JPS6260368B2 - - Google Patents
Info
- Publication number
- JPS6260368B2 JPS6260368B2 JP22016782A JP22016782A JPS6260368B2 JP S6260368 B2 JPS6260368 B2 JP S6260368B2 JP 22016782 A JP22016782 A JP 22016782A JP 22016782 A JP22016782 A JP 22016782A JP S6260368 B2 JPS6260368 B2 JP S6260368B2
- Authority
- JP
- Japan
- Prior art keywords
- fructose
- diuretic
- disorders
- sucrose
- prevention
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 239000002934 diuretic Substances 0.000 claims description 17
- 230000001882 diuretic effect Effects 0.000 claims description 15
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 11
- 229930091371 Fructose Natural products 0.000 claims description 8
- 239000005715 Fructose Substances 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 229930006000 Sucrose Natural products 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 229940030606 diuretics Drugs 0.000 claims description 6
- 239000005720 sucrose Substances 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- 206010030113 Oedema Diseases 0.000 claims description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 4
- 239000002699 waste material Substances 0.000 claims description 4
- QNTKVQQLMHZOKP-NEJDVEAASA-N (2r,3r,4s,5s,6r)-2-[(2s,3s,4s,5r)-2-[[(2r,3s,4s,5r)-2-[[(2r,3s,4s,5r)-2-[[(2r,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxymethyl]-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxymethyl]-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxymethyl]- Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(OC[C@]3(O[C@@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O4)O)[C@H]([C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 QNTKVQQLMHZOKP-NEJDVEAASA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- FLDFNEBHEXLZRX-DLQNOBSRSA-N Nystose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(O[C@@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 FLDFNEBHEXLZRX-DLQNOBSRSA-N 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 208000017169 kidney disease Diseases 0.000 claims description 3
- FLDFNEBHEXLZRX-UHFFFAOYSA-N nystose Natural products OC1C(O)C(CO)OC1(CO)OCC1(OCC2(OC3C(C(O)C(O)C(CO)O3)O)C(C(O)C(CO)O2)O)C(O)C(O)C(CO)O1 FLDFNEBHEXLZRX-UHFFFAOYSA-N 0.000 claims description 3
- 208000019622 heart disease Diseases 0.000 claims description 2
- 201000006370 kidney failure Diseases 0.000 claims description 2
- 238000009825 accumulation Methods 0.000 claims 2
- BJHIKXHVCXFQLS-UYFOZJQFSA-N fructose group Chemical group OCC(=O)[C@@H](O)[C@H](O)[C@H](O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 claims 2
- 208000019423 liver disease Diseases 0.000 claims 2
