JPH0148249B2 - - Google Patents
Info
- Publication number
- JPH0148249B2 JPH0148249B2 JP55187752A JP18775280A JPH0148249B2 JP H0148249 B2 JPH0148249 B2 JP H0148249B2 JP 55187752 A JP55187752 A JP 55187752A JP 18775280 A JP18775280 A JP 18775280A JP H0148249 B2 JPH0148249 B2 JP H0148249B2
- Authority
- JP
- Japan
- Prior art keywords
- reagent
- blood
- positive
- false positive
- water
- 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
- 208000007536 Thrombosis Diseases 0.000 claims description 58
- 239000004615 ingredient Substances 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 239000003153 chemical reaction reagent Substances 0.000 claims description 16
- 208000011580 syndromic disease Diseases 0.000 claims description 16
- 235000017803 cinnamon Nutrition 0.000 claims description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 235000000346 sugar Nutrition 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- 238000010521 absorption reaction Methods 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 7
- 238000000862 absorption spectrum Methods 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 238000004809 thin layer chromatography Methods 0.000 claims description 6
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 claims description 5
- 150000008163 sugars Chemical class 0.000 claims description 5
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 claims description 4
- PNNNRSAQSRJVSB-SLPGGIOYSA-N Fucose Natural products C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O PNNNRSAQSRJVSB-SLPGGIOYSA-N 0.000 claims description 4
- 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 4
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000008103 glucose Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- 238000001179 sorption measurement Methods 0.000 claims description 4
- 229930091371 Fructose Natural products 0.000 claims description 3
- 239000005715 Fructose Substances 0.000 claims description 3
- 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 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 150000001413 amino acids Chemical class 0.000 claims description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 3
- 239000000470 constituent Substances 0.000 claims description 3
- 238000000354 decomposition reaction Methods 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- OQUKIQWCVTZJAF-UHFFFAOYSA-N phenol;sulfuric acid Chemical compound OS(O)(=O)=O.OC1=CC=CC=C1 OQUKIQWCVTZJAF-UHFFFAOYSA-N 0.000 claims description 3
- MYKOKMFESWKQRX-UHFFFAOYSA-N 10h-anthracen-9-one;sulfuric acid Chemical compound OS(O)(=O)=O.C1=CC=C2C(=O)C3=CC=CC=C3CC2=C1 MYKOKMFESWKQRX-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000012029 Fehling's reagent Substances 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 238000000921 elemental analysis Methods 0.000 claims description 2
- 150000004676 glycans Chemical class 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 claims description 2
- 229940067157 phenylhydrazine Drugs 0.000 claims description 2
- 229920001282 polysaccharide Polymers 0.000 claims description 2
- 239000005017 polysaccharide Substances 0.000 claims description 2
- 238000000045 pyrolysis gas chromatography Methods 0.000 claims description 2
- 229920001503 Glucan Polymers 0.000 claims 3
- 241000723347 Cinnamomum Species 0.000 claims 1
- 210000004369 blood Anatomy 0.000 description 19
- 239000008280 blood Substances 0.000 description 19
- 230000000694 effects Effects 0.000 description 16
- 240000007235 Cyanthillium patulum Species 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 13
- 210000004204 blood vessel Anatomy 0.000 description 13
- 210000003743 erythrocyte Anatomy 0.000 description 12
- 208000024891 symptom Diseases 0.000 description 11
- 244000223760 Cinnamomum zeylanicum Species 0.000 description 10
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 9
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 9
- 108010073385 Fibrin Proteins 0.000 description 9
- 102000009123 Fibrin Human genes 0.000 description 9
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 9
- 229950003499 fibrin Drugs 0.000 description 9
- 230000003480 fibrinolytic effect Effects 0.000 description 9
- 235000001674 Agaricus brunnescens Nutrition 0.000 description 8
- 108010049003 Fibrinogen Proteins 0.000 description 8
- 102000008946 Fibrinogen Human genes 0.000 description 8
- 229940012952 fibrinogen Drugs 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 230000036772 blood pressure Effects 0.000 description 7
- 239000002158 endotoxin Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 108090000190 Thrombin Proteins 0.000 description 6
- 239000004019 antithrombin Substances 0.000 description 6
- 230000023555 blood coagulation Effects 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000003527 fibrinolytic agent Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 230000035699 permeability Effects 0.000 description 6
- 229940012957 plasmin Drugs 0.000 description 6
- 238000010998 test method Methods 0.000 description 6
- 229960004072 thrombin Drugs 0.000 description 6
- 210000003462 vein Anatomy 0.000 description 6
- -1 7.61% Inorganic materials 0.000 description 5
- 206010033557 Palpitations Diseases 0.000 description 5
- 108010094028 Prothrombin Proteins 0.000 description 5
- 102100027378 Prothrombin Human genes 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 150000002632 lipids Chemical class 0.000 description 5
- 229940039716 prothrombin Drugs 0.000 description 5
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 206010008479 Chest Pain Diseases 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 208000031226 Hyperlipidaemia Diseases 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 102000013142 Amylases Human genes 0.000 description 3
- 108010065511 Amylases Proteins 0.000 description 3
- 206010013975 Dyspnoeas Diseases 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 206010062713 Haemorrhagic diathesis Diseases 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 3
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 description 3
- 238000009534 blood test Methods 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000015271 coagulation Effects 0.000 description 3
- 238000005345 coagulation Methods 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 208000031169 hemorrhagic disease Diseases 0.000 description 3
- 230000000936 membranestabilizing effect Effects 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000000197 pyrolysis Methods 0.000 description 3
- 201000005665 thrombophilia Diseases 0.000 description 3
- 229960005356 urokinase Drugs 0.000 description 3
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 2
- 239000004382 Amylase Substances 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- 241000221198 Basidiomycota Species 0.000 description 2
- 208000007257 Budd-Chiari syndrome Diseases 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 208000000059 Dyspnea Diseases 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- 206010019713 Hepatic vein thrombosis Diseases 0.000 description 2
- 206010020608 Hypercoagulation Diseases 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 235000019418 amylase Nutrition 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000001567 anti-fibrinolytic effect Effects 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 229940082620 antifibrinolytics Drugs 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 229940127088 antihypertensive drug Drugs 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000002374 bone meal Substances 0.000 description 2
