clinical symptoms of drug-induced renal failure include acute renal failure such as prerenal acute renal failure, renal acute renal failure, and postrenal acute renal failure, and chronic renal dysfunction that leads to end-stage renal failure It is roughly classified into renal failure.
- Renal acute renal failure includes vasculitis, glomerular lesions, acute glomerulonephritis, rapidly progressive nephritis, hemolytic uremic syndrome, malignant hyperemia, renal cortical necrosis, disseminated intravascular coagulation, scleroderma, It can cause symptoms such as acute interstitial nephritis, nephrotic syndrome or acute pyelonephritis.
- the drug that can cause drug-induced renal disorder is not particularly limited. Any drug can cause kidney damage. Examples include, but are not limited to, antibiotics (penicillin, mitomycin, cyclosporine, amphotericin B, methicillin, cephalosporin, aminoglycoside, etc.), non-steroidal anti-inflammatory drugs (NSAIDs), antitumor agents (cisbratin, ifosfamide, Methotrexate, etc.), gold preparations, heavy metals (mercury), contrast agents, pesticides, etc.).
- antibiotics penicillin, mitomycin, cyclosporine, amphotericin B, methicillin, cephalosporin, aminoglycoside, etc.
- NSAIDs non-steroidal anti-inflammatory drugs
- antitumor agents cisbratin, ifosfamide, Methotrexate, etc.
- gold preparations heavy metals (mercury), contrast agents, pesticides, etc.
- BH4 when administered to patients with drug-induced nephropathy, can normalize NOS function by restoring reduced endothelial cell function and prevent or treat these diseases.
- the compounds of formula (I) which are the active ingredients of the present invention include the following and their pharmaceutically acceptable salts: (6 R) —L—Eris 1-5, 6, 7, 8—tetrahydropiopterin (BH)
- a preferred compound is 5,6,7,8-tetrahydrobopterin or a salt thereof, and the most preferred compound is ⁇ 4 or a salt thereof.
- the compound represented by the formula (I) used as an active ingredient in the present invention is a known compound.
- Japanese Unexamined Patent Publication Nos. Sho 59-25332, Sho 59-76086, Sho 61-276 718, Sho 63 _266778 See No. 1 gazette.
- These may be used as appropriate salts, and such salts include pharmacologically non-toxic acids, for example, mineral acids such as hydrochloric acid, phosphoric acid, sulfuric acid, boric acid, and acetic acid, formic acid, maleic acid, and the like. Examples thereof include salts with organic acids such as fumaric acid and mesylic acid.
- the drug of the present invention is effective for the above-mentioned diseases. In other words, it covers a wide range of conditions in which kidney lesions are caused by drugs.
- the therapeutic agent of the present invention comprises a compound represented by the formula (I) and a carrier used in general pharmaceutical preparations, and is orally, rectally or parenterally (including intravenous and cerebrospinal fluid administration) by a conventional method. It is manufactured by preparing a formulation suitable for administration.
- the carrier used in these pharmaceutical preparations depends on the dosage form used, but generally includes excipients, binders, disintegrants and the like.
- excipients include starch, lactose, sucrose, glucose, mannitol
- binder include polyvinylpyrrolidone, starch, sucrose, hydroxypropylcellulose, and gum arabic.
- disintegrant include starch, agar, gelatin powder, cellulose, CMC, etc., but any other commonly used excipients, binders and disintegrants may be used.
- the therapeutic agent of the present invention preferably contains an antioxidant for stabilizing the active ingredient, in addition to the above carrier.
- the antioxidant is appropriately selected from those commonly used in pharmaceutical preparations, and examples thereof include ascorbic acid, N-acetylcystine, L-cysteine, d1-hytotocopherol, and natural tocopherol.
- the amount used may be any amount that stabilizes the active ingredient (one or more), but is generally preferably from 0.2 to 2.0 by weight based on 1 active ingredient.
