JPS6157808B2 - - Google Patents
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- Publication number
- JPS6157808B2 JPS6157808B2 JP2227880A JP2227880A JPS6157808B2 JP S6157808 B2 JPS6157808 B2 JP S6157808B2 JP 2227880 A JP2227880 A JP 2227880A JP 2227880 A JP2227880 A JP 2227880A JP S6157808 B2 JPS6157808 B2 JP S6157808B2
- Authority
- JP
- Japan
- Prior art keywords
- cardiac
- effects
- effect
- observed
- heart
- 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
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- 239000004480 active ingredient Substances 0.000 claims description 6
- 239000000496 cardiotonic agent Substances 0.000 claims description 6
- 230000000694 effects Effects 0.000 description 23
- 230000000747 cardiac effect Effects 0.000 description 16
- 238000000034 method Methods 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 10
- 241000283973 Oryctolagus cuniculus Species 0.000 description 7
- 230000002964 excitative effect Effects 0.000 description 7
- 230000033001 locomotion Effects 0.000 description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 241000599931 Paris quadrifolia Species 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 229930182470 glycoside Natural products 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 241000196324 Embryophyta Species 0.000 description 4
- 206010060891 General symptom Diseases 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 231100000517 death Toxicity 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 230000001052 transient effect Effects 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- -1 L-rhamnopyranosyl Chemical group 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229940097217 cardiac glycoside Drugs 0.000 description 3
- 239000002368 cardiac glycoside Substances 0.000 description 3
- 150000002338 glycosides Chemical class 0.000 description 3
- 230000001766 physiological effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229930002534 steroid glycoside Natural products 0.000 description 3
- 150000008143 steroidal glycosides Chemical class 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- FBFJAXUYHGSVFN-IYUYFXHASA-N 68124-04-9 Chemical compound C([C@@]12[C@H]([C@@]3([C@@]4(C)CC[C@@H]5[C@@]6(C)CC[C@@H](CC6=CC[C@H]5[C@@H]4C[C@@H]3O2)O[C@H]2[C@@H]([C@@H](O)[C@H](O[C@H]3[C@@H]([C@H](O)[C@@H](O[C@H]4[C@@H]([C@H](O)[C@@H](O)[C@H](C)O4)O)[C@H](C)O3)O)[C@@H](CO)O2)O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)O)C)C[C@@H](C)CO1 FBFJAXUYHGSVFN-IYUYFXHASA-N 0.000 description 2
- 206010003591 Ataxia Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000208011 Digitalis Species 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000234280 Liliaceae Species 0.000 description 2
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 2
- 206010038678 Respiratory depression Diseases 0.000 description 2
- 206010039897 Sedation Diseases 0.000 description 2
- IUJDSEJGGMCXSG-UHFFFAOYSA-N Thiopental Chemical compound CCCC(C)C1(CC)C(=O)NC(=S)NC1=O IUJDSEJGGMCXSG-UHFFFAOYSA-N 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 230000004531 blood pressure lowering effect Effects 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 230000003177 cardiotonic effect Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 210000003191 femoral vein Anatomy 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 210000001699 lower leg Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000000401 methanolic extract Substances 0.000 description 2
- SYYHBUHOUUETMI-WJOMMTHPSA-N pennogenin Chemical compound C([C@@]12[C@H]([C@@]3([C@@]4(C)CC[C@@H]5[C@@]6(C)CC[C@H](O)CC6=CC[C@H]5[C@@H]4C[C@@H]3O2)O)C)C[C@@H](C)CO1 SYYHBUHOUUETMI-WJOMMTHPSA-N 0.000 description 2
- GZMJEZQPYGGHGJ-UHFFFAOYSA-N pennogenin tetraglycoside Natural products O1C2CC3C4CC=C5CC(OC6C(C(O)C(O)C(CO)O6)OC6C(C(O)C(OC7C(C(O)C(OC8C(C(O)C(O)C(C)O8)O)C(C)O7)O)C(C)O6)O)CCC5(C)C4CCC3(C)C2(O)C(C)C21CCC(C)CO2 GZMJEZQPYGGHGJ-UHFFFAOYSA-N 0.000 description 2
- 230000036280 sedation Effects 0.000 description 2