- 229940036811 bone meal Drugs 0.000 description 2
- 238000011088 calibration curve Methods 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 230000035602 clotting Effects 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 230000003027 hypercoagulation Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 229960002895 phenylbutazone Drugs 0.000 description 2
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 208000013220 shortness of breath Diseases 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 231100000699 Bacterial toxin Toxicity 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010006582 Bundle branch block right Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 101710196208 Fibrinolytic enzyme Proteins 0.000 description 1
- 241000222336 Ganoderma Species 0.000 description 1
- 240000008397 Ganoderma lucidum Species 0.000 description 1
- 235000001637 Ganoderma lucidum Nutrition 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 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 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000007330 LDL Lipoproteins Human genes 0.000 description 1
- 108010007622 LDL Lipoproteins Proteins 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000258241 Mantis Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 244000183278 Nephelium litchi Species 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010030302 Oliguria Diseases 0.000 description 1
- 244000273256 Phragmites communis Species 0.000 description 1
- 235000014676 Phragmites communis Nutrition 0.000 description 1
- 102100038124 Plasminogen Human genes 0.000 description 1
- 108010051456 Plasminogen Proteins 0.000 description 1
- 208000035755 Psychosomatic disease Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241001122767 Theaceae Species 0.000 description 1
- 208000009205 Tinnitus Diseases 0.000 description 1
- 206010046996 Varicose vein Diseases 0.000 description 1
- 208000024248 Vascular System injury Diseases 0.000 description 1
- 208000012339 Vascular injury Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 206010047513 Vision blurred Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 230000004931 aggregating effect Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 238000011888 autopsy Methods 0.000 description 1
- 239000000688 bacterial toxin Substances 0.000 description 1
- AYJRCSIUFZENHW-DEQYMQKBSA-L barium(2+);oxomethanediolate Chemical compound [Ba+2].[O-][14C]([O-])=O AYJRCSIUFZENHW-DEQYMQKBSA-L 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000010876 biochemical test Methods 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 235000021152 breakfast Nutrition 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 108010015046 cell aggregation factors Proteins 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- OZECDDHOAMNMQI-UHFFFAOYSA-H cerium(3+);trisulfate Chemical compound [Ce+3].[Ce+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O OZECDDHOAMNMQI-UHFFFAOYSA-H 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000009190 disseminated intravascular coagulation Diseases 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 210000003617 erythrocyte membrane Anatomy 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 239000000208 fibrin degradation product Substances 0.000 description 1
- 239000000282 fibrinogen degradation product Substances 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000014105 formulated food Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 244000022778 quail grass Species 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- ILXAOQAXSHVHTM-UHFFFAOYSA-M sodium;2-amino-2-(hydroxymethyl)propane-1,3-diol;chloride Chemical compound [Na+].[Cl-].OCC(N)(CO)CO ILXAOQAXSHVHTM-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000006227 trimethylsilylation reaction Methods 0.000 description 1
- 208000027185 varicose disease Diseases 0.000 description 1
- 230000003966 vascular damage Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Description
この発明はマンネンタケの薬効成分、ことに血
管内血栓形成症候群の予防と治療用組成物に関す
る。
この発明で、原料物質として用いられるマンネ
ンタケは「原色日本菌類図鑑」（保育社版、今関
六也、本郷次雄共著）によれば、担子菌類、同担
子菌亜綱、菌葦類、ヒダナシタケ目、サルノコシ
カケ科に属し、古くから霊芝と称され、万病に効
くといわれてきた。現在日本では人工栽培によつ
て生産され、比較的容易に入手できるキノコの一
種である。
この発明は、マンネンタケより抽出分離した薬
効成分を有効成分として含有し、以下に述べる血
管内血栓形成症候群の予防と治療に用いる医薬組
成物を提供するものである。
血栓とは血管内で血液が固まつた状態をいゝ、
血管内皮の損傷、炎症、血流の変化、血液凝固能
の亢進に伴つて起る。特に手術後仰臥している患
者などに起り易い。
例えば血管の内皮に損傷があると、そこに血小
板が付着して凝集をおこし、主として血小板から
なる白色血栓がことに動脈中に生成する。また白
色血栓の形成部位を中心にして凝固機能が進行
し、フイブリンの網を有する強固な血栓が形成さ
れる。この血栓は赤血球をも含有し赤色を呈する
ので赤色血栓といわれ、主として静脈中に生成す
る。一方、血管内でこれら血栓が生成すると、生
体内で血栓を溶解しようとする伝令が発せられプ
ラスミンという血栓を溶解する物質が血液中に増
加してくる。従つて血栓形成と同時に出血傾向も
生起し、この血栓形成の度合と出血傾向の強さは
バランスがとれたものである。健康状態でも量は
少ないが絶えず血栓形成と溶解がなされ健康状態
が保持されている。
しかしながら、血管内で血栓が異常に多量形成
されると、その形成部位から先の血流が著しく阻
害され、組織に重大な障害をもたらし、いわゆる
血栓症がおこる。すなわち心臓や脳の血管が血栓
でつまるとそれぞれ心筋梗塞及び脳梗塞をおこ
し、またその他の部位の静脈が血栓でつまると静
脈瘤が形成され危険な状態となる。さらに各種内
臓器（例えば肝臓）等に障害がある場合、血栓が
形成すると同時に起る出血傾向のためにそれらの
症状が一層悪化する。
上記のごとき強度の血栓症ほどではないが正常
状態よりも血栓形成量が増大するとほとんどの人
が例えばめまい、肩こり、頭痛、目のかすみ、腰
痛、関節痛、不眠、頭帽感、冷え症などの軽度の
血栓症の自覚症状を訴える。さらに血栓形成が進
むと息切れ、動悸、胸部痛、油汗、血圧異常、顔
面そう白、不整脈、乏尿、意識障害などの強度の
血栓症の症状を呈する。
このように血管内の血栓形成が原因でおこる広
範囲にわたる一群の疾病は血管内血栓形成症候群
と呼ばれている。
この発明の発明者らは、先に、マンネンタケよ
り抽出分離された薬効成分が高血圧症、高脂血症
及び動脈硬化症並びに心身症に対し著効を有する
ことを見出したが、血管内血栓形成症候群に対す
る効力については全く知られていなかつた。この
発明の発明者らは鋭意研究の結果、この発明のマ
ンネンタケ薬効成分が血管内血栓形成症候群に著
効を有することを見出しこの発明に想到したもの
である。
この発明のマンネンタケ成分は、マンネンタケ
好ましくはその子実体を適量の水で熱抽出し、不
溶分を除去した水抽出液を室温〜約60℃程度で真
空濃縮し、遠心分離に付して得られる沈澱物を凍
結乾燥して得られる。
この発明のマンネンタケの薬効成分は、次の事
項によつて特徴づけられるものである。
） 約3450、2970、1700、1460、1390および
1040cm-1に吸収極大を有する赤外吸収スペクト
ル（KBr法）を示す（第１図参照）
） 水溶液（0.0067％）中で約257〜258nmに
吸収極大を有する紫外吸収スペクトルを示す
（第２図参照）、
） 特有の可視吸収極大（0.2％水溶液中）を
示さない（第３図参照）、
） フエーリング試薬に陽性、フエニルヒドラ
ジン試薬に疑陽性、アンスロン−硫酸試薬に疑
陽性、フエノール−硫酸試薬に陽性、ビユーレ
ツト反応試薬に陽性、リーベルマン−ブルヒア
ルト反応試薬に疑陽性、塩化第二鉄試薬に疑陽
性およびニンヒドリン反応試薬に陽性をそれぞ
れ示す。
） 薄層クロマトグラフイ−〔吸着層：シリカ
ゲル、展開剤：ｎ−ブタノール：イソプロパノ
ール：水（10：５：４）で、低分子の遊離の糖
およびアミノ酸がほとんど含まれない、
） 元素分析で炭素、水素、窒素原子が測定さ
れる〔詳しくはＣ、57.25％、Ｈ、7.61％、Ｎ、
1.4％で、全灰分量は3.70％（Ｋ、2.42％、ナト
リウム、0.49％、マグネシウム、0.49％、カル
シウム、0.10％、マンガン、0.03％、亜鉛、
0.01％）である〕、
） 主としてグルコース、フコース、フルクト
ースを少なくとも構成糖として含む（詳しくは
糖質63.5％で、糖組成は、グルコース32.7％、
フコース28.9％、フルクトース1.9％である）、
また更にニンヒドリン反応物質4.12％を含む、
） 熱水にわずかに溶解し、常温の水およびメ
タノールに対して極めて溶け難い〔詳しくは溶
媒全量100mlに対する本品100mgの溶解性は次の
通りである；常温の水に対して46mg溶解し、酢
酸エチル／水（１：１）の上層に約63mg溶解
し、下層に32mg溶解し、クロロホルム／メタノ
ール／水（７：３：１）の上層に９mg、下層に
71mg溶解する〕、
） 熱分解ガスクロマトグラフイ−（分解温度
は350℃でカラム温度は170℃〜200℃で、毎分
３℃の昇温式で行つた）で６個のピークを示す
（第４図〜第６図参照）〔詳しくは、以下のピー
クを示し、比較サンプルのマルトース、デキス
トラン等と区別可能である：
本品
リテンシヨンタイム 強度
（分）
0.53 1826
0.68 401010
0.90 92700
0.99 110500
1.24 169600
1.48 820740
比較対照
The present invention relates to the medicinal components of Cinnamon mushroom, and particularly to compositions for the prevention and treatment of intravascular thrombosis syndrome. According to the "Illustrated Encyclopedia of Illustrated Japanese Fungi" (Yukusha edition, co-authored by Rokuya Imaseki and Tsuguo Hongo), the mushrooms used as raw materials in this invention are classified as Basidiomycota, subclass Basidiomycota, fungi reeds, and order Hydanashitake. , belongs to the family Salmonaceae, and has been called Reishi since ancient times, and is said to be effective against all kinds of illnesses. Currently in Japan, it is a type of mushroom that is produced through artificial cultivation and is relatively easily available. The present invention provides a pharmaceutical composition containing as an active ingredient a medicinal ingredient extracted and separated from Cinnamon mantis, and used for the prevention and treatment of intravascular thrombosis syndrome described below. A thrombus is a condition in which blood clots within a blood vessel.