- Formulations of the present invention suitable for oral administration include tablets, sublingual tablets, capsules, powders, powders, granules or granules, each containing a predetermined amount of the active ingredient (s), or a syrup, It can be provided as a suspension in a non-aqueous liquid such as an emulsion or one-off preparation.
- granules are prepared by uniformly mixing the active ingredient (one or more) with one or more of the above-mentioned carriers, auxiliary ingredients such as antioxidants, granulating, and preparing a mesh using a sieve.
- a tablet may be made by compression or moulding, the active ingredient (one or more), optionally with one or more accessory ingredients.
- Capsules are made by filling a powder or granules of the active ingredient (one or more), optionally with one or more accessory ingredients, in a suitable capsule using a filler. .
- Formulations for rectal administration can be presented as suppositories using conventional carriers such as cocoa butter.
- Formulations for parenteral administration may be provided by sealing the active ingredient (one or more) as a dry solid in a sterile nitrogen-purified container.
- This dry solid preparation can be administered to a patient after parenteral administration by dispersing or dissolving in a predetermined amount of sterile water.
- antioxidants in addition to the active ingredient and the usual carrier, and if necessary, a buffer, a flavor imparting agent, a surfactant, a thickener, It may further contain one or more auxiliary components selected from lubricants, lubricants and the like.
- the dosage of the active ingredient, ie, the compound of formula (I) will, of course, vary with the route of administration, the condition being treated and the patient being treated, but will ultimately be at the discretion of the physician. You can leave it.
- the appropriate dose for treating drug-induced nephropathy depends on the purpose of administration, the age, weight, and condition of the subject, but for oral administration, 0.1 to 50 mgZkg (body weight)
- a typical preferred dose is 0.5 to 10 mgZkg (body weight) Z days.
- the desired dosage may be such that the active ingredient is administered once a day, but may be administered in 2 to 4 divided doses at appropriate intervals throughout the day.
- the active ingredient can be administered alone or as it is without being mixed with other ingredients.However, other active ingredients are administered as a pharmaceutical formulation according to the indication for reasons such as to facilitate adjustment of the dosage. You can also.
- the preparation of the present invention comprises a compound represented by the formula (I) as an active ingredient,
- At least one selected from the group consisting of an OS substrate or a coenzyme or cofactor, for example, L-arginine, flavins (eg, FAD, FMN, etc.) and calcium may be contained as an auxiliary active ingredient. By mixing these active ingredients, a more excellent therapeutic effect can be expected as compared to the case where the compound represented by the formula (I) is used alone.
- the ratio of each of the above components in the preparation of the present invention is not particularly limited. For example, the ratio is selected from the group consisting of L_arginine, flavins and calcium with respect to 1 of the compound represented by the formula (I) by weight. At least one species may be in the range of 0.1 to 10, preferably in the range of 0.5 to 2.
- the appropriate dose of this mixed preparation depends on the purpose of the administration, the age, weight, and condition of the subject, but for oral administration, the total amount of the active ingredient It is in the range of 0.1 to 50 mgZkg (body weight) days, preferably 0.5 to 1 OmgZkg (body weight) days.
- the selection of a preparation containing the compound represented by the formula (I) alone as an active ingredient and a preparation containing the active ingredient together with other active ingredients is appropriately selected by a physician according to age, symptoms, and the like.
- the active ingredient used in the present invention is (6R) —L—Eris mouth—5, 6, 7, 8- W 9 tetrahydropiopterin (BH4) and its salts are most preferred, but (6 R, S) — 5, 6, 7, 8—tetrahydropiopterin, ⁇ , 2′—diacetyl — 5, 6, 7, 8— Tetrahydropiopterin, sepiapterin, 6-methyl-1,5,6,7,8-tetrahydropterin, 6-hydroxymethyl-5,6,7,8-tetrahydropterin or 6-phenyl-1,5,6,7 Similar compounds such as 8-tetrahydropterin and salts thereof may be used.