- ODEHMIGXGLNAKK-OESPXIITSA-N 6-kestotriose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@@H]1[C@@H](O)[C@H](O)[C@](CO)(O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1 ODEHMIGXGLNAKK-OESPXIITSA-N 0.000 claims 1
- 206010003445 Ascites Diseases 0.000 claims 1
- 208000003174 Brain Neoplasms Diseases 0.000 claims 1
- 208000010412 Glaucoma Diseases 0.000 claims 1
- 206010019196 Head injury Diseases 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 claims 1
- 201000011510 cancer Diseases 0.000 claims 1
- 230000002490 cerebral effect Effects 0.000 claims 1
- 229940125904 compound 1 Drugs 0.000 claims 1
- 208000035475 disorder Diseases 0.000 claims 1
- 230000004410 intraocular pressure Effects 0.000 claims 1
- 210000003734 kidney Anatomy 0.000 claims 1
- 210000004185 liver Anatomy 0.000 claims 1
- 201000007270 liver cancer Diseases 0.000 claims 1
- 208000014018 liver neoplasm Diseases 0.000 claims 1
- 230000001575 pathological effect Effects 0.000 claims 1
- 210000002700 urine Anatomy 0.000 description 16
- 210000004369 blood Anatomy 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 229910052708 sodium Inorganic materials 0.000 description 9
- 241000700159 Rattus Species 0.000 description 8
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 239000011575 calcium Substances 0.000 description 7
- 229910052791 calcium Inorganic materials 0.000 description 7
- FTSSQIKWUOOEGC-RULYVFMPSA-N fructooligosaccharide Chemical group OC[C@H]1O[C@@](CO)(OC[C@@]2(OC[C@@]3(OC[C@@]4(OC[C@@]5(OC[C@@]6(OC[C@@]7(OC[C@@]8(OC[C@@]9(OC[C@@]%10(OC[C@@]%11(O[C@H]%12O[C@H](CO)[C@@H](O)[C@H](O)[C@H]%12O)O[C@H](CO)[C@@H](O)[C@@H]%11O)O[C@H](CO)[C@@H](O)[C@@H]%10O)O[C@H](CO)[C@@H](O)[C@@H]9O)O[C@H](CO)[C@@H](O)[C@@H]8O)O[C@H](CO)[C@@H](O)[C@@H]7O)O[C@H](CO)[C@@H](O)[C@@H]6O)O[C@H](CO)[C@@H](O)[C@@H]5O)O[C@H](CO)[C@@H](O)[C@@H]4O)O[C@H](CO)[C@@H](O)[C@@H]3O)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@@H](O)[C@@H]1O FTSSQIKWUOOEGC-RULYVFMPSA-N 0.000 description 6
- 229940107187 fructooligosaccharide Drugs 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- 208000004880 Polyuria Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 208000037147 Hypercalcaemia Diseases 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 4
- 229940109239 creatinine Drugs 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 230000000148 hypercalcaemia Effects 0.000 description 4
- 208000030915 hypercalcemia disease Diseases 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- VAWYEUIPHLMNNF-OESPXIITSA-N 1-kestose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 VAWYEUIPHLMNNF-OESPXIITSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000700157 Rattus norvegicus Species 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 230000010534 mechanism of action Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 230000002485 urinary effect Effects 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- GIUOHBJZYJAZNP-DVZCMHTBSA-N 1-kestose Natural products OC[C@@H]1O[C@](CO)(OC[C@]2(O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)O[C@@H](O)[C@@H](O)[C@@H]2O)[C@@H](O)[C@@H]1O GIUOHBJZYJAZNP-DVZCMHTBSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 241000223678 Aureobasidium pullulans Species 0.000 description 2
- 206010010071 Coma Diseases 0.000 description 2
- 206010024264 Lethargy Diseases 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 2
- 229960003883 furosemide Drugs 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- VAWYEUIPHLMNNF-UHFFFAOYSA-N kestotriose Natural products OC1C(O)C(CO)OC1(CO)OCC1(OC2C(C(O)C(O)C(CO)O2)O)C(O)C(O)C(CO)O1 VAWYEUIPHLMNNF-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- -1 mitalamycin Chemical compound 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000003451 thiazide diuretic agent Substances 0.000 description 2
- WROUWQQRXUBECT-UHFFFAOYSA-N 2-ethylacrylic acid Chemical compound CCC(=C)C(O)=O WROUWQQRXUBECT-UHFFFAOYSA-N 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- JBMKAUGHUNFTOL-UHFFFAOYSA-N Aldoclor Chemical class C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC=NS2(=O)=O JBMKAUGHUNFTOL-UHFFFAOYSA-N 0.000 description 1
- 208000037157 Azotemia Diseases 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- 208000020446 Cardiac disease Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010010075 Coma hepatic Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 206010020707 Hyperparathyroidism primary Diseases 0.000 description 1
- 206010020850 Hyperthyroidism Diseases 0.000 description 1
- 108010042889 Inulosucrase Proteins 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 206010035039 Piloerection Diseases 0.000 description 1
- 201000000981 Primary Hyperparathyroidism Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- 208000012998 acute renal failure Diseases 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 229960004015 calcitonin Drugs 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 201000001059 hepatic coma Diseases 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 208000007386 hepatic encephalopathy Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 208000009928 nephrosis Diseases 0.000 description 1
- 231100001027 nephrosis Toxicity 0.000 description 1
- 239000002337 osmotic diuretic agent Substances 0.000 description 1
- 230000005371 pilomotor reflex Effects 0.000 description 1
- 206010036067 polydipsia Diseases 0.000 description 1