It occurs due to damage to the vascular endothelium, inflammation, changes in blood flow, and increased blood coagulation ability. This is especially likely to occur in patients who are lying on their backs after surgery. For example, when the endothelium of a blood vessel is damaged, platelets adhere there and aggregate, resulting in the formation of a white thrombus consisting mainly of platelets, especially in the artery. In addition, the coagulation function progresses centering around the site where the white thrombus is formed, and a strong thrombus with a fibrin network is formed. This thrombus is called a red thrombus because it contains red blood cells and is red in color, and is mainly generated in veins. On the other hand, when these thrombi are formed in blood vessels, a message is sent in the body to dissolve the thrombus, and plasmin, a substance that dissolves thrombi, increases in the blood. Therefore, a bleeding tendency occurs simultaneously with thrombus formation, and the degree of thrombus formation and the strength of the bleeding tendency are well balanced. Even in a healthy state, blood clots are constantly formed and dissolved, although the amount is small, and a healthy state is maintained. However, when an abnormally large amount of thrombi is formed within a blood vessel, blood flow beyond the site of thrombus formation is significantly inhibited, causing serious damage to tissues, resulting in so-called thrombosis. That is, if blood vessels in the heart or brain become clogged with blood clots, myocardial infarction or cerebral infarction occurs, respectively, and if veins in other parts of the body become clogged with blood clots, varicose veins are formed, creating a dangerous situation. Furthermore, when there is damage to various internal organs (for example, the liver), the symptoms are further aggravated due to the bleeding tendency that occurs simultaneously with the formation of blood clots. Although not as severe as the severe thrombosis described above, most people experience symptoms such as dizziness, stiff shoulders, headaches, blurred vision, lower back pain, arthralgia, insomnia, a feeling of hating, and sensitivity to cold when the amount of blood clot formation increases compared to the normal state. The patient complained of subjective symptoms of mild thrombosis. If the formation of blood clots progresses further, symptoms of severe thrombosis will occur, such as shortness of breath, palpitations, chest pain, oily sweating, abnormal blood pressure, white facial appearance, arrhythmia, oliguria, and impaired consciousness. A wide range of diseases caused by the formation of blood clots in blood vessels are called intravascular thrombosis syndromes. The inventors of this invention previously discovered that the medicinal components extracted and separated from Cinnamon mushroom have remarkable effects on hypertension, hyperlipidemia, arteriosclerosis, and psychosomatic diseases, Nothing was known about its efficacy against the syndrome. As a result of intensive research, the inventors of the present invention discovered that the medicinal component of the present invention has a remarkable effect on intravascular thrombosis syndrome, and came up with the present invention. The component of Stone Clover of the present invention is a precipitate obtained by heat-extracting the fruiting body of L. spinach with an appropriate amount of water, removing insoluble matter, vacuum concentrating the aqueous extract at room temperature to about 60°C, and subjecting it to centrifugation. Obtained by freeze-drying. The medicinal ingredients of the Ganoderma mushroom of this invention are characterized by the following items. ) about 3450, 2970, 1700, 1460, 1390 and
It shows an infrared absorption spectrum (KBr method) with an absorption maximum at 1040 cm -1 (see Figure 1). It shows an ultraviolet absorption spectrum with an absorption maximum at about 257 to 258 nm in an aqueous solution (0.0067%) (Figure 2). ), ) Does not show the characteristic visible absorption maximum (in 0.2% aqueous solution) (see Figure 3), ) Positive for Fehling's reagent, false positive for phenylhydrazine reagent, false positive for Anthrone-sulfuric acid reagent, phenol-sulfuric acid Positive for the reagent, positive for the Bühlett reaction reagent, false positive for the Lieberman-Burchardt reaction reagent, false positive for the ferric chloride reagent, and positive for the ninhydrin reaction reagent, respectively. ) Thin layer chromatography - [Adsorption layer: silica gel, developer: n-butanol: isopropanol: water (10:5:4), containing almost no low molecular weight free sugars and amino acids] Elemental analysis Carbon, hydrogen, and nitrogen atoms are measured [Details: C, 57.25%, H, 7.61%, N,
1.4%, total ash content is 3.70% (K, 2.42%, sodium, 0.49%, magnesium, 0.49%, calcium, 0.10%, manganese, 0.03%, zinc,
0.01%], ) Contains at least glucose, fucose, and fructose as constituent sugars (specifically, 63.5% carbohydrates; the sugar composition is 32.7% glucose,
Fucose 28.9%, fructose 1.9%),
Furthermore, it contains 4.12% of ninhydrin-reactive substances.) It is slightly soluble in hot water and extremely insoluble in water and methanol at room temperature. Dissolve 46 mg in water at room temperature, dissolve approximately 63 mg in the upper layer of ethyl acetate/water (1:1), dissolve 32 mg in the lower layer, and dissolve 9 mg in the upper layer of chloroform/methanol/water (7:3:1). to the lower layer
71mg dissolved], ) Pyrolysis gas chromatography (decomposition temperature was 350°C, column temperature was 170°C to 200°C, heating rate was 3°C per minute) showed 6 peaks (1st (See Figures 4 to 6) [For details, it shows the following peaks and can be distinguished from comparison samples such as maltose and dextran: This product Retention time Intensity (min) 0.53 1826 0.68 401010 0.90 92700 0.99 110500 1.24 169600 1.48 820740 Compare and contrast
【表】
上記の性質の外に更に加えて次のような性状
を示す、
） 分解温度がおよそ120℃近辺である、
XI） 試料を充分の量の温水（約30℃）に溶解
し、専門のパネラ−５人にパネルテストを実施
したところ、0.02％の溶液では明らかに苦味を
感じるが、0.01％になると、ほとんどの者が苦
味を感じられなかつた、
XII） 試料の１％水懸濁液のPHは、および4.2〜
4.4である。
なお、上記の項目のうち、自明なものを除い
て、その測定方法を述べる。
薄層クロマトグラフイー（TLC）
ａ 糖類の確認の場合のTLCの条件．
吸着層：シリカゲル60F254〔メルク社製〕
展開剤：ｎ−ブタノール：イソプロパノール：
水（10：５：４）
発色剤：１％硫酸セリウム／10％硫酸
ｂ アミノ酸類の確認の場合のTLCの条件．
吸着層：シリカゲル60F254〔メルク社製〕
展開剤：ｎ−ブタノール：イソプロパノール：
水（10：５：４）
発色剤：ニンヒドリン試薬
灰分の分析
試料粉末を低温灰化したのち、その灰分を精製
水に溶解して測定液となし、日立製作所製高周波
プラズマスキヤン分析装置ならびに日立製作所製
ゼーマン原子吸光分析装置で測定した。
糖質の分析
試料20mgに1N−硫酸５mlを加え、105℃の乾熱
器中で５時間加熱分解を行う。次いで炭酸バリウ
ムにて中和し、過した後50mlにする。その１ml
によりフエノール硫酸法にて全糖量を測定する。
また残液をすべて濃縮乾固し、五酸化リン上デシ
ケーター中で一夜放置後、３mlのピリジン溶液
（内部標準C22パラフインを含む）にて溶解し、そ
の2.0mlを小型バイアル瓶にとり、トリメチルシ
リル化（TMS化）試薬0.25mlを加え、２分間よ
く振とう後、30分後にガスクロマトグラフイーに
付し、糖組成を求める（検量線も同様に標準糖液
にて測定しておく）。
ニンヒドリン反応物質
試料10mgに1N−塩酸を５ml加え、105℃の乾熱
器中で５時間加水分解を行い、減圧濃縮を繰返し
塩酸を除去後10mlの緩衝溶液（PH2.2）にて溶解
し、その１mlにてニンヒドリン反応を行い、予め
グルタミン酸にて求めた検量線より、その量を求
める。
このような特徴を有するマンネンタケの成分
は、後記薬理実験及び臨床例で顕著に血管内血栓
形成症候群の予防と治療作用があることが確かめ
られた。また毒性が極めて低いという特徴を有す
る。
この発明におけるマンネンタケの薬効成分の投
与量は、症状の軽重あるいは投与されるヒトの体
重等に応じて異なるが、成人に対する内服の場
合、通常１回当り10〜300mg、好ましくは空腹時
に30〜100mgを１日２〜３回投与される。
この発明における薬剤は、この発明のマンネン
タケ薬効成分単体、またはマンネンタケ薬効成分
と固体もしくは液体の賦形剤とからなるものであ
る。
そして投与法ならびに投与の剤型としては通常
錠剤、散剤、カプセル剤、乳剤、茶剤、顆粒剤、
液剤（酒精剤、流エキス剤、シロツプ剤などを含
む）などの内服の形がある。また点滴剤のごとく
体内注入する形態であつてもよい。ここに使用さ
れる固体または液体の賦形剤としては、当該分野
で公知のものが使用される。
ただ前述したような１回の投与量に必要なこの
発明の薬効成分を含むように製剤化するのが望ま
しい。
いくつかの具体例を挙げると、散剤、その他の
内服用粉末剤における賦形剤としては、乳糖、澱
粉、ボーンミール、CMC（カルボキシメチルセル
ロース）、デキストリン、リン酸カルシウム、炭
酸カルシウム、合成および天然ケイ酸アルミニウ
ム、酸化マグネシウム、乾燥水酸化アルミニウ
ム、ステアリン酸マグネシウム、重炭酸ナトリウ
ム、乾燥酵母などが挙げられる。液剤における賦
形剤としては、水、単シロツプ、エタノール等が
挙げられる。その他当該分野で用いられる崩壊
剤、矯味剤、甘味剤、着色剤等を適宜添加しても
よい。
次にマンネンタケ薬効成分製造例、薬理実験、