- BH4 which is a natural substance existing in the living body, is preferable.
- Example 1 (granules, fine granules)
- Example 3 (capsule)
- Example 4 (Injection)
- the above-mentioned components were dissolved in sterilized purified water, and sterilized to 10 OmI.
- the resulting solution was placed in vials or ampoules in lmi or 2 ml portions, and freeze-dried and sealed.
- Example 7 (granules)
- a uniform solution was prepared using the above components.
- Blood pressure was measured by the tan-cuff method at the beginning of the experiment, 2 weeks, 4 weeks, and 6 weeks later.
- 3 H-citrulline produced by renal tissue N ⁇ S was measured and determined as NOS activity.
- a thin section was prepared from the frozen kidney tissue, and NADP H-diaphorase (diaphrose) staining was performed to examine NOS activity on the tissue.
- tissue staining was performed using a monoclonal antibody against macrophage cell membrane antigen ED-1 to examine the NOS isoform.
- kidney tissue specimens After completion of urine collection and blood pressure measurement after 6 weeks, the abdomen was opened under anesthesia, blood was removed from the abdominal aorta, and physiological saline was injected and perfused therefrom.
- the extirpated kidney was fixed in 10% formaldehyde, embedded in paraffin, and sliced to 4 m with a microtome to prepare a kidney tissue specimen.
- Hematoxylin and eosin (HE) staining and periodicacacid—Shiff staining were performed.
- the pathological findings observed in rat kidney tissue specimens that is, the appearance frequency of arteriole vascular disorders (arteriopati) were compared and examined.
- Renal cortical NO S activity significantly increased in the CyA group compared to the control group by 260.814 mmo 1 / day (mean).
- the BH4 group increased by 140.60 Ommo 1 / day (average) compared to the control group.
- Table 1 shows the frequency of appearance of histopathological findings in renal tissue specimens.
- the arteriolar vascular damage that significantly (p ⁇ 0.001) appeared in the CyA group was significantly (p ⁇ 0.001) suppressed.
- Table 1 Frequency of pathological findings in renal tissue Percentage (%) Arteriole vascular disorder
- BH4 group 36.814 Sat 2.093 SE
- the histopathological findings of arteriovascular disorders were observed in the CyA group. Furthermore, it was revealed that the level of inducible NOS activity derived from macrophages was increased.
- the present invention provides a therapeutic agent that effectively prevents and / or ameliorates drug-induced nephropathy. Further, since the active ingredient of the therapeutic agent of the present invention is a substance which is originally present in the living body, there is no concern about side effects even if it is used for a long time.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE69925225T DE69925225T2 (de) | 1998-02-27 | 1999-02-26 | Propylaxe und behandlung der arzneimittel induzierten nierenstörungen |
JP54342399A JP4486167B2 (ja) | 1998-02-27 | 1999-02-26 | 薬剤性腎障害の予防または治療剤 |
AT99906500T ATE295172T1 (de) | 1998-02-27 | 1999-02-26 | Propylaxe und behandlung der arzneimittel induzierten nierenstörungen |