- 238000009138 potassium supplementation Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 208000037921 secondary disease Diseases 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 125000000185 sucrose group Chemical group 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
本発明は利尿剤に関し、詳しくはシユークロー
スにフラクトースが１〜４分子結合したフラクト
オリゴ糖を主成分とする利尿剤に関する。さらに
詳しくは、本発明はグルコース(G)とフラクトース
(F)が結合したシユークロース（GF）および該シ
ユークロースのフラクトース部分にフラクトース
がβ２−１結合により１〜３分子結合したもので
あつて下記分子式、分子量ならびに構造式で特定
される化合物１−ケストース（GF2）、ニストー
ス（GF3）、1Fフラクトフラノシルニストース
（GF4）を有効成分として含有する利尿剤に関す
る。
【表】
トース
上記フラクトオリゴ糖の製造法は特開昭56−
154967号、同57−12973号に開示されており、シ
ヨ糖にオーレオバシデイウム・プルランス・バ
ル・メレニゲナム（Aureobasidium pullulans
var.melenigenum）の生産するフラクトシルト
ランスフエラーゼを作用させることによつて得る
ことができる。フラクトオリゴ糖の糖組成は製造
条件により変化するが、たとえばシヨ糖の60％溶
液に該酵素をPH5.0、60℃で48時間作用させたと
き、次の組成からなる反応生成物が得られる。す
なわち、フラクトース(F)３％、グルコース(G)35
％、シユークロース（GF）10％、１−ケストー
ス（GF2）23％、ニストース（GF3）23％、1F−
フラクトフラノシルニストース（GF4）６％であ
る。
この反応生成物からフラクトオリゴ糖を精製す
るには、たとえば該反応生成物１Kgを30の活性
カラムに充填し、水200、次いで３％エタノー
ル溶液180を通液し、Ｆ、Ｇ、GFを溶出、除去
する。その後、20％エタノール溶液50でフラク
トオリゴ糖（GF2、GF3およびGF4の混合物）を
回収する。このフラクトオリゴ糖を調製用高速液
体クロマトグラフを用いて分画し、GF2、GF3お
よびGF4をそれぞれ単離する。
次に、GF2およびGF3は70％濃度となるように
メタノールに溶解し、室温に７日間放置すること
によりそれぞれの結晶を析出させて回収する。
GF4は調製用高速液体クロマトグラフにより単離
溶出した液を凍結乾燥して粉末とする。
以上の工程で、GF2110ｇ、GF3120ｇ、GF440
ｇが得られる。
次に、これらフラクトオリゴ糖の奏する効果に
ついて説明する。
心臓障害および急性腎炎、腎不全、ネフローゼ
等の腎障害など各種の疾患により浮腫が発生す
る。浮腫は、基礎疾患を増悪させる場合が多く、
さらに二次的な障害を招来する場合も知られてい
る。
浮腫の治療剤としては現在、サイアザイド剤、
エタクリン酸、フロセミド、スピラノラクトンお
よび浸透圧利尿剤などが知られ、浮腫の治療に多
用されている。
フラクトオリゴ糖を有効成分とする本発明の利
尿剤は、上記したいずれの利尿剤とも異なる作用
機序で、強い利尿効果を有する。たとえば、実験
動物であるラツトを用いた実験では、静脈内投与
で50mg／Kg量より利尿作用が発現し、500mg／Kg
量では、投与後３時間目までの排尿量およびナト
リウムとクロール量が、本発明のフラクトオリゴ
糖利尿剤無投与群の約10倍にも増加し、血液中の
ナトリウムとクロール量も著しく減少する。その
利尿作用強度は臨床で糖質利尿剤として用いられ
ているマンニトールの16倍である。
さらに、各種の高血圧症において、利尿剤を用
い体内ナトリウムを***させて高血圧の改善をは
かる場合が多く見られ、この場合の利尿剤として
はサイアザイド剤が好んで用いられている。とこ
ろで、本発明のフラクトオリゴ糖利尿剤も上記し
たごとく、強力なナトリウム***作用を有するの
で、高血圧治療を目的とした利尿剤としても用い
ることができる。
重症の肝障害および腎不全時などに、アンモニ
ア、クレアチニン、尿素体窒素などの通常体内で
見られない成分や老廃物が体内に増加または蓄積
し、全身倦怠、脱力状態、嗜眠、昏睡などが招来
される。このような症状に対し、本発明のフラク
トオリゴ糖利尿剤を適用することにより前記した
血中老廃物を顕著に低下させることができる。た
とえば、実験動物であるラツトに静脈内投与する
と、50mg／Kg量から作用が発現し、500mg／Kg量
では、フラクトオリゴ糖利尿剤無投与ラツトに比
較し、尿中への尿素体窒素***量を約５倍増加さ
せ、クレアチニンについても、尿中***量を約７
倍増加させる。
原発性副甲状腺機能亢進症、偽性副甲状腺機能
亢進症および甲状腺機能亢進症などの疾患により
高カルシウム血症が発症することが知られてい
る。この高カルシウム血症は、病態の進行につれ
全身倦怠感、多飲多尿、便秘、食思不振、嘔吐、
嗜眠、脱力、錯乱、次いで昏睡の順に症状が悪化
するので治療する必要がある。高カルシウム血症
治療剤としては、現在、EDTA、硫酸ナトリウ
ム、ミタラマイシン、フロセミド、ステロイド、
カルシトニンなどが知られている。
本発明のフラクトオリゴ糖利尿剤は、上記した
いずれの薬剤とも異なる作用機序でカルシウムを
尿中に強力に***させ、血中のカルシウム値を低
下させることができる。たとえば、ラツトを用い
た実験では静脈内投与で50mg／Kg量より作用が発
現し、500mg／Kg量投与では、薬物無投与ラツト
の平均血中カルシウム値9.6mg／dlを8.7mg／dl平
均まで低下させる。また、尿中へはフラクトオリ
ゴ糖利尿剤無投与ラツトの５倍***させることが
できる。
フラクトオリゴ糖の臨床使用にあたつては、フ
ラクトオリゴ糖は殆んど経口吸収されないため、
経口以外の経路、好ましくは静脈内に投与しなけ
ればならない。投与量は、ラツトを用いた１回静
脈内投与でのLD50値がGF2、GF3、GF4ともに４
ｇ／Kg量以上であることから、無制限に投与する
ことが可能である。また、上記したいずれの効果
もフラクトオリゴ糖の中ではGF2にもつとも強く
見られるため、臨床使用にあたつては、GF2を用