- 230000004622 sleep time Effects 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 229960003279 thiopental Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000269350 Anura Species 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- TYYDXNISHGVDGA-UHFFFAOYSA-N Corotoxigenin Natural products CC12CCC3C(CCC4CC(O)CCC34C=O)C1CCC2C5=CC(=O)OC5 TYYDXNISHGVDGA-UHFFFAOYSA-N 0.000 description 1
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 1
- WDJUZGPOPHTGOT-OAXVISGBSA-N Digitoxin Natural products O([C@H]1[C@@H](C)O[C@@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@@](C)([C@H](C6=CC(=O)OC6)CC5)CC4)CC3)CC2)C[C@H]1O)[C@H]1O[C@@H](C)[C@H](O[C@H]2O[C@@H](C)[C@@H](O)[C@@H](O)C2)[C@@H](O)C1 WDJUZGPOPHTGOT-OAXVISGBSA-N 0.000 description 1
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 241000006064 Heloniopsis orientalis Species 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- 206010020852 Hypertonia Diseases 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- GMBQZIIUCVWOCD-UQHLGXRBSA-N Isosarsasapogenin Natural products O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)C[C@H]4CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 GMBQZIIUCVWOCD-UQHLGXRBSA-N 0.000 description 1
- SHZGCJCMOBCMKK-JFNONXLTSA-N L-rhamnopyranose Chemical compound C[C@@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O SHZGCJCMOBCMKK-JFNONXLTSA-N 0.000 description 1
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 description 1
- 241000234435 Lilium Species 0.000 description 1
- 241000555684 Paris verticillata Species 0.000 description 1
- SYYHBUHOUUETMI-UHFFFAOYSA-N Pennogenin Natural products O1C2CC3C4CC=C5CC(O)CCC5(C)C4CCC3(C)C2(O)C(C)C21CCC(C)CO2 SYYHBUHOUUETMI-UHFFFAOYSA-N 0.000 description 1
- 241000270934 Rana catesbeiana Species 0.000 description 1
- 206010038687 Respiratory distress Diseases 0.000 description 1
- 244000166550 Strophanthus gratus Species 0.000 description 1
- 241000219793 Trifolium Species 0.000 description 1
- 241000245029 Trillium camschatcense Species 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 238000013155 cardiography Methods 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- SIHHLZPXQLFPMC-UHFFFAOYSA-N chloroform;methanol;hydrate Chemical compound O.OC.ClC(Cl)Cl SIHHLZPXQLFPMC-UHFFFAOYSA-N 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960000648 digitoxin Drugs 0.000 description 1
- WDJUZGPOPHTGOT-XUDUSOBPSA-N digitoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)CC5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O WDJUZGPOPHTGOT-XUDUSOBPSA-N 0.000 description 1
- 229960005156 digoxin Drugs 0.000 description 1
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 1
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000005021 gait Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- 238000009115 maintenance therapy Methods 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 230000037000 normothermia Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 235000017807 phytochemicals Nutrition 0.000 description 1
- 229930000223 plant secondary metabolite Natural products 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229930002600 steroidal saponin Natural products 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Description
【発明の詳細な説明】
〔〕 発明の背景
本発明は、ペンノゲニンテトラグリコシド（以
下、Tgということがある）を有効成分とする強
心剤に関する。DETAILED DESCRIPTION OF THE INVENTION [] Background of the Invention The present invention relates to a cardiotonic agent containing pennogenin tetraglycoside (hereinafter sometimes referred to as Tg) as an active ingredient.
本発明者らは、ユリ科植物Paris quadrifolia
（ヨーロツパ産）をメタノールに付し、得られる
メタノール抽出物を分離精製して得られた抽出物
のある画分についてその分析を行なつたところ、
この化合物はおおばなのえんれいそう等から得ら
れるペンノゲニンテトラグリコシド（Tg）と同
一であること、ならびにTgが強心作用を有する
ことを見出した。 The present inventors have discovered that the liliaceous plant Paris quadrifolia
(produced in Europe) was subjected to methanol, the resulting methanol extract was separated and purified, and a certain fraction of the resulting extract was analyzed.
It was discovered that this compound is the same as pennogenine tetraglycoside (Tg) obtained from neritic root and that Tg has cardiotonic effects.
〔〕 発明の概要 要 旨 本発明はこの発見に基くものである。[] Summary of the invention Summary The present invention is based on this discovery.