EP99906500A EP1004308B1 (en) | 1998-02-27 | 1999-02-26 | Preventives or remedies for drug-induced renal disturbance |
US09/427,550 US6288067B1 (en) | 1998-02-27 | 1999-10-27 | Prophylactic or therapeutic agents for drug-induced renal injury |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP4815898 | 1998-02-27 | ||
JP10/48158 | 1998-02-27 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/427,550 Continuation US6288067B1 (en) | 1998-02-27 | 1999-10-27 | Prophylactic or therapeutic agents for drug-induced renal injury |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999043324A1 true WO1999043324A1 (fr) | 1999-09-02 |
Family
ID=12795582
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1999/000916 WO1999043324A1 (fr) | 1998-02-27 | 1999-02-26 | Agents prophylactiques ou remedes contre les troubles renaux d'origine medicamenteuse |
Country Status (7)
Country | Link |
---|---|
US (1) | US6288067B1 (ja) |
EP (1) | EP1004308B1 (ja) |
JP (1) | JP4486167B2 (ja) |
AT (1) | ATE295172T1 (ja) |
DE (1) | DE69925225T2 (ja) |
ES (1) | ES2242381T3 (ja) |
WO (1) | WO1999043324A1 (ja) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE252385T1 (de) * | 1996-08-30 | 2003-11-15 | Daiichi Suntory Pharma Co Ltd | Vorbeugende oder heilende mittel für krankheiten, die durch mangel an stickoxid-synthase (nos) ausgelöst sind |
ES2596827T3 (es) * | 2003-11-17 | 2017-01-12 | Biomarin Pharmaceutical Inc. | Tratamiento de la fenilcetonuria con BH4 |
EP2436379A1 (en) * | 2004-11-17 | 2012-04-04 | BioMarin Pharmaceutical Inc. | Stable tablet formulation |
SI2545939T1 (sl) | 2007-04-11 | 2021-04-30 | Biomarin Pharmaceutical Inc. | Tetrahidrobiopterin za zdravljenje stanj povezanih s povišanimi nivoji fenilalanina |
US20140050728A1 (en) * | 2011-01-28 | 2014-02-20 | Board Of Regents Of The University Of Nebraska | Methods and compositions for inhibiting cyclophilin d for the treatment and prevention of obesity and kidney indications |
US9216178B2 (en) | 2011-11-02 | 2015-12-22 | Biomarin Pharmaceutical Inc. | Dry blend formulation of tetrahydrobiopterin |
KR101942568B1 (ko) | 2017-01-24 | 2019-01-30 | 주식회사 우성제약 | 아세트아미노펜을 함유하는 주사제 조성물 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5925323A (ja) * | 1982-03-03 | 1984-02-09 | 鐘淵化学工業株式会社 | プテリン誘導体からなる脳内神経伝達物質の関わる疾病の治療剤 |
JPS5976086A (ja) * | 1982-09-20 | 1984-04-28 | ザ ウエルカム フアウンデ−シヨン リミテツド | プテリジン化合物 |
JPS61277618A (ja) * | 1985-06-04 | 1986-12-08 | Suntory Ltd | 自閉症治療剤 |
JPS63267781A (ja) * | 1987-04-24 | 1988-11-04 | Suntory Ltd | 悪性腫瘍および重症ウイルス感染症に伴う神経症状を改善するための治療剤 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH02157755A (ja) | 1988-12-09 | 1990-06-18 | Daito Denshi Color Kk | 自動給液システム |
WO1992007566A2 (en) * | 1990-11-01 | 1992-05-14 | Board Of Regents, The University Of Texas System | Antifungal activity of and prevention of drug induced nephrotoxicity by methylxanthine analogues |
JPH0656669A (ja) * | 1992-06-11 | 1994-03-01 | Asahi Breweries Ltd | 活性酸素消去作用を持つプテリン誘導体製剤 |
ATE252385T1 (de) * | 1996-08-30 | 2003-11-15 | Daiichi Suntory Pharma Co Ltd | Vorbeugende oder heilende mittel für krankheiten, die durch mangel an stickoxid-synthase (nos) ausgelöst sind |
-
1999