いることが好ましい。
実際的な使用にあたつては、１回20〜30ｇを１
日１〜２回投与することが望ましく、投与は輸液
500mlに添加するかもしくは濃厚溶液としてゆつ
くり行うべきである。尚、血液と等浸透圧は約20
％である。
フラクトオリゴ糖、特にGF2の利尿作用は強力
であるため、ナトリウム、クロール、老廃物以外
にもカルシウムおよび弱いが水も***させるの
で、浮腫治療と予防および体内老廃物***促進を
目的として本発明の利尿剤を著しく多量に使用す
る場合は、カルシウムとカリウムの補給を必要と
する場合もある。また、高カルシウム血症の治療
と予防を目的として本発明の利尿剤を著しく多量
投与する場合も、前記と同様の目的でナトリウ
ム、カリウムの補給を必要とする場合も生じる。
以上のように、本発明のフラクトオリゴ糠利尿
剤は、従来の利尿剤とは異なる作用機序で強力な
利尿効果を発現する利尿剤である。今後、各種疾
患による浮腫患者の治療と予防および肝性昏睡や
***の予防と治療にも効果を発揮するものと思
われ、さらに入院患者の高血圧治療などに顕著な
効果を発現することが期待され、人類の健康維持
上に極めて有用な物質である。
以下に実施例をもつて本発明を説明する。
実施例 １
夜間17時間絶食負荷したウイスター系ラツト
（SPF）の雄を１群３〜６匹として用いた。
それら動物に37℃に加温した生理食塩水を３ml
経口投与し、その直後にGF2、GF3、GF4および
対照としてマンニトールの500mg／Kgと1000mg／
Kg量を１回静脈内投与した。被験物質はすべて注
射用蒸留水に溶解し、動物１匹あたりの投与容量
が１ml容量となるように濃度を調製し供試した。
動物は静脈内投与終了後、直ちに個別採尿ケー
ジに入れ０〜３時間、３〜６時間の排尿を蓄尿し
採取した。尚、採尿期間中は絶食、絶水とした。
動物は採尿終了後、頚部動静脈切断による採血に
供した。採取した血液は、直ちに血清を分離し
た。
血清と尿について次の項目を測定した。
尿：排尿量、ナトリウム、カリウム、クロール、
カルシウム、尿素体窒素、浸透圧およびクレア
チニンを測定した。
血清：排尿量と浸透圧を除いた同上の項目を測定
した。
結果を次の表−１および表−２に示す。
【表】
【表】
【表】
【表】
【表】
実施例 ２
夜間17時間絶食負荷したウイスター系ラツト
（SPF）の雄を１群８匹として用いた。
それら動物に37℃に加温した生理食塩液を３ml
経口投与した。その直後にGF2の50、100、200、
400、800mg／Kg量および、対照としてマンニトー
ルの800mg／Kg量を静脈内に１回投与した。被験
物質は、いずれの場合も１ml／ラツト量となるよ
うに局方注射用蒸留水で濃度を調整し供試した。
被験物質投与後、ただちに動物を個別採尿ケー
ジに入れ、０〜３時間、３〜６時間の排尿を蓄尿
して採取した。尚、採尿期間中は絶食絶水とし
た。６時間目の採尿終了後に、供試動物の頚部動
静脈を切断して採血した。血液は直ちに遠沈し、
血清を採取した。
尿については、浸透圧、尿素体窒素、クレアチ
ニン、排尿量、ナトリウム、カリウム、クロール
を、血清に関してはナトリウム、カリウムおよび
クロールをそれぞれ測定した。
結果を表−３および表−４に示す。
【表】
【表】
【表】
【表】
実施例 ３
供試動物は体重平均224ｇのウイスター系ラツ
ト（SPF）の雄を１群２〜３匹として用いた。
GF2は局方注射用蒸留水に44.8％に溶解して供
試した。投与量は２ｇ／Kgと４ｇ／Kg量とし、尾
静脈内に１回静脈内投与した。対照として、蒸留
水２ml投与群を設けた。
一般状態の観察は、投与後６時間目までと体重
測定の前後に実施した。体重の測定は投与後１、
３および９日目に実施した。
結果を以下に示す。
(イ) 一般状態：投与直後より沈うつ状態となり、
投与１時間後では、加えて立毛を、さらに1.5
〜２時間後より著しい利尿状態（ケージ下に尿
大量貯留）を認めた。６時間後の観察時におい
ても同様であつた。２ｇ／Kg群においてはこれ
ら症状は翌日に回復したが、４ｇ／Kg群では正
常に復帰するのに２日間を要した。以降は、対
照群と同様に推移した。
(ロ) 体重推移および死亡例
【表】 DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a diuretic, and more particularly to a diuretic whose main component is fructooligosaccharide, in which 1 to 4 molecules of fructose are bound to sucrose. More specifically, the present invention provides glucose (G) and fructose
(F) is bound to seuucrose (GF) and 1 to 3 molecules of fructose are bound to the fructose portion of the sucrose through β 2 -1 bonds, and the compound is specified by the following molecular formula, molecular weight, and structural formula: 1-kestose (GF 2 ), nystose (GF 3 ), and 1F fructofuranosylnystose (GF 4 ) as active ingredients. [Front] Toth
The method for producing the above-mentioned fructooligosaccharide was published in Japanese Patent Application Laid-Open No.
No. 154967 and No. 57-12973, in which sucrose contains Aureobasidium pullulans val melenigenum ( Aureobasidium pullulans) .