従つて、本発明による強心剤は、ペンノゲニン
―３―Ｏ―α―Ｌ―ラムノピラノシル（１→４）
―α―Ｌ―ラムノピラノシル（１→４）―〔α―
Ｌ―ラムノピラノシル（１→２）〕―β―Ｄ―グ
ルコピラノシドを有効成分とすること、を特徴と
するものである。 Therefore, the cardiotonic agent according to the present invention comprises pennogenin-3-O-α-L-rhamnopyranocyl (1→4)
-α-L-rhamnopyranosyl (1→4)-[α-
It is characterized by containing L-rhamnopyranosyl (1→2)]-β-D-glucopyranoside as an active ingredient.
効 果
従来公知の強心糖体はカルデノリド配糖体（ジ
ギタリス、ストロフアンツス型）およびブフオジ
エノリド配糖体に限られているが、Tgのような
スピロスタノールの配糖体において初めて心臓興
奮作用が発見されたことは極めて注目されるとこ
ろである。Effects Conventionally known cardiotonic glycosides are limited to cardenolide glycosides (digitalis, strophanthus type) and bufodienolide glycosides, but cardiac excitatory effects were discovered for the first time in spirostanol glycosides such as Tg. This is something that deserves a lot of attention.
〔〕 発明の具体的説明
１ Tg
(1) 化学構造
本発明による強心剤の有効成分であるTg
は、下記の一般式で表わされる。[] Detailed description of the invention 1 Tg (1) Chemical structure Tg which is the active ingredient of the cardiotonic agent according to the present invention
is expressed by the following general formula.
ユリ科植物Paris quadrifolia（ヨーロツパ
産）から抽出回収されたこの化合物はTLC
のRf値、発色およびIRの検討によりペンノ
ゲニン（pennogenin）の配糖体であること
が推定され、T.kamtschaticum（おおばな
のえんれいそう）、Heloniopsis orientalis
Thund（しようじようばかま）およびParis
tetrophylla（つくばねそう）より得られた
ペンノゲニンテトラグリコシドと比較したと
ころ、融点（混融）、旋光度、IRおよびTLC
のいずれの観点からもこの公知のTgと一致
した。 This compound, extracted and recovered from the lily plant Paris quadrifolia (from Europe), was analyzed by TLC.
It is estimated that it is a glycoside of pennogenin by examining the Rf value, color development, and IR of T. kamtschaticum, Heloniopsis orientalis.
Thund and Paris
Melting point (mixed melt), optical rotation, IR and TLC compared with pennogenin tetraglycoside obtained from Tetrophylla (Tsukubanesou).
The Tg was consistent with this known Tg in all respects.
すなわち、この化合物は、ペンノゲニン―
３―Ｏ―α―Ｌ―ラムノピラノシル（１→
４）―α―Ｌ―ラムノピラノシル（１→４）
―〔α―Ｌ―ラムノピラノシル（１→２）〕
―β―Ｄ―グルコピラノシドである。 That is, this compound is pennogenin-
3-O-α-L-rhamnopyranosyl (1→
4)-α-L-rhamnopyranosyl (1→4)
- [α-L-rhamnopyranosyl (1 → 2)]
-β-D-glucopyranoside.
この化合物（ｎ―ブタノールからの再結晶
品）の理化学的性質の一部を示せば、下記の
通りである。 Some of the physical and chemical properties of this compound (recrystallized from n-butanol) are as follows.
外 観 無色針状晶
融 点 256〜258℃（分解）
〔α〕１９ Ｄ −108.3°（Ｃ＝１、MeOH）
IRνＫＢｒ ｎａｘ cm-1 3700−3020（OH）、980、91
5、
900、885（スピロケタール）
TLC Rf 0.76
展開溶媒 CHCl3−MeOH−H2O
（７：３：0.5）
発色試薬 10％H2SO4−MeOH
(2)取 得
本発明で使用するTgは、公知の植物から
のTg、すなわちおおばなのえんれいそう
（Chem.Pharm.Bull.（Tokyo）23、872
（1975））、しようじようばかま（Chem.