臨床例を挙げて、この発明を説明する。
マンネンタケ薬効成分製造例 １
成熟したマンネンタケ（LK1：飛騨高山地方で
人工栽培されたもの）の子実体を充分乾燥させ、
その約１Kgを流水中で軽く洗滌し、水を充分に切
つて乾燥後、破砕機にかける。細かく破砕された
子実体の小片に約20倍量の脱イオン水を加え加熱
する。煮沸下に約１時間抽出する。新たな脱イオ
ン水を前抽出液と入れ替え、同様にもう１回抽出
操作を行う。こうして得られた熱水抽出液総量約
35を真空濃縮乾燥装置を用いて、温度65℃以下
で濃縮を行う。全量が約１になつたら、濃縮を
終了し、次いで、平均約6000Gにて約15分間遠心
分離を行う。得られた沈澱物質を約500mlの水に
懸濁させ、凍結乾燥を行い、マンネンタケ熱水抽
出精製粉末約30ｇを得た。この粉末は前述したよ
うな性質を示した。
薬理実験
１ 血管内血栓形成の抑制作用
Ａ 試験方法
成長ラツト（〓、体重200〜250ｇ）の尾静
脈にエンドトキシン（菌体内毒素、大腸菌よ
り調製）の0.5mg/Kgを注射し、４時間後に採
血し次の事項を測定した。
血小板数…直径約２〜5μｍの不整形の小体
でヒトの血液中には15〜35万／mm
３存在し、寿命は５〜10日である
といわれている。
フイブリノーゲン量…血液凝固の重要物質で
あるフイブリンの前駆物質で、ヒ
トの血液中には150〜340mg/dl存
在する。
プロトロンビン時間…トロンビンの前駆物質
であるプロトロンビンがトロンビ
ンに変化するまでの時間であつ
て、正常値はヒトの血液で12.5±
0.7秒といわれている。
FDP（フイブリン及びフイブリノーゲン分解
産物）
量…ヒトの血液中に普通５μｇ/ml以下存在
する。この量が多いことは血液凝
固が進んでいることを示唆してい
る。
一方、製造例１で得たマンネンタケ薬効成
分を、予めラツトに100mg/Kg経口投与してお
いてから上記と同様にエンドトキシンを注射
して同じ事項を測定し結果を第１表に示し
た。[Table] In addition to the above properties, the following properties are exhibited: ) The decomposition temperature is around 120°C. When a panel test was conducted on five panelists, it was found that a 0.02% solution clearly tasted bitter, but most of them could not feel any bitterness at 0.01%. XII) 1% water suspension of sample The pH of the liquid is 4.2~
It is 4.4. The measurement methods for the above items will be described except for the obvious ones. Thin layer chromatography (TLC) a. TLC conditions for confirming sugars. Adsorption layer: Silica gel 60F254 [Merck & Co., Ltd.] Developer: n-butanol: Isopropanol:
Water (10:5:4) Color former: 1% cerium sulfate/10% sulfuric acid B TLC conditions for confirmation of amino acids. Adsorption layer: Silica gel 60F254 [Merck & Co., Ltd.] Developer: n-butanol: Isopropanol:
Water (10:5:4) Coloring agent: Ninhydrin reagent Ash content analysis After the sample powder is incinerated at low temperature, the ash content is dissolved in purified water to prepare a measurement solution, and a high-frequency plasma scan analyzer made by Hitachi, Ltd. and Hitachi, Ltd. It was measured using a Zeeman atomic absorption spectrometer. Analysis of carbohydrates Add 5 ml of 1N sulfuric acid to 20 mg of sample, and heat decompose in a dry heat oven at 105°C for 5 hours. Next, neutralize with barium carbonate, filter, and make up to 50 ml. That 1ml
Measure the total sugar content using the phenol sulfuric acid method.
All remaining liquid was concentrated to dryness, left overnight in a desiccator over phosphorous pentoxide, dissolved in 3 ml of pyridine solution (containing internal standard C 22 paraffin), 2.0 ml of the solution was placed in a small vial, and trimethylsilylation was carried out. Add 0.25 ml of the (TMS) reagent, shake well for 2 minutes, and 30 minutes later apply gas chromatography to determine the sugar composition (the calibration curve is also measured using a standard sugar solution). Ninhydrin reactant: Add 5 ml of 1N hydrochloric acid to 10 mg of sample, perform hydrolysis in a dry heat oven at 105°C for 5 hours, repeat vacuum concentration to remove hydrochloric acid, and dissolve in 10 ml of buffer solution (PH2.2). Perform a ninhydrin reaction with 1 ml of the solution, and determine the amount using a calibration curve previously determined using glutamic acid. It has been confirmed in pharmacological experiments and clinical examples described below that the components of Cinnamon edulis having these characteristics have remarkable preventive and therapeutic effects on intravascular thrombosis syndrome. It is also characterized by extremely low toxicity. The dosage of the medicinal ingredient of Cinnamon mushroom in this invention varies depending on the severity of the symptoms and the weight of the person to whom it is administered, but when administered orally to adults, it is usually 10 to 300 mg per dose, preferably 30 to 100 mg on an empty stomach. is administered 2 to 3 times a day. The drug in this invention is composed of the medicinal ingredient of C. chinensis alone, or the medicinal ingredient of C. chinensis and a solid or liquid excipient. The administration method and dosage form are usually tablets, powders, capsules, emulsions, tea preparations, granules,
There are oral forms such as liquid preparations (including alcoholic agents, liquid extracts, syrups, etc.). It may also be in a form injected into the body, such as an intravenous drip. As solid or liquid excipients used herein, those known in the art are used. However, it is desirable to formulate the drug so that it contains the medicinal ingredients of the present invention necessary for one dose as described above. To name a few specific examples, excipients in powders and other powders for internal use include lactose, starch, bone meal, CMC (carboxymethyl cellulose), dextrin, calcium phosphate, calcium carbonate, synthetic and natural aluminum silicates. , magnesium oxide, dried aluminum hydroxide, magnesium stearate, sodium bicarbonate, dried yeast, and the like. Excipients in liquid formulations include water, simple syrup, ethanol, and the like. Other disintegrants, flavoring agents, sweeteners, coloring agents, etc. used in the field may be added as appropriate. Next, an example of manufacturing the medicinal ingredients of C. chinensis, pharmacological experiments,
This invention will be explained by giving a clinical example. Example of manufacturing the medicinal ingredient of C. chinensis 1. Thoroughly dry the fruiting bodies of mature C. chinensis (LK1: artificially cultivated in the Hida Takayama region).
Lightly wash about 1 kg of the material under running water, drain it thoroughly, dry it, and then put it in a crusher. Approximately 20 times the volume of deionized water is added to small pieces of finely crushed fruiting bodies and heated. Extract for about 1 hour under boiling. Replace the previous extraction solution with fresh deionized water and perform another extraction operation in the same manner. The total amount of hot water extract obtained in this way is approx.
Concentrate 35 using a vacuum concentration dryer at a temperature of 65°C or lower. When the total volume becomes about 1, the concentration is finished, and then centrifugation is performed at an average of about 6000 G for about 15 minutes. The obtained precipitate was suspended in about 500 ml of water and freeze-dried to obtain about 30 g of a hot water-extracted and purified powder of Stone Manga. This powder exhibited the properties described above. Pharmacological experiment 1 Inhibitory effect on intravascular thrombus formation A Test method 0.5 mg/Kg of endotoxin (prepared from Escherichia coli) was injected into the tail vein of adult rats (200-250 g in weight), and blood was collected 4 hours later. The following items were measured. Platelet count: Irregularly shaped bodies with a diameter of approximately 2 to 5 μm, 150,000 to 350,000/mm in human blood
There are 3 species, and their lifespan is said to be 5 to 10 days. Fibrinogen content: A precursor of fibrin, an important substance in blood coagulation, present in human blood at 150 to 340 mg/dl. Prothrombin time: The time it takes for prothrombin, a precursor of thrombin, to change into thrombin.The normal value is 12.5± in human blood.
It is said to be 0.7 seconds. FDP (fibrin and fibrinogen degradation products) Amount: Normally present in human blood at 5 μg/ml or less. A large amount suggests that blood coagulation is progressing. On the other hand, 100 mg/Kg of the medicinal ingredient obtained in Production Example 1 was orally administered to rats in advance, and then endotoxin was injected in the same manner as above, and the same items were measured. The results are shown in Table 1.