It can be obtained by reacting with fructosyltransferase produced by var. melenigenum ). The sugar composition of fructooligosaccharide varies depending on the production conditions, but for example, when the enzyme is allowed to act on a 60% solution of sucrose at PH 5.0 and 60°C for 48 hours, a reaction product having the following composition is obtained. That is, fructose (F) 3%, glucose (G) 35
%, seuucrose (GF) 10%, 1-kestose (GF 2 ) 23%, nystose (GF 3 ) 23%, 1F-
Fructofuranosylnystose (GF 4 ) 6%. To purify fructooligosaccharides from this reaction product, for example, 1 kg of the reaction product is packed into a 30-unit active column, and 200 units of water and then 180 units of a 3% ethanol solution are passed through it to elute F, G, and GF. Remove. Then, collect the fructooligosaccharides (a mixture of GF2 , GF3 and GF4 ) with 50% ethanol solution. This fructooligosaccharide is fractionated using a preparative high performance liquid chromatograph to isolate GF 2 , GF 3 and GF 4 , respectively. Next, GF 2 and GF 3 are dissolved in methanol to a concentration of 70% and left at room temperature for 7 days to precipitate and collect their respective crystals.
GF 4 is isolated and eluted using a preparative high-performance liquid chromatograph, and the solution is freeze-dried to form a powder. In the above process, GF 2 110g, GF 3 120g, GF 4 40
g is obtained. Next, the effects of these fructooligosaccharides will be explained. Edema occurs due to various diseases such as cardiac disorders and renal disorders such as acute nephritis, renal failure, and nephrosis. Edema often worsens the underlying disease,
It is also known that it may lead to secondary disorders. Currently, thiazide drugs,
Ethacrylic acid, furosemide, spiranolactone, and osmotic diuretics are known and are frequently used to treat edema. The diuretic of the present invention containing fructooligosaccharide as an active ingredient has a strong diuretic effect with a different mechanism of action from any of the diuretics described above. For example, in experiments using rats, which are experimental animals, a diuretic effect was expressed at a dose of 50 mg/Kg when administered intravenously, and a dose of 50 mg/Kg
In terms of amounts, the urinary volume and the amounts of sodium and chloride up to 3 hours after administration increased by about 10 times compared to the group not administered with the fructooligoglycodiuretic of the present invention, and the amounts of sodium and chloride in the blood were also significantly reduced. Its diuretic strength is 16 times that of mannitol, which is clinically used as a glucodiuretic. Furthermore, in various cases of hypertension, diuretics are often used to excrete sodium from the body to improve hypertension, and thiazides are preferably used as diuretics in this case. By the way, since the fructooligoglycodiuretic of the present invention also has a strong sodium excretion effect as described above, it can also be used as a diuretic for the purpose of treating hypertension. During severe liver damage and renal failure, components and waste products that are not normally found in the body, such as ammonia, creatinine, and urea nitrogen, increase or accumulate in the body, leading to general fatigue, weakness, lethargy, and coma. be done. By applying the fructooligoglycodiuretic of the present invention to such symptoms, the above-mentioned blood waste products can be significantly reduced. For example, when administered intravenously to rats, which are experimental animals, the effect appears at a dose of 50 mg/Kg, and at a dose of 500 mg/Kg, the amount of urea nitrogen excreted in the urine decreases compared to rats without fructooligoglycodiuretic administration. The amount of urinary excretion of creatinine was increased by approximately 7 times.
Increase twice. Hypercalcemia is known to occur in diseases such as primary hyperparathyroidism, pseudohyperparathyroidism, and hyperthyroidism. As the disease progresses, hypercalcemia causes general malaise, polydipsia, polyuria, constipation, anorexia, vomiting,
Symptoms worsen in this order: lethargy, weakness, confusion, and then coma, which must be treated. Currently, hypercalcemia treatments include EDTA, sodium sulfate, mitalamycin, furosemide, steroids,
Calcitonin is known. The fructooligoglycodiuretic of the present invention has a mechanism of action different from that of any of the above-mentioned drugs, and is capable of strongly excreting calcium into the urine and lowering blood calcium levels. For example, in an experiment using rats, the effect appeared at a dose of 50 mg/Kg when administered intravenously, and when administered at a dose of 500 mg/Kg, the average blood calcium level of rats without drug administration was 9.6 mg/dl, and the average blood calcium level decreased to 8.7 mg/dl. lower. In addition, the fructooligoglycodiuretic can be excreted into the urine five times more than in rats without administration of the fructooligoglycodiuretic. When using fructooligosaccharides clinically, since they are hardly absorbed orally,
It must be administered by a route other than orally, preferably intravenously. The dosage is such that the LD 50 value after a single intravenous administration in rats is 4 for both GF 2 , GF 3 and GF 4 .