Pharm.Bull.23、925（1975））、およびつくば
ねそう（日本薬学会第95年会（西宮）要旨集
、第257頁（1975）、からのもの、と同一で
ある。従つて、本発明で使用するTgは、こ
れら公知のものとして取得することができ
る。Appearance Colorless needle crystals Melting point 256-258℃ (decomposed) [α] 19 D -108.3° (C=1, MeOH) IRν KBr nax cm -1 3700-3020 (OH), 980, 91
Five,
900, 885 (Spiroketal) TLC Rf 0.76 Developing solvent CHCl 3 -MeOH-H 2 O (7:3:0.5) Coloring reagent 10% H 2 SO 4 -MeOH (2) Obtaining Tg used in the present invention is known Tg from the plant, that is, Obana trifolium (Chem.Pharm.Bull. (Tokyo) 23 , 872
(1975)), Shōji Yobakama (Chem.
Pharm.Bull. 23 , 925 (1975)) and Tsukubaneso (Collection of Abstracts of the 95th Annual Meeting of the Pharmaceutical Society of Japan (Nishinomiya), p. 257 (1975). Therefore, this book The Tg used in the invention can be obtained from these known Tg's.
Tgは、ユリ科植物Paris quadrifoliaの抽
出により取得することもできる。この場合の
抽出の一例を示せば下記の通りである。
Paris quadrifolia Linn.の全草（1.87Kg）を
冷メタノール（10リツトル）に浸漬して、メ
タノール抽出エキスを得る。このエキスをｎ
―ブタノール／水で有機層と水性層とに分
け、有機層をクロロホルムで処理して、クロ
ロホルム不溶部を得る。このクロロホルム不
溶部にｎ―ブタノール／酢酸エチル（１：
４）と水とを加えて、有機層と水性層とに分
ける。この有機層についてシルカゲルカラム
クロマトグラフイーを繰返して、Tg（620
mg）を得る。 Tg can also be obtained by extracting Paris quadrifolia, a plant of the lily family. An example of extraction in this case is as follows.
The whole plant of Paris quadrifolia Linn. (1.87Kg) is soaked in cold methanol (10 liters) to obtain methanol extract. This extract
- Separate into an organic layer and an aqueous layer with butanol/water, and treat the organic layer with chloroform to obtain a chloroform-insoluble part. Add n-butanol/ethyl acetate (1:
4) and water are added to separate into an organic layer and an aqueous layer. This organic layer was subjected to repeated silica gel column chromatography and Tg (620
mg).
Tgはまた、ユリ科の他の植物、すなわち
Paris verticillata M.V.Bieb（くるまつくば
ねそう）、から抽出により得ることもでき
る。 Tg is also used in other plants of the Liliaceae family, viz.
It can also be obtained by extraction from Paris verticillata MVBieb.
２ 強心剤
(1) Tgの心臓興奮作用
Tgは心臓興奮作用という薬理作用を有す
る。2 Cardiotropes (1) Cardiac excitatory action of Tg Tg has a pharmacological action of cardiac excitatory action.
Tgの心臓興奮作用は、後記実験例に示す
通りである。 The cardiac excitatory effect of Tg is as shown in the experimental examples below.
(2) 毒 性
後記実験例の結果によれば、マウス腹腔内
投与時のLD50は、30（25−37）mg／Kgであ
る。 (2) Toxicity According to the results of the experimental examples described below, the LD 50 when administered intraperitoneally to mice is 30 (25-37) mg/Kg.
(3) 剤形、投与方法および有効量
強心配糖体を有効成分とする強心剤は公知
である、本発明での強心配糖体もこれら公知
の強心剤に実用あるいは採用されうる剤形、
投与方法および有効量のものとして製剤化す
ることができる。 (3) Dosage form, administration method, and effective amount Cardiotropes containing cardiac glycosides as active ingredients are known.
The method of administration and effective amount can be formulated.
ちなみに、強心配糖体の一つの代表例であ
るジギタリス製剤の場合に、たとえばジゴキ
シンおよびジギトキシンは維持療法として用
いる場合の１日当りの経口投与量がそれぞれ
0.125〜0.75mgおよび0.05〜0.15mgとされてお
り、また投与法として経口および静注があげ
られている（「医薬ジヤーナル」第15巻、第
６号、第843頁（1979年））。 By the way, in the case of digitalis preparations, which are representative examples of cardiac glycosides, for example, the daily oral dosage of digoxin and digitoxin when used as maintenance therapy is
It is said to be 0.125 to 0.75 mg and 0.05 to 0.15 mg, and oral and intravenous injections are listed as administration methods ("Yakuhaku Journal" Vol. 15, No. 6, p. 843 (1979)).