【表】
Ｂ 考察
エンドトキシンを静圧されたラツトは、血
小板数が減少し、プロトロンビン時間が延長
され、フイブリノーゲン量が減少しかつ
FDP量が増加している。明らかに凝固亢進
による消費性凝固障害と凝固亢進に対する線
溶能の亢進が認められ、血管内血栓形成症を
示している。一方この発明のマンネンタケの
薬効成分を予め経口投与しておくと、血小板
数の減少、プロトロンビン時間の延長、
FDP量の増加が顕著に抑制されることが分
かる。この結果からこの発明のマンネンタケ
薬効成分が血管内血栓形成症の予防及び治療
に極めて有効であることが分かる。
２ 赤血球膜安定化作用
赤血球が異常血管内膜又は血栓と衝突する
と、赤血球は破壊され赤血球中から血小板凝集
因子であるADP（アデノシンジホスフエート）
が放出され、血管内血栓形成症が助長されると
考えられる。従つて赤血球膜を安定化する作用
があれば血管内血栓形成症を抑制することにな
る。
Ａ 試験方法
成長ラツト（〓、体重200〜250ｇ）から採
取した血液を53℃で加熱し、遠心分離によつ
て得た赤血球をリン酸緩衝液にとかしたもの
を破壊してその溶液の透過度を測定した（対
照例）。次に同じ血液に、赤血球膜安定化剤
として知られているフエニルブタゾン又は製
造例１で得たマンネンタケ薬効成分を予め添
加しておいて53℃に加熱して赤血球を破壊し
その溶液の透過度を測定しこれらの測定結果
を第２表に示した。[Table] B Discussion Rats exposed to static pressure of endotoxin had decreased platelet counts, prolonged prothrombin time, decreased fibrinogen levels, and
FDP amount is increasing. Consumptive coagulopathy due to hypercoagulability and increased fibrinolytic ability in response to hypercoagulability were clearly observed, indicating intravascular thrombosis. On the other hand, if the medicinal component of the present invention is orally administered in advance, the number of platelets decreases, the prothrombin time increases,
It can be seen that the increase in FDP amount is significantly suppressed. These results demonstrate that the medicinal component of the present invention is extremely effective for the prevention and treatment of intravascular thrombosis. 2 Erythrocyte membrane stabilization effect When red blood cells collide with abnormal blood vessel intima or thrombus, the red blood cells are destroyed and ADP (adenosine diphosphate), a platelet aggregation factor, is released from the red blood cells.
is released, promoting intravascular thrombosis. Therefore, if it has the effect of stabilizing red blood cell membranes, it will suppress intravascular thrombosis. A. Test method: Blood taken from a growing rat (200-250 g in weight) is heated at 53°C, red blood cells obtained by centrifugation are dissolved in a phosphate buffer solution, and the permeability of the solution is determined. was measured (control example). Next, to the same blood, phenylbutazone, which is known as a red blood cell membrane stabilizer, or the medicinal ingredient obtained in Production Example 1 was added in advance and heated to 53°C to destroy the red blood cells and reduce the permeability of the solution. The measurement results are shown in Table 2.
【表】
Ｂ 考察
赤血球の破壊が著しい程、血液の透過度は
増大するが、この発明のマンネンタケ薬効成
分を500μｇ/ml血液、位添加するとフエニル
ブタゾンと同程度の赤血球膜安定化作用を有
することがわかる。
３ 血小板凝集抑制作用
血液が凝固亢進状態のさい、血管損傷部位に
付着した血小板に流血中の血小板が付着して血
小板の凝集体（白色血栓）ができる。このと
き、生体の線溶能（血栓を溶解する能力）が低
下していたり高脂血症の状態のように線溶酵素
が働かない場合は生成した血栓が溶解されなく
なる。このような状態になると血管内血栓形成
症候群がひきおこされる。従つて血小板凝集抑
制作用は血管内血栓形成症候群の予防及び治療
のために重要な作用である。
Ａ 試験方法
血小板を凝集させる化合物としてはADP、
エピネフリン、セロトニン、トロンビビン、
ある種の脂肪酸などがある。現在では、血小
板凝集の最終的役割を果すのはADPと考え
られており、またADP自体が血小板中の
ADPを放出させる作用を有している。従つ
て血小板凝集剤としては、ADPを用いた。
健康な20才の男性の血液から血小板をとり
だしそれにADP（0.05μM）を添加した場合
（対照例）と、同じ血液に予め製造例１で得
たマンネンタケ薬効成分を１ml血液当り１mg
添加しておいてからADPを対照例と同様に
添加した場合についてその血小板溶液の透過
度を測定して結果をそれぞれ第７図のａ及び
ｂに示した。
Ｂ 考察
予めマンネンタケ薬効成分を添加しておい
た方が明らかに上記透過度が低く凝血が抑制
されていることが分かる。
４ 抗トロンビン作用
血管損傷部位では、血液中に生成したトロン
ビンによりフイブリノーゲンがフイブリンにな
り、前記血小板凝集体をさらに成長させ、出血
を停止させる。このような血液凝固亢集状態で
は、析出したフイブリンが血管内に蓄積して血
栓になると考えられる。従つてこのトロンビン
の作用を抑制するいわゆる抗トロンビン作用は
血管内血栓形成症候群の予防及び治療のために
重要な作用である。
Ａ 試験方法
フイブリノーゲン液（牛から得たフイブリ
ノーゲンをトリス−NaCl緩衝液に溶解した
0.5％フイブリノーゲン液、PH7.4）に抗トロ
ンビン剤のヘパリンを10U/ml添加した後、
及び該フイブリノーゲン液に製造例１で得た
マンネンタケ薬効成分を１mg/ml添加した液
にそれぞれトロンビンを0.2U/ml添加してそ
の凝固時間（秒）を測定し第３表に示した。[Table] B Discussion The more severe the destruction of red blood cells, the higher the permeability of blood, but when the medicinal ingredient of this invention is added to 500 μg/ml of blood, it has the same level of red blood cell membrane stabilizing effect as phenylbutazone. Recognize. 3. Platelet aggregation inhibitory effect When blood is in a hypercoagulable state, platelets in the bloodstream adhere to platelets attached to the site of blood vessel damage, forming platelet aggregates (white thrombus). At this time, if the body's fibrinolytic ability (ability to dissolve blood clots) is reduced or fibrinolytic enzymes do not work, such as in hyperlipidemia, the formed blood clots will not be dissolved. This condition causes intravascular thrombosis syndrome. Therefore, the platelet aggregation inhibitory effect is an important effect for the prevention and treatment of intravascular thrombosis syndrome. A Test method Compounds that aggregate platelets include ADP,
epinephrine, serotonin, thrombin,
There are certain types of fatty acids. Currently, it is believed that ADP plays the final role in platelet aggregation, and ADP itself is
It has the effect of releasing ADP. Therefore, ADP was used as the platelet aggregating agent. When platelets were taken from the blood of a healthy 20-year-old man and ADP (0.05 μM) was added to them (control example), the same blood was preliminarily treated with 1 mg of the medicinal ingredient of C. chinensis obtained in Production Example 1 per 1 ml of blood.
After ADP was added, the permeability of the platelet solution was measured in the same manner as in the control example, and the results are shown in FIGS. 7a and 7b, respectively. B. Discussion It can be seen that the above permeability is clearly lower and blood clotting is suppressed by adding the medicinal ingredient of C. chinensis in advance. 4. Antithrombin Effect At the site of vascular damage, fibrinogen is converted to fibrin by thrombin generated in the blood, causing the platelet aggregate to grow further and stopping bleeding. In such a state of hypercoagulation, it is thought that the precipitated fibrin accumulates within the blood vessel and becomes a thrombus. Therefore, the so-called antithrombin effect, which suppresses the action of thrombin, is an important effect for the prevention and treatment of intravascular thrombosis syndrome. A Test method Fibrinogen solution (fibrinogen obtained from cattle was dissolved in Tris-NaCl buffer)
After adding 10U/ml of heparin, an antithrombin agent, to 0.5% fibrinogen solution (PH7.4),
And to the fibrinogen solution to which 1 mg/ml of the medicinal ingredient obtained in Production Example 1 was added, thrombin was added at 0.2 U/ml, and the clotting time (seconds) was measured and shown in Table 3.