Since the amount is more than g/Kg, it can be administered without limit. In addition, since all of the above-mentioned effects are strongly observed in GF 2 among fructooligosaccharides, it is preferable to use GF 2 for clinical use. For practical use, take 20-30g at a time.
It is recommended to administer once or twice a day, and administration is through infusion.
It should be added to 500 ml or stirred up as a concentrated solution. In addition, the isosmotic pressure is approximately 20 with blood.
%. Since the diuretic effect of fructooligosaccharide, especially GF 2 , is strong, it excretes not only sodium, chlorine, and waste products, but also calcium and, although weakly, water. If diuretics are used in significant amounts, calcium and potassium supplementation may be required. In addition, when the diuretic of the present invention is administered in a significantly large amount for the purpose of treating and preventing hypercalcemia, there are also cases where supplementation of sodium and potassium is required for the same purpose as above. As described above, the fructooligo bran diuretic of the present invention is a diuretic that exhibits a strong diuretic effect through a mechanism of action that is different from that of conventional diuretics. In the future, it is expected to be effective in the treatment and prevention of patients with edema due to various diseases, as well as in the prevention and treatment of hepatic coma and uremia, and is also expected to be effective in the treatment of hypertension in hospitalized patients. It is an extremely useful substance for maintaining human health. The present invention will be explained below with reference to Examples. Example 1 Three to six male Wistar rats (SPF) were used in each group and were subjected to a 17-hour night fasting test. The animals were given 3 ml of physiological saline warmed to 37°C.
Oral administration immediately followed by 500 mg/Kg and 1000 mg/Kg of GF 2 , GF 3 , GF 4 and mannitol as a control.
A single dose of Kg was administered intravenously. All test substances were dissolved in distilled water for injection, and the concentration was adjusted so that the volume administered per animal was 1 ml. Immediately after the completion of intravenous administration, the animals were placed in individual urine collection cages to collect and collect urine from 0 to 3 hours and 3 to 6 hours. Furthermore, during the urine collection period, the subjects were fasted from food and water.
After the urine collection was completed, the animals were subjected to blood collection by cutting the cervical artery and vein. Serum was immediately separated from the collected blood. The following items were measured for serum and urine. Urine: urinary volume, sodium, potassium, chloride,
Calcium, urea nitrogen, osmolality and creatinine were measured. Serum: The same items as above except for urine volume and osmotic pressure were measured. The results are shown in Tables 1 and 2 below. [Table] [Table] [Table] [Table] [Table] Example 2 A group of 8 male Wistar rats (SPF) that had been subjected to a 17-hour night fasting test were used. The animals were given 3 ml of physiological saline solution warmed to 37°C.
Administered orally. Immediately after that GF 2 's 50, 100, 200,
400, 800 mg/Kg doses and, as a control, 800 mg/Kg amount of mannitol were intravenously administered once. In each case, the concentration of the test substance was adjusted to 1 ml/rat using distilled water for pharmacopoeial injection. Immediately after administration of the test substance, the animals were placed in individual urine collection cages, and urine collected from 0 to 3 hours and from 3 to 6 hours was collected. During the urine collection period, the subjects were kept without food or water. After the 6th hour urine collection was completed, the cervical artery and vein of the test animal was cut and blood was collected. The blood is immediately spun down;
Serum was collected. For urine, osmotic pressure, urea nitrogen, creatinine, urinary volume, sodium, potassium, and chloride were measured, and for serum, sodium, potassium, and chloride were measured. The results are shown in Table-3 and Table-4. [Table] [Table] [Table] [Table] Example 3 Two to three male Wistar rats (SPF) with an average body weight of 224 g were used per group. GF 2 was dissolved in distilled water for pharmacopoeial injection at a concentration of 44.8%. The doses were 2 g/Kg and 4 g/Kg, and each dose was intravenously administered once into the tail vein. As a control, a group administered with 2 ml of distilled water was provided. General conditions were observed up to 6 hours after administration and before and after body weight measurements. Body weight was measured 1 after administration.