３ その他の生理活性
本発明はTgを有効成分とする強心剤に関す
るが、Tgを強心剤として使用するに際しては
この化合物の心臓興奮作用以外の生理活性につ
いても考慮する必要があろう。3. Other Physiological Activities The present invention relates to a cardiotonic agent containing Tg as an active ingredient, but when using Tg as a cardiotonic agent, it is necessary to consider the physiological activities of this compound other than the cardiac excitatory effect.
Tgの心臓興奮作用以外の生理活性について
は前記した公知文献を参照されたいが、Paris
quadrifoliaから抽出したTgについて得られた
薬理作用と循環系におよぼす影響を検討した結
果を簡単に示せば、後記した通りである。 Regarding the physiological activities of Tg other than the cardiac excitatory effect, please refer to the above-mentioned known documents, but Paris
The following is a brief summary of the results of examining the pharmacological effects and effects on the circulatory system of Tg extracted from quadrifolia.
４ 実験例
１ 実験材料ならびに方法
(1) 実験材料 実験に使用した動物はddY系
雄性マウス、ウシガエルならびに雄性白色
ウサギであり、各動物の体重および使用匹
数は実験方法の項で述べる。4 Experimental Examples 1 Experimental Materials and Methods (1) Experimental Materials The animals used in the experiments were ddY male mice, bullfrogs, and male white rabbits, and the weights of each animal and the number of animals used are described in the experimental methods section.
本実験に用いたTgは九州大学薬学部植
物薬品化学教室でParis quadrifoliaから抽
出された白色針状結晶の粉末で、
pennogenin骨格の３位の水酸基に１ケの
glucoseと３ケのrhamnoseが結合してステ
ロイド系サポニンの構造を有したものであ
る。本試験物質は0.5％のカルボキシメチ
ルセルロース（CMC）溶液に懸濁して、
マウスでは0.1ml／10ｇとなるように調製
して腹腔内に投与した。また、ウサギでは
0.1ml／Kgとなるように調製して大股静脈
より投与した。 The Tg used in this experiment was a powder of white needle-like crystals extracted from Paris quadrifolia at the Department of Phytochemical Chemistry, Faculty of Pharmaceutical Sciences, Kyushu University.
One hydroxyl group at the 3rd position of the pennogenin skeleton
It has the structure of steroidal saponin, which is a combination of glucose and three rhamnose. The test substance was suspended in a 0.5% carboxymethyl cellulose (CMC) solution.
For mice, the solution was prepared at 0.1 ml/10 g and administered intraperitoneally. Also, in rabbits
The dose was prepared at 0.1 ml/Kg and administered through the femoral vein.
(2) 実験方法
(1) 一般症状の観察
体重18―20ｇのddY系雄系マウス18匹
を使用してTgの腹腔内投与による一般
症状の変化を検討した。１群３匹のマウ
スにTgの各用量を投与し、体位、歩行
その他の一般症状を観察した。また致死
作用についても検討しLD50をLitchfied
―Wilcoxon法（J.Pharmacol.exp.Ther.
96、99（1949））により算出した。 (2) Experimental method (1) Observation of general symptoms Changes in general symptoms due to intraperitoneal administration of Tg were examined using 18 male ddY mice weighing 18-20 g. Each dose of Tg was administered to 3 mice per group, and body position, gait, and other general symptoms were observed. We also examined the lethal effect and Litchfied LD 50 .
―Wilcoxon method (J.Pharmacol.exp.Ther.
96 , 99 (1949)).
(2) 心臓におよぼす影響
(2‐1) カエル摘出心臓に対する作用
ウシガエル８匹を用いて八木―
Hartung法によつて心臓を摘出し、そ
の心運動に対するTgの影響を検討し
た。なお心運動の記録はキモグラフイ
オン上に描記した。被検物質はカエル
用リンゲル液に溶解したものを心臓の
動きが一定になつてから静脈カニユー
レ（容積３c.c.）内に応用した。 (2) Effects on the heart (2-1) Effects on isolated frog hearts Yagi-
The heart was removed using the Hartung method and the influence of Tg on cardiac motion was investigated. Note that the recording of cardiac motion was drawn on a kymograph ion. The test substance was dissolved in Ringer's solution for frogs and was applied into the venous cannula (volume 3 c.c.) after the heart movement had stabilized.