【表】
Ｂ 考察
上記の結果からこの発明のマンネンタケ薬
効成分には、ヘパリンほどではないが強い抗
トロンビン作用が認められる。またこの抗ト
ロンビン作用は、１の血管内血栓形成の抑制
作用の項で示したフイブリノーゲン量の減少
効果及びプロトロンビン時間の延長効果とあ
いまつて、この発明のマンネンタケ薬効成分
が血管内血栓形成症候群に対して有効なこと
を示している。
またこの発明のマンネンタケ薬効成分が赤
血球膜安定化作用を有することは２の赤血球
膜安定化作用の項で示したが、この作用と抗
トロンビン用とによつて主として静脈中に生
成する赤色血栓に特に有効であると考えられ
る。
５ 抗線溶活性化作用
正常な生体内において、血管損傷部位を覆つ
た血栓は、血管の修復と同時に溶解される。こ
のように析出したフイブリンを溶解する現象を
線溶といい、血栓の形成、成長を抑制する。血
栓の形成後、プラスミノーゲンをプラスミンに
活性化する物質であるプラスミン活性化因子群
が遊離し、これによつてプラスミンが活性化さ
れさらにこのプラスミンが血栓の主体であるフ
イブリンを溶解する。
Ａ 試験方法
プラスミン活性化因子としてウロキナーゼ
を用い被検液0.1mlにウロキナーゼ（100U/
ml）0.1mlを混ぜ30分後にフイブリン平板の
穴に20μずつ注入した。31℃、20hr放置後
フイブリン溶解円の直径を測定した。次いで
各種濃度のマンネンタケ薬効成分の溶液につ
いて試験したが、ほとんどこの線溶作用が認
められなかつた。そこで経口投与に近い状態
を想定し、マンネンタケ薬効成分を唾液酵素
アミラーゼで処理したものについて試験した
ところ抗線溶活性化作用が認められた。
この発明のマンネンタケ薬効成分の線溶活
性を示すために、前記ウロキナーゼの溶解円
の直径に対する前記アミラーゼ処理したマン
ネンタケ成分の溶解円の直径の百分率で表わ
し第４表に示した。[Table] B Discussion Based on the above results, the medicinal ingredient of the present invention shows that the active ingredient of Cinnamon chinensis has a strong antithrombin effect, although it is not as strong as that of heparin. In addition, this antithrombin effect, together with the fibrinogen level reducing effect and prothrombin time prolonging effect shown in section 1. This shows that it is effective. In addition, as shown in 2. Red blood cell membrane stabilizing effect, the medicinal ingredient of this invention has a red blood cell membrane stabilizing effect, and due to this effect and antithrombin effect, it is mainly effective against red blood clots formed in veins. It is considered to be particularly effective. 5. Anti-fibrinolytic activating effect In a normal living body, a thrombus covering a vascular injury site is dissolved at the same time as the blood vessel is repaired. The phenomenon of dissolving fibrin deposited in this manner is called fibrinolysis, which suppresses the formation and growth of thrombus. After the formation of a thrombus, plasmin activating factors, which are substances that activate plasminogen to plasmin, are released, plasmin is activated, and this plasmin dissolves fibrin, which is the main component of thrombus. A Test method Urokinase (100U/
ml) was mixed and 30 minutes later, 20μ aliquots were injected into the holes of the fibrin plate. After standing at 31°C for 20 hours, the diameter of the fibrin dissolution circle was measured. Next, we tested solutions of various concentrations of the medicinal ingredients of Cinnamon lucidum, but almost no fibrinolytic effect was observed. Therefore, when we tested the medicinal ingredients of C. chinensis treated with the salivary enzyme amylase, assuming conditions similar to oral administration, an anti-fibrinolytic activating effect was observed. In order to show the fibrinolytic activity of the medicinal ingredient of C. chinensis according to the present invention, it is expressed as a percentage of the diameter of the dissolution circle of the amylase-treated C. chinensis component relative to the diameter of the dissolution circle of the urokinase, and is shown in Table 4.
【表】
Ｂ 考察
この発明のマンネンタケ薬効成分の構成成
分は多糖類などの唾液中のアミラーゼによる
分解が考えられる。その結果、抗線溶性が認
められたのは特筆されるべきことである。
エンドトキシン投与による血管内血栓形成
症候群においては、凝固系の異常亢進と同時
に線溶系の異常亢進もみられるので、単純に
線溶活性化作用（ウロキナーゼ活性化作用）
が血管内血栓形成症候群に対し有効であると
はいいがたい。後記の臨床例の結果と考え合
わせると、この発明のマンネンタケ薬効成分
は、凝固系が亢進しているときはこれを抑制
し、線溶系が亢進しているときはこれを抑制
する所謂へモスタテイツク・バランスを保つ
のに有効な物質といえる。
６ 実験的肝静脈血栓症に対する作用
血液凝固の機構には血漿脂質が関係している
ことはよく知られており、この脂質の血液凝固
に及ぼす作用としては次のものが挙げられる。
血小板の粘着及び凝集の亢進（ある種の脂
肪酸は血小板を凝集させる）
凝固因子の活性化
線溶活性の低下。血栓の周りに脂質が付着
すると、線溶酵素のプラスミンが親水性のた
め、血栓の所まで行き着かないので、線溶さ
れないのである。
血管壁に脂質が沈着、すなわち、動脈硬化
をもつていると、種々の原因による血管炎を
起こしやすく、血管壁を構成しているコラー
ゲンが露出されて、血管内での血栓が形成さ
れやすい。
従つて、高脂血症では、凝固亢進状態にな
り、血栓をおこしやすい状態にあるといえる。
この試験ではラツトを高脂血状態にしておい
て次のような試験を行つた。
Ａ 試験方法
ウイスター系ラツト（〓、７週令）を合成
食餌（バター：30％；コレステロール：５
％；胆汁末：２％；粉末餌料：63％）で15週
間餌育した後、サルモネラ由来のエンドトキ
シン0.5mg/Kg体重を尾静脈注射した、このラ
ツトを対照例とし、一方該エンドトキシンを
尾静注する１週間前から毎日１回、製造例１
で得たマンネンタケ薬効成分を１ｇ/Kg体重
ずつ経口投与したラツトと比較した。
尾静脈注射して８時間後にエーテル麻酔下
で心臓より採血し、諸項目を測定した。また
８時間以内に死亡したものはその都度採血し
て測定した。その結果マンネンタケ成分が血
液学的には有効であるような結果は得られな
かつたが、生化学的検査（コレステロール、
中性脂肪）では若干血中脂質の低下作用が認
められた。
さらに上記２群のラツトについてその死亡
率の時間経過を第８図（ａ及びｂ）に示し
た。その結果対照例（第８図のａ）ではエン
ドトキシン注射後６時間で60％が死亡したの
に対し、マンネンタケ成分を予め経口投与し
た方（第８図のｂ）は注射後６時間で死亡し
たのは20％に過ぎない。また解剖して観察し
た結果、対照例では肝臓、腸管の各臓器には
著しい血栓形成と出血が認められたがマンネ
ンタケ成分投与群にはその傾向が少なく、明
らかにこの発明のマンネンタケ薬効成分が血
管内血栓形成を抑制していることが分かつ
た。
我々は日常生活上、生体が高脂血症となる
ような生活環境におかれており、また社会的
活動上、常にストレスをうけて生活してお
り、腸内の菌の分布異常による腸内菌毒素例
えばエンドトキシンにより、本実験系と同様
なことが、生体内で常におこりうる可能性を
はらんでいる。
上記の試験結果から、この発明のマンネンタ
ケ薬効成分は高脂血症を伴つた血管内血栓形成
症候群の予防及び治療に有効であると考えられ
る。
７ マンネンタケ薬効成分の急性毒性試験
ddY系マウス〓の４週令、１群５匹を用い、
各マウスを４時間絶食させた後、この発明のマ
ンネンタケ薬効成分の0.2％ナトリウムカルボ
キシメチルセルロース懸濁液として、50mg/Kg、
100mg/Kg、200mg/Kg、300mg/Kgを経口投与し
た。１週間観察を続けたが、各投与例とも特に
異常を認めなかつた。
次に臨床試験結果にてこの発明を説明する。
臨床試験には、製造例１で得られたマンネンタ
ケ薬効成分が１錠当り40mg含有する下記組成の錠
剤（Ｌ錠と称す）を用いた。
Ｌ錠4000錠調製用組成物
製造例１で得たマンネンタケ薬効成分 160ｇ
ボーンミール 200ｇ
コーンスターチ 90ｇ
乳 糖 148.4ｇ
ヒドロキシプロピルセルロース（結合剤）23.1ｇ 〃 〃 （崩解剤）18.5ｇ
合 計 640.0ｇ コーテイング剤 640.0ｇ
総 量 1280.0ｇ
注：マンネンタケ成分以外のものはいずれも日本
薬局方のものを使用した。
臨床例 １
男性 56才
20年前から慢性肝炎で、病院からも色々と薬を
もらつて服用したが、なおりきらず、５年前には
糖尿病で動脈硬化症でもあると言われた。
Ｌ錠を朝食、夕食の食前に１錠ずつ服用しはじ
めた所、下記のように自覚症状が著しく改善し、
血液検査値も有意に改善していた。明らかに血管
内血栓形成症候群の治療にも有効であると考えら
れる。[Table] B Discussion It is thought that the constituent components of the medicinal ingredient of the Cinnamon mushroom of this invention are degraded by amylase in saliva, such as polysaccharides. It is noteworthy that anti-fibrinolysis was observed as a result. In intravascular thrombosis syndrome caused by endotoxin administration, an abnormal increase in the coagulation system and an abnormal increase in the fibrinolytic system are observed, so it is simply a fibrinolytic activation effect (urokinase activation effect).