It was carried out on the 3rd and 9th day. The results are shown below. (b) General condition: Became depressed immediately after administration,
One hour after administration, piloerection was increased by an additional 1.5 hours.
After ~2 hours, a marked diuretic state (a large amount of urine was stored under the cage) was observed. The same thing was observed when observed 6 hours later. In the 2g/Kg group, these symptoms recovered the next day, but in the 4g/Kg group, it took two days to return to normal. Thereafter, the trend was similar to that of the control group. (b) Weight trends and death cases [Table]
Claims (1)
ユークロース（GF）および該シユークロースの
フラクトース部分にフラクトースがβ２−１結合
により１〜３分子結合したものであつて下記分子
式、分子量ならびに構造式で特定される化合物１
−ケストース（GF2）、ニストース（GF3）、1Fフ
ラクトフラノシルニストース（GF4）を有効成分
として含有する利尿剤。 【表】 トース
２ 肝、腎および心疾患、癌などのあらゆる病態
により招来される浮腫、腹水蓄留の予防と治療
に、および脳腫瘍時、頭部外傷時の脳圧下降、緑
内障の眼圧降下に用いられる特許請求の範囲第１
項記載の利尿剤。 ３ 腎障害などによる老廃物の体内蓄積および肝
障害、癌などの疾患による体内恒常成分もしくは
通常体内に見られない成分の血中増加により招来
されるあらゆる障害の発症予防と治療に用いられ
る特許請求の範囲第１項記載の利尿剤。[Scope of Claims] 1. Sucrose (GF) in which glucose (G) and fructose (F) are bonded, and one to three molecules of fructose bonded to the fructose portion of the sucrose through β 2 -1 bonds, which has the following molecular formula: , Compound 1 specified by molecular weight and structural formula
- A diuretic containing kestose (GF 2 ), nystose (GF 3 ), and 1F fructofuranosylnystose (GF 4 ) as active ingredients. [Front] Toth
2. Patents used for the prevention and treatment of edema and ascites accumulation caused by various pathological conditions such as liver, kidney and heart diseases, cancer, etc., as well as for lowering cerebral pressure during brain tumors and head trauma, and for lowering intraocular pressure in glaucoma. Claim 1
Diuretics listed in section. 3. Patent claims used for the prevention and treatment of all kinds of disorders caused by the accumulation of waste products in the body due to kidney disorders, etc., and the increase in the body's constant components or components not normally found in the body due to diseases such as liver disorders and cancer. The diuretic according to item 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP22016782A JPS59110621A (en) | 1982-12-17 | 1982-12-17 | Diuretic |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP22016782A JPS59110621A (en) | 1982-12-17 | 1982-12-17 | Diuretic |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS59110621A JPS59110621A (en) | 1984-06-26 |
| JPS6260368B2 true JPS6260368B2 (en) | 1987-12-16 |
Family
ID=16746929
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP22016782A Granted JPS59110621A (en) | 1982-12-17 | 1982-12-17 | Diuretic |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS59110621A (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1052402C (en) * | 1994-04-07 | 2000-05-17 | 中国人民解放军军事医学科学院毒物药物研究所 | Oligosaccharid type antipsychotic |
| DE69520528T2 (en) * | 1994-06-14 | 2001-09-27 | Raffinerie Tirlemontoise Sa | Use of a composition containing inulin or oligofructose as an anti-cancer agent |
| JP3579128B2 (en) * | 1995-05-31 | 2004-10-20 | 明治製菓株式会社 | Lipid peroxide rise inhibitor |
| US6706287B2 (en) * | 2001-05-15 | 2004-03-16 | Kibow Biotech Inc. | Prebiotic and probiotic compositions and methods for their use in gut-based therapies |
| JP2005532294A (en) * | 2002-03-13 | 2005-10-27 | キボー バイオテック、インク | Compositions and methods for enhancing renal function |
| JP2012176907A (en) * | 2011-02-25 | 2012-09-13 | Glico Dairy Products Co Ltd | Myosin light chain dephosphorylation promoter having fructo-oligosaccharide as active constituent, disease preventive or therapeutic agent, and food and drink |
-
1982
- 1982-12-17 JP JP22016782A patent/JPS59110621A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS59110621A (en) | 1984-06-26 |
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