(2‐2) ウサギ生体心臓に対する作用
体重1.8―2.5Kgの白色ウサギ５匹を
使用し、urethane1ｇ／Kg皮下注射麻
酔の下に貫式カルジオンタンプール法
（日薬理誌、58、127（1962））によつ
て心運動を心尖および心側運動に分け
てキモグラフオン上に描記した。同時
に呼吸を気管カニユーレおよびタンプ
ールで、頚動脈圧を動脈カニユーレお
よび水銀マノメーターを介してそれぞ
れキモグラフオンに描記した。なお被
検物質は溶媒（プロピレングリコール
40％、エタノール10％）に溶解して大
股静脈に挿入したカテーテルより投与
した。 (2-2) Effect on living rabbit heart Using five white rabbits weighing 1.8-2.5 kg, the transcardial tamphole method was administered under anesthesia by subcutaneous injection of urethane (1 g/kg) (Japanese Pharmacological Journal, 58 , 127 (1962). )) The cardiac motion was divided into apical and ventral motion and drawn on the kymograph. At the same time, respiration was recorded via the tracheal cannula and tampon, and carotid artery pressure was recorded on the kymograph via the arterial cannula and mercury manometer, respectively. The test substance is a solvent (propylene glycol).
40% and ethanol (10%)) and administered through a catheter inserted into the femoral vein.
２ 実験結果
(1) 一般症状の観察
Tgの２―10mg／Kgを腹腔内に注射する
と、投与後0.5―１時間にマウスの活動性
は軽度に増加し、その後わずかの鎮静状態
を示した。外来音刺激に対する反応は正常
であつた。またこれらの用量で、体温下降
もみられたが、筋弛緩や運動失調などは認
められなかつた。50mg／Kgの投与では鎮静
状態が著明で死亡例も認められた。死亡例
では、著しい運動失調がみられ、苦悶状態
の後呼吸困難で死亡した。なおTgのマウ
ス腹腔内投与時のLD50は30（25―37）
mg／Kgであつた。 2. Experimental Results (1) Observation of General Symptoms When 2-10 mg/Kg of Tg was injected intraperitoneally, the activity of mice increased slightly 0.5-1 hour after administration, and thereafter they showed a slight state of sedation. Responses to extraneous sound stimuli were normal. At these doses, a decrease in body temperature was also observed, but no muscle relaxation or ataxia were observed. Administration of 50 mg/Kg resulted in marked sedation and even death. In the case of death, severe ataxia was observed, and the patient died from respiratory distress after being in a state of agony. The LD 50 of Tg when administered intraperitoneally to mice is 30 (25-37).
It was mg/Kg.
(2) 心臓におよぼす影響
(2‐1) カエル摘出心臓に対する作用
カエル摘出心臓を用いた八木―Hartung
法によるTgの作用については、Tg3.3×
10-7ｇ／mlの応用では認むべき変化は認め
られなかつたが、3.3×10-6ｇ／mlの応用
では投与直後に一過性の心臓興奮、その後
さらに持続的な心臓興奮が認められた。ま
たリンゲル液で洗浄するとこれらの興奮作
用は回復した。この作用パターンは
ATP3.3×10-5ｇ／mlの応用時と類似して
いた。Tg3.3×10- 5ｇ／mlを応用すると基
線の著明な上昇が認められた。この現象
は、Ｇ―ストロフアンチン7.5×10- 3ｇ／
mlの応用時と類似していた。この濃度にな
るとリンゲル液で洗浄しても、投与前の幅
までは回復しなかつた。またTg各濃度投
与では心拍数には殆ど変化を示さなかつ
た。 (2) Effect on the heart (2-1) Effect on the removed frog heart Yagi-Hartung using the removed frog heart
Regarding the effect of Tg according to the method, Tg3.3×
No appreciable change was observed when applying 10 -7 g/ml, but when applying 3.3 x 10 -6 g/ml, transient cardiac excitation was observed immediately after administration, followed by sustained cardiac excitation. It was done. Furthermore, these excitatory effects were restored after washing with Ringer's solution. This pattern of action is
It was similar to that when ATP 3.3×10 -5 g/ml was applied. When Tg3.3×10 −5 g /ml was applied, a marked increase in the baseline was observed. This phenomenon is caused by G-strophanthine 7.5×10 - 3 g/
It was similar to the application of ml. At this concentration, even when washed with Ringer's solution, the width could not be restored to the width before administration. Furthermore, there was almost no change in heart rate when Tg was administered at each concentration.