It is difficult to say that it is effective against intravascular thrombosis syndrome. When considered together with the results of the clinical examples described below, the medicinal ingredient of the present invention has the so-called hemostatic effect that suppresses the coagulation system when it is activated, and suppresses it when the fibrinolytic system is activated. It can be said to be an effective substance for maintaining balance. 6 Effects on experimental hepatic vein thrombosis It is well known that plasma lipids are involved in the mechanism of blood coagulation, and the effects of these lipids on blood coagulation include the following. Increased adhesion and aggregation of platelets (certain fatty acids cause platelets to aggregate) Activation of clotting factors Decreased fibrinolytic activity. When lipids adhere around a thrombus, the fibrinolytic enzyme plasmin is hydrophilic, so it cannot reach the thrombus and is not fibrinolyzed. When lipids are deposited on blood vessel walls, that is, arteriosclerosis occurs, vasculitis is likely to occur due to various causes, and the collagen that makes up the blood vessel walls is exposed, making it easy for blood clots to form within the blood vessels. Therefore, it can be said that hyperlipidemia leads to a state of hypercoagulation and a state where thrombosis is likely to occur. In this test, rats were kept in a hyperlipidemic state and the following tests were conducted. A Test method Wistar rats (7 weeks old) were fed a synthetic diet (butter: 30%; cholesterol: 5
%; bile powder: 2%; powdered feed: 63%) for 15 weeks, and then 0.5 mg/Kg body weight of endotoxin derived from Salmonella was injected into the tail vein.This rat was used as a control; Once a day for one week before injection, Manufacturing Example 1
A comparison was made with rats to which the medicinal ingredients of C. chinensis obtained were orally administered at a dose of 1 g/Kg body weight. Eight hours after the tail vein injection, blood was collected from the heart under ether anesthesia and various items were measured. In addition, blood was collected and measured each time the animal died within 8 hours. As a result, we were unable to obtain any results showing that the ingredients of C. chinensis were effective in terms of hematology, but biochemical tests (cholesterol,
A slight lowering effect on blood lipids (neutral fats) was observed. Further, the time course of the mortality rate of the two groups of rats mentioned above is shown in Figure 8 (a and b). As a result, 60% of the control cases (Figure 8 a) died 6 hours after endotoxin injection, whereas those who had been orally administered with the ingredients of C. chinensis (Figure 8 b) died 6 hours after the injection. is only 20%. Furthermore, as a result of autopsy and observation, significant thrombus formation and bleeding were observed in the liver and intestinal tract organs in the control cases, but this tendency was less in the group administered with the L. chinensis ingredient, and it is clear that the medicinal ingredients of the LL. It was found that internal thrombus formation was suppressed. In our daily lives, we live in environments where our bodies become hyperlipidemic, and we live under constant stress due to social activities. There is always a possibility that something similar to this experimental system could occur in vivo due to bacterial toxins such as endotoxin. From the above test results, it is considered that the medicinal ingredient of the present invention is effective in the prevention and treatment of intravascular thrombosis syndrome accompanied by hyperlipidemia. 7. Acute toxicity test of medicinal ingredients of C. chinensis Using 4-week-old ddY mice, 5 mice per group,
After each mouse was fasted for 4 hours, 50 mg/Kg of the medicinal ingredient of Cinderaceae of this invention as a 0.2% sodium carboxymethyl cellulose suspension,
100mg/Kg, 200mg/Kg, and 300mg/Kg were administered orally. Observation was continued for one week, but no particular abnormality was observed in each case. Next, this invention will be explained using clinical test results. Tablets with the following composition (referred to as L tablets) each containing 40 mg of the medicinal ingredient of Manchuria obtained in Production Example 1 were used in the clinical test. Composition for Preparing 4000 L Tablets Composition for Preparing 4000 Tablets Composition for Preparation Example 1. Medicinal ingredients of Cinnamon medicinal ingredients 160g Bone meal 200g Corn starch 90g Lactose 148.4g Hydroxypropyl cellulose (binder) 23.1g Disintegrant (disintegrant) 18.5g Total 640.0g Coating Agent: 640.0g Total amount: 1280.0g Note: All ingredients other than the ingredients of C. chinensis were used from the Japanese Pharmacopoeia. Clinical Case 1 A 56-year-old man had been suffering from chronic hepatitis for 20 years.He had received various medications from the hospital, but the symptoms did not get better, and five years ago he was told that he had diabetes and arteriosclerosis. When I started taking one L tablet before breakfast and one before dinner, my subjective symptoms improved significantly, as shown below.
Blood test values also improved significantly. It is clearly considered to be effective in the treatment of intravascular thrombosis syndrome.
【表】
〓耳鳴 ＋
− −
尚自覚症状のはかなり重度、＋中度
、−なし
臨床例 ２
男性59才
動脈硬化性高血圧で動悸、肩こりがひどく、血
圧も最高が178、最低が108と高く、そのほか血中
のコレステロール、中性脂肪、β−リポ蛋白も下
記のように高かつた。以前から服用している強心
剤ノイキノンと併用してＬ錠を、朝、晩食前に２
錠ずつ服用した所、６週間後には動悸も完全にな
くなり、肩こりもすつかりなくなつた。Ｌ錠はそ
の降圧作用以外に、血液の検査値からも、血管内
血栓形成症候群に有効であることが確認された。[Table] 〓Tinnitus +
− −
Subjective symptoms are quite severe, +moderate, and -noneClinical case 2 Male, 59 years old, has severe heart palpitations and stiff shoulders due to arteriosclerotic hypertension.His blood pressure is high, with a maximum of 178 and a minimum of 108.In addition, blood cholesterol and Sexual fat and β-lipoprotein were also high as shown below. Take 2 L tablets in the morning and before dinner in combination with the cardiotonic drug neuquinone that you have been taking.
I took it one tablet at a time, and after six weeks, my palpitations were completely gone and my stiff shoulders were gone. In addition to its antihypertensive effect, the L tablet was also confirmed to be effective against intravascular thrombosis syndrome based on blood test values.
【表】
臨床例 ３
女性 70才
浮腫と胸部苦悶感があり、血圧は220/110で、
心電図では、完全右脚ブロツクの心不全であつ
た。すぐに降圧剤と心臓薬を与えた所、１ヶ月後
に血圧は170/90となり、胸部痛も大分減つてき
た。そこでＬ錠を朝晩食前に２錠ずつ、心臓薬と
のみ併用し、降圧剤は中止した所、１ヶ月後の検
査では、血圧は140/82となり、その他の血液検査
値も下記のように改善された。自覚症状も全くな
くなつた。Ｌ錠の降圧作用と血管内血栓形成作用
の抑制効果がはつきりとでた症例であろう。[Table] Clinical case 3 A 70-year-old woman had edema and chest pain, and her blood pressure was 220/110.
An electrocardiogram showed complete right bundle branch block heart failure. We immediately gave him antihypertensive drugs and heart medication, and after a month, his blood pressure was 170/90, and his chest pain had significantly decreased. Therefore, I took two L tablets in the morning and before dinner in combination with my heart medication, and stopped taking antihypertensive drugs, and a test one month later showed that my blood pressure was 140/82, and other blood test values improved as shown below. It was done. All subjective symptoms disappeared. This is a case in which the antihypertensive effect and inhibitory effect on intravascular thrombus formation of L tablets were clearly demonstrated.
【表】
臨床例 ４
男性 62才
以前から高血圧症状(180/110)があつた。従つ
て、息切れもはげしく、時々動悸もあつた。その
後、胸部痛も発症し、Ｌ錠服用による、本格治療
を始めた。最初の１週間は、なんの変化もなかつ
たが、10日目位から、息切れ、動悸も、めだつて
減り、２ヶ月後には下記のように各検査値が改善
され、自覚症状もことごとく改善され、また血圧
も安定化(140/90)した。Ｌ錠が降圧作用及び血管
内血栓形成症候群に有効であつた好例であろう。[Table] Clinical case 4 Male, 62 years old, had had hypertension symptoms (180/110) for some time. As a result, he was severely short of breath and had palpitations at times. Afterwards, he developed chest pain and began full-scale treatment by taking L tablets. For the first week, there was no change, but from about the 10th day, shortness of breath and palpitations decreased noticeably, and after 2 months, various test values improved as shown below, and all subjective symptoms also improved. , blood pressure also stabilized (140/90). This is a good example of L tablets being effective in lowering blood pressure and treating intravascular thrombosis syndrome.