- 1999-02-26 DE DE69925225T patent/DE69925225T2/de not_active Expired - Lifetime
- 1999-02-26 EP EP99906500A patent/EP1004308B1/en not_active Expired - Lifetime
- 1999-02-26 ES ES99906500T patent/ES2242381T3/es not_active Expired - Lifetime
- 1999-02-26 JP JP54342399A patent/JP4486167B2/ja not_active Expired - Fee Related
- 1999-02-26 WO PCT/JP1999/000916 patent/WO1999043324A1/ja active IP Right Grant
- 1999-02-26 AT AT99906500T patent/ATE295172T1/de not_active IP Right Cessation
- 1999-10-27 US US09/427,550 patent/US6288067B1/en not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5925323A (ja) * | 1982-03-03 | 1984-02-09 | 鐘淵化学工業株式会社 | プテリン誘導体からなる脳内神経伝達物質の関わる疾病の治療剤 |
JPS5976086A (ja) * | 1982-09-20 | 1984-04-28 | ザ ウエルカム フアウンデ−シヨン リミテツド | プテリジン化合物 |
JPS61277618A (ja) * | 1985-06-04 | 1986-12-08 | Suntory Ltd | 自閉症治療剤 |
JPS63267781A (ja) * | 1987-04-24 | 1988-11-04 | Suntory Ltd | 悪性腫瘍および重症ウイルス感染症に伴う神経症状を改善するための治療剤 |
Also Published As
Publication number | Publication date |
---|---|
ATE295172T1 (de) | 2005-05-15 |
EP1004308A4 (en) | 2001-03-14 |
DE69925225D1 (de) | 2005-06-16 |
EP1004308B1 (en) | 2005-05-11 |
ES2242381T3 (es) | 2005-11-01 |
US6288067B1 (en) | 2001-09-11 |
DE69925225T2 (de) | 2006-02-23 |
EP1004308A1 (en) | 2000-05-31 |
JP4486167B2 (ja) | 2010-06-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR100650962B1 (ko) | 질소산화물합성효소(nos)의기능저하에의해유발되는질환의예방또는치료제 | |
RU2268732C2 (ru) | Способы лечения митохондриальных нарушений | |
US20090191265A1 (en) | Capsule Formulation of Pirfenidone and Pharmaceutically Acceptable Excipients | |
IE57793B1 (en) | Orally administerable antidiabetic compositions | |
JP2003535034A (ja) | ジペプチジルペプチダーゼiv阻害剤並びにジペプチジルペプチダーゼiv阻害剤の製造及び使用法 | |
JP2009520697A (ja) | サイトカイン調節性を有する化合物 | |
WO1999013875A1 (en) | Use of nitroxides for the treatment of essential hypertension | |
CA2631740A1 (en) | Methods and compositions for the treatment of disease | |
JPH06234635A (ja) | インターロイキン1ベータを阻害するためのレフルノミドの使用 | |
JP4486167B2 (ja) | 薬剤性腎障害の予防または治療剤 | |
EP0983765B1 (en) | Preventives or remedies for diseases in association with vascular functional anomaly relating to insulin resistance | |
JPH0372463A (ja) | 腎機能改善剤 | |
JP2000515559A (ja) | 体重減量方法 | |
JP4609877B2 (ja) | 慢性拒絶反応抑制剤 | |
JPH0625059B2 (ja) | 悪性腫瘍治療剤 | |
JP2009531379A (ja) | 鉄代謝機能障害を治療するためのストロビルリンの使用 | |
TW201500042A (zh) | 與血液透析有關的低血壓的治療 | |
KR100367877B1 (ko) | 구연산칼륨을 주제로 한 요로결석 치료제중 분말 및 미립제형 의 제조방법 | |
JPH01131113A (ja) | 脳障害治療剤 | |
JPS6054320A (ja) | 腎疾患治療剤 | |
CN111643498B (zh) | 一种治疗肾结石的药物组合物及其用途 | |
JP2710638B2 (ja) | 膵臓疾患治療剤 | |
WO2023185911A1 (zh) | 一种吡啶磺酰胺磷酸酯类化合物在制备抗脑水肿药物中的用途 | |
EP1649855A1 (en) | Medicinal composition | |
EP3955907A1 (en) | Pharmaceutical formulations containing p2y14 antagonists |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): JP US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1999906500 Country of ref document: EP |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWP | Wipo information: published in national office |
Ref document number: 1999906500 Country of ref document: EP |
|
WWG | Wipo information: grant in national office |
Ref document number: 1999906500 Country of ref document: EP |