(2‐2) ウサギ生体心臓におよぼす影響
Tgのウサギ生体心臓におよぼす影響を
貫式カージオグラフ法で検討した結果で
は、溶媒を投与しても何ら作用は認められ
なかつたが、Tg0.5mg／Kgを投与すると一
過性の血圧下降と呼吸抑制がみられた。ま
た心尖運動については頂点および脚点の上
昇がみられ、右心側では頂点および脚点の
下降が認められた。なおTg1―２mg／Kgの
応用では死亡する例もあらわれた。 (2-2) Effects of Tg on living rabbit hearts The results of examining the effects of Tg on living rabbit hearts using transcardial cardiography showed that no effect was observed even when the solvent was administered, but 0.5 mg of Tg /Kg, a transient drop in blood pressure and respiratory depression were observed. Regarding the apex movement, an increase in the apex and crus was observed, and a decrease in the apex and crus on the right side of the heart. In addition, some cases of death occurred when Tg1-2mg/Kg was applied.
３ 考 察
(1) Tgの一般薬理作用および循環系におよ
ぼす影響
Tgはオープンフイールド法およびフオ
トセル法におけるマウス自発運動には影響
を与えなかつた。またTg2―10mg／Kgの投
与では筋弛緩作用も認められなかつた。し
かしながら、thiopentalによる睡眠に関し
てはTgの２および５mg／Kgの投与で
thicpental睡眠時間の短縮が認められ、逆
に10および20mg／Kgでは延長が認められ
た。この二相性の作用はTgの少量で弱い
中枢性の作用を有していると考えられる。
また大量投与時のthiopental睡眠の延長作
用は毒性が強いことからも選択的な作用と
は考え難い。Tgは、マウスの正常体温を
下降させた。Tgは他の中枢作用をあまり
有していないので、体温中枢に対する選択
的な作用かもしれない。いずれにせよ、
Tgの中枢性の作用は少ないものと考えう
る。 3. Discussion (1) Effects of Tg on the general pharmacological effects and circulatory system Tg had no effect on the locomotor activity of mice in the open field method and photocell method. Furthermore, no muscle relaxant effect was observed when Tg2-10mg/Kg was administered. However, regarding sleep due to thiopental, Tg doses of 2 and 5 mg/Kg
A reduction in thicpental sleep time was observed, and an increase in thicpental sleep time at 10 and 20 mg/Kg. This biphasic effect is thought to have a weak central effect with a small amount of Tg.
In addition, the effect of prolonging thiopental sleep when administered in large doses is highly toxic, so it is difficult to believe that it is a selective effect. Tg lowered normothermia in mice. Since Tg does not have many other central effects, it may be a selective action on the temperature center. in any case,
The central effects of Tg can be considered to be small.
循環系におよぼす影響について検討した
結果については、Tg1―20mg／Kgのマウス
尾静脈投与で一過性の血圧下降を起こし20
mg／Kg以上の濃度では死亡例もみられた。
この血圧下降作用は副交感神経末梢遮断薬
のatropineによつて減弱されたが、この拮
抗の程度は弱く、このことよりTgの血圧
下降作用は血管平滑筋に対する直接作用も
関与しているのかもしれない。 Regarding the results of examining the effects on the circulatory system, administration of Tg1-20mg/Kg through the tail vein of mice caused a transient drop in blood pressure20.
Deaths were also observed at concentrations above mg/Kg.
This blood pressure lowering effect was attenuated by atropine, a peripheral parasympathetic blocker, but the degree of antagonism was weak, suggesting that the blood pressure lowering effect of Tg may also be related to its direct action on vascular smooth muscle. do not have.