第１図はこの発明に係るマンネンタケ薬効成分
の赤外吸収スペクトル、第２図はその水溶液の紫
外吸収スペクトル、第３図はその水溶液の可視吸
収スペクトル、第４図は熱分解ガスクロマトグラ
ム、第５図、第６図は各々比較対照であるマルト
ース並びにデキストランの熱分解ガスクロマトグ
ラムである。第７図は血小板凝集抑制作用を測定
した透過度経時曲線である。第８図は実験的肝静
脈血栓症に対する作用の実験時のラツトの死亡率
の経時変化を示すグラフである。
Fig. 1 shows the infrared absorption spectrum of the medicinal ingredient of Cinnamon mushroom according to the present invention, Fig. 2 shows the ultraviolet absorption spectrum of its aqueous solution, Fig. 3 shows its visible absorption spectrum of the aqueous solution, Fig. 4 shows its pyrolysis gas chromatogram, and Fig. 5 shows its pyrolysis gas chromatogram. 6 and 6 are pyrolysis gas chromatograms of maltose and dextran, respectively, for comparison. FIG. 7 is a permeability time curve for measuring the platelet aggregation inhibitory effect. FIG. 8 is a graph showing changes over time in the mortality rate of rats during the experiment of the effect on experimental hepatic vein thrombosis.
Claims (1)
び1040cm-1に吸収極大を有する赤外吸収スペク
トル（KBr法）を示す、 ） 水溶液中で約257nm〜258nmに吸収極大を
有する紫外吸収スペクトルを示す、 ） 特有の可視吸収極大（水溶液中）を示さな
い、 ） フエーリング試薬に陽性、フエニルヒドラ
ジン試薬に疑陽性、アンスロン−硫酸試薬に疑
陽性、フエノール−硫酸試薬に対し陽性、ビユ
ーレツト反応試薬に陽性、リーベルマン−ブル
ヒアルト反応試薬に疑陽性、塩化第二鉄試薬に
疑陽性およびニンヒドリン反応試薬に陽性をそ
れぞれ示す、 ） 薄層クロマトグラフイー〔吸着層：シリカ
ゲル、展開剤：ｎ−ブタノール：イソプロパノ
ール：水（10：５：４）〕で、低分子の遊離の
糖およびアミノ酸がほとんど含まれない、 ） 元素分析で少なくとも炭素原子、水素原子
および窒素原子を含む、 ） 主としてグルコース、フコースおよび少量
のフルクトースを構成糖として含む、 ） フコースは多糖体の末端部に主として位置
し、グルコースはたとえば次に示すような、結
合割合となつている、 １−３ グルカン 45〜60％ １−４ グルカン 10〜20％ １−３，４ グルカン 10〜20％ その他 15〜25％ ） 熱水にわずかに溶解し、常温の水に対し
て、極めて溶け難い、常温のメタノールに極め
て溶け難い、 ） 熱分解ガスクロマトグラフイー（分解温度
350℃）で６個のピークを示す、 で特徴付けられるマンネンタケの薬効成分を有効
成分として含有することからなる血管内血栓形成
症候群の予防と治療用組成物。 ２ 経口投与用である特許請求の範囲第１項記載
の組成物。[Claims] 1) exhibits an infrared absorption spectrum (KBr method) having absorption maxima at approximately 3450, 2970, 1700, 1460, 1390 and 1040 cm -1 ; ) exhibits an absorption maximum at approximately 257 nm to 258 nm in an aqueous solution; ) Shows no characteristic visible absorption maximum (in aqueous solution); ) Positive for Fehling's reagent, false positive for phenylhydrazine reagent, false positive for Anthrone-sulfuric acid reagent, positive for phenol-sulfuric acid reagent , positive for Buuretz reaction reagent, false positive for Lieberman-Burchart reaction reagent, false positive for ferric chloride reagent, and positive for ninhydrin reaction reagent, respectively) Thin layer chromatography [Adsorption layer: silica gel, developer: n-butanol:isopropanol:water (10:5:4), contains almost no small free sugars and amino acids, contains at least carbon, hydrogen and nitrogen atoms according to elemental analysis, contains mainly glucose , contains fucose and a small amount of fructose as constituent sugars, ) Fucose is mainly located at the terminal end of the polysaccharide, and glucose has a binding ratio as shown below, for example: 1-3 Glucan 45-60% 1 -4 Glucan 10-20% 1-3,4 Glucan 10-20% Others 15-25%) Slightly soluble in hot water, extremely insoluble in water at room temperature, extremely insoluble in methanol at room temperature, ) Pyrolysis gas chromatography (decomposition temperature
A composition for the prevention and treatment of intravascular thrombosis syndrome, which contains as an active ingredient a medicinal ingredient of Cinnamon lucidum, which exhibits six peaks at 350°C). 2. The composition according to claim 1, which is for oral administration.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP55187752A JPS57112331A (en) | 1980-12-29 | 1980-12-29 | Medical composition of ganoderma lucidum component |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP55187752A JPS57112331A (en) | 1980-12-29 | 1980-12-29 | Medical composition of ganoderma lucidum component |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS57112331A JPS57112331A (en) | 1982-07-13 |
| JPH0148249B2 true JPH0148249B2 (en) | 1989-10-18 |
Family
ID=16211574
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP55187752A Granted JPS57112331A (en) | 1980-12-29 | 1980-12-29 | Medical composition of ganoderma lucidum component |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS57112331A (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60184025A (en) * | 1984-03-02 | 1985-09-19 | Toyo Yakushiyoku Kogyo Kk | Polysaccharide, separation and use thereof |
| JP4536360B2 (en) * | 2003-11-28 | 2010-09-01 | 日本メナード化粧品株式会社 | Antithrombotic |
| JP4607484B2 (en) * | 2004-04-09 | 2011-01-05 | 日本メナード化粧品株式会社 | Cancer metastasis inhibitor |
| JP4643936B2 (en) * | 2004-07-21 | 2011-03-02 | 日本メナード化粧品株式会社 | Thrombosis ameliorating agent |
| JP2012131754A (en) * | 2010-12-24 | 2012-07-12 | Nippon Menaade Keshohin Kk | Antithrombotic agent |
| CN103616339B (en) * | 2013-11-07 | 2017-01-18 | 培力(南宁)药业有限公司 | Detection method for preparation containing ganoderan |
| JP6042500B2 (en) * | 2015-07-21 | 2016-12-14 | 日本メナード化粧品株式会社 | Antithrombotic |
-
1980
- 1980-12-29 JP JP55187752A patent/JPS57112331A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS57112331A (en) | 1982-07-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4405596A (en) | Pharmaceutical preparations for and treatment procedures involving increasing plasma bicarbonate level | |
| JPS6324976B2 (en) | ||
| US20060068043A1 (en) | Composition for treating chronic venous insufficiencies using an extract of red vine leaves | |
| JP3714426B2 (en) | Cancer metastasis inhibitor containing fucoidan oligosaccharide composition | |
| KR950009094B1 (en) | Pharmaceutical compositions containing pyridoxine derivatives for use in the prevention and treatment of hyperlipemia and atherosclerosis | |
| EP2035027A1 (en) | Therapeutic uses of tomato extracts | |
| WO1999001144A1 (en) | Peritoneal dialysis fluid | |
| JPH03366B2 (en) | ||
| US4985248A (en) | Pharmaceutical composition containing a safe extracts of fruits and vegetables for the treating and preventing of diabetes | |
| JPH0148249B2 (en) | ||
| JPS6237615B2 (en) | ||
| EP0630649A1 (en) | Combination of an inhibitor of inducible nitric oxide synthase (iNOS) and an antiinflammatory agent, e.g. a corticosteroid | |
| JPS62255430A (en) | Treatment for mammalian vas disease | |
| WO2005110383A1 (en) | The use of kauranes compounds in the manufacture of medicament | |
| KR20200062784A (en) | Anti-Thrombotic Composition Comprising Fermented Garlic | |
| WO2016079553A1 (en) | A method and a composition having prophylactic activity against venoms and toxins | |
| WO2009000150A1 (en) | The use of sanchinoside in treating septicemia | |
| JPS6213927B2 (en) | ||
| JPS636527B2 (en) | ||
| KR100345040B1 (en) | The Product for Improving the Blood Circulation with Mixtures of Red Ginseng and Natural Substances and Manufacturing Method Theirof | |
| JP2783367B2 (en) | Heparin-containing preparations | |
| KR100832321B1 (en) | Healthy food comprising Red ginseng acid polysaccharide for hyperlipidemia improvement | |
| US4919933A (en) | Method for the treatment of dental disease | |
| JPH0426624A (en) | Remedy for chronic renal failure | |
| JPH0212449B2 (en) |