(2) 心臓におよぼす影響
心臓については、八木―Hartung法によ
る摘出心臓に対してTg3.3×10-6ｇ／mlの
濃度で一過性の心運動の興奮、その後さら
に持続的な興奮が認められた。この作用パ
ターンはATP投与時の心臓作用に類似
し、さらに3.3×10-5ｇ／mlの応用では基
線の上昇を示し、Ｇ―ストロフアンチンな
どの強心配糖体の作用に類似している。こ
の心臓作用をさらにウサギの生体心臓を用
いて検討した。生体心臓の場合は、Tg0.5
mg／Kgの用量で血圧下降、呼吸抑制ととも
に心臓収縮力の増強と心筋の緊張亢進が認
められた。これらのことよりTgはＧ―ス
トロフアンチンまたはATPを投与した時
と同様な心運動の亢進作用が認められた。 (2) Effects on the heart Regarding the heart, a concentration of Tg of 3.3 x 10 -6 g/ml caused transient cardiac motor excitement and then sustained excitement in isolated hearts using the Yagi-Hartung method. Admitted. This pattern of action is similar to the cardiac effects upon administration of ATP, and also shows an increase in baseline at 3.3 × 10 -5 g/ml, similar to the effects of cardiac glycosides such as G-strophanthine. . This cardiac effect was further investigated using a living rabbit heart. For living hearts, Tg0.5
At a dose of mg/Kg, a decrease in blood pressure and respiratory depression, as well as an increase in cardiac contractility and hypertonicity of the myocardium, were observed. From these results, Tg was found to have the same effect on enhancing cardiac movement as when G-strophanthine or ATP was administered.
Claims (1)
ノシル（１→４）―α―Ｌ―ラムノピラノシル
（１→４）―〔α―Ｌ―ラムノピラノシル（１→
２）〕―β―Ｄ―グルコピラノシドを有効成分と
することを特徴とする、強心剤。[Scope of Claims] 1 Pennogenin-3-O-α-L-rhamnopyranosyl (1→4)-α-L-rhamnopyranosyl (1→4)-[α-L-rhamnopyranosyl (1→
2) A cardiotonic agent characterized by containing -β-D-glucopyranoside as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2227880A JPS56120700A (en) | 1980-02-26 | 1980-02-26 | Cardiac stimmulant |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2227880A JPS56120700A (en) | 1980-02-26 | 1980-02-26 | Cardiac stimmulant |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS56120700A JPS56120700A (en) | 1981-09-22 |
| JPS6157808B2 true JPS6157808B2 (en) | 1986-12-09 |
Family
ID=12078287
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2227880A Granted JPS56120700A (en) | 1980-02-26 | 1980-02-26 | Cardiac stimmulant |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS56120700A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107648430A (en) * | 2015-10-22 | 2018-02-02 | 江西中医药大学 | A kind of preparation method of the effective constituents of steroid saponin containing trilliaceae capsule preparations and its application in various kinds of drug is prepared |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0650186U (en) * | 1992-12-18 | 1994-07-08 | 鹿島建設株式会社 | Equipment plate |
| CZ280195A3 (en) * | 1993-04-28 | 1996-02-14 | Pfizer | Crystalline spirostanyl glycoside, monohydrate thereof, pharmaceutical composition based thereon and process for preparing crystalline steroidal glycoside |
| CN100420444C (en) * | 2005-06-17 | 2008-09-24 | 云南白药集团股份有限公司 | Pennogenic compound liquid molecular dispersible preparation |
| CN105232891B (en) * | 2015-10-23 | 2019-05-21 | 江西中医药大学 | The preparation method of trilliaceae extract and wherein saponins compound and its preparing the application in anti-ischemic heart medicine |
-
1980
- 1980-02-26 JP JP2227880A patent/JPS56120700A/en active Granted
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107648430A (en) * | 2015-10-22 | 2018-02-02 | 江西中医药大学 | A kind of preparation method of the effective constituents of steroid saponin containing trilliaceae capsule preparations and its application in various kinds of drug is prepared |
| CN107890470A (en) * | 2015-10-22 | 2018-04-10 | 江西中医药大学 | A kind of preparation method of the effective constituents of steroid saponin containing trilliaceae tablet and its application in various kinds of drug is prepared |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS56120700A (en) | 1981-09-22 |
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