JPS6325600B2 - - Google Patents
Info
- Publication number
- JPS6325600B2 JPS6325600B2 JP55155486A JP15548680A JPS6325600B2 JP S6325600 B2 JPS6325600 B2 JP S6325600B2 JP 55155486 A JP55155486 A JP 55155486A JP 15548680 A JP15548680 A JP 15548680A JP S6325600 B2 JPS6325600 B2 JP S6325600B2
- Authority
- JP
- Japan
- Prior art keywords
- nsq
- water
- active ingredient
- organic solvent
- extract
- 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
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Landscapes
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Compounds Of Unknown Constitution (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
本発明は、新規生理活性物質(以下、NSQと
記す)その製法及び該物質を有効成分として含有
する医薬に関する。
本発明者は、各種ポツクスウイルスを接種し、
発痘させた各種動物組織(ヒトを除く)培養細胞
若しくは培養組織(以下これらを単に発痘組織と
いう)を処理して抽出した医薬活性物質につき研
究した結果、特定有効成分を高濃度に含有する新
規生理活性物質NSQの抽出精製に成功した。
NSQは各種のストレス、例えばウイルス、細
菌、原虫、リケツチア等の生物学的ストレス、酸
素欠乏、薬物(ACTH、コーチゾン等)等の化
学的ストレス、寒冷、騒音、放射線等の物理的ス
トレス、恐怖、不安、焦躁感等の精神的ストレス
等によつて惹き起こされる生体有機損傷時に生ず
る神経系、内分秘系、免疫系等の歪みを調節し修
復する生体恒常性維持機構に作用し、生体の自然
治瘉力を高め、生体機能を正常化する作用を有す
る。
後述するように、NSQは、鎮痛、鎮静、抗ス
トレス、抗潰瘍、降圧、抗アレルギー、免疫調
整、抗腫瘍等の薬剤として有用であるばかりでな
く、広く各種ストレスや自律神経失調に伴う各種
疾患に適用でき、又、他の薬剤と併用することに
より該薬剤の副作用を軽減し、相乗効果を期待す
ることができる。
本発明によればNSQは、発痘組織を磨砕し、
これに抽出溶媒を加えて除蛋白した後、抽出液を
酸性条件下で吸着剤と接触せしめ、次いで水又は
有機溶媒を用いて有効成分を溶出し、さらにこれ
を水に溶かして不溶物を除去し、酸性条件下で吸
着剤と接触させた後、弱塩基性有機溶媒若しくは
その水混合液を用いて溶出することにより製造さ
れる。
本発明方法につき、さらに詳しく述べる。
本発明において発痘組織とは、ワクチニアウイ
ルス、牛痘ウイルス、エクトロメリアウイルス等
のポツクスウイルスの各種接種方法又は培養方法
にて得たウイルス感染培養組織、培養細胞及び各
種動物のウイルス感染炎症組織又はふ化鶏卵の漿
尿膜等である。この発痘組織を無菌的に採取して
磨砕し、その1〜5倍量の抽出溶媒を加えて乳状
とする。抽出溶媒としては、蒸留水、生理食塩
水、弱酸性ないし弱塩基性の緩衝液あるいはグリ
セリン水溶液等を用いることができ、適宜殺菌、
防腐のためフエノール等を添加してもよい。又、
この時凍結融解、超音波、細胞膜溶解酵素、界面
活性剤等の処理により細胞組織を破壊して、抽出
をより容易にすることができる。
得られた乳状抽出液をろ過又は遠心分離して組
織片を除去して除蛋白を行う。除蛋白操作は、公
知の物理化学的方法により実施でき、加熱、超音
波、蛋白変性剤例えば酸、塩基、尿素、グアニジ
ン、有機溶媒、界面活性剤等による処理、等電点
沈殿、塩析等の方法を適用することができる。次
いで、石綿、セライト、ザイツろ板、限外ろ過、
イオン交換樹脂、遠心分離等により不溶蛋白を除
去する。
こうして得られた有効成分含有抽出液を、塩
酸、硫酸、臭化水素酸等を用いて弱酸性とし、適
当な吸着剤に吸着させる。吸着剤としては、カオ
リン、活性炭、イオン交換樹脂を用いることがで
き、吸着剤を充填したカラム中を前記抽出液を通
過させるか若しくは抽出液中に吸着剤を添加、撹
拌することにより有効成分の吸着を達成すること
ができる。
前記吸着物は水又はメタノール、エタノール、
イソプロパノール等の有機溶媒で抽出する。この
とき、溶出液として後述する弱塩基性有機溶媒若
しくはその水混合液を用いた場合には、以下の工
程は必らずしも必要ではない。
得られた溶出液は、適宜中性とした後、減圧下
に蒸発乾固又は凍結乾燥して有効成分含有物質を
得る。
さらに、前記物質に5〜15倍量の水を加え、水
に不溶性の物質を除去した後、前記同様酸性条件
下で吸着剤に吸着させる。
次いで、弱塩基性有機溶媒若しくはその水混合
液で溶出させる。特に好ましい弱塩基性有機溶媒
としてピリジン、ルチジン等が使用できる。
なお所望により、得られた精製物質はさらにシ
リカゲル、微結晶セルロース等を用いたカラムク
ロマトグラフイーで、水、メタノール、アセトニ
トリル等で分画精製してもよい。
本発明方法によつて抽出、精製されるNSQは
実質的に無機物質を含まず、水に可溶性の有機物
質有効成分を含有し、以下の物理化学的特性を有
する。
性状:淡黄褐色無定形の吸湿性粉末
溶解性:水、メタノールに可溶
ベンゼン、エーテルに不溶
PH:6.5〜7.5
紫外部吸収:λnax265〜275nm
元素分析:C 41.4〜47.0%
H 5.4〜 7.8%
O 32.1〜37.4%
N 11.4〜15.6%
ニンヒドリン反応:陽性
オルシン−塩酸反応:陽性
ヒ素モリブデン酸法による呈色反応:陽性
各種蛋白検出反応:陰性
次に、NSQの製造例を示す。
実施例 1
健康な成熟家兎の皮膚にワクチニアウイルスを
接種し、発痘した皮膚を無菌的に剔出してこれを
細切したのち、フエノール加グリセリン水を加え
ホモゲナイザーで磨砕し乳状液を得た。次いでこ
れを遠心ろ過し、得たろ液を塩酸でPH4.8−5.5と
し流通蒸気で100℃に加熱しろ過した。ろ液はさ
らにザイツろ板を用いてろ過したのち、水酸化ナ
トリウムでPH9.2とし、100℃に加熱した後ろ過し
た。ろ液を塩酸でPH4.5とし、活性炭1.5%を加え
1〜5時間撹拌した後ろ過し、この活性炭に水を
加え、水酸化ナトリウムでPH9.4−10とし3〜5
時間撹拌した後ろ過した。ろ液を塩酸でPH7.0−
7.2とし、減圧下に乾固した。これに水を加えて
溶かし不溶物をろ過して、ろ液を塩酸でPH4.0と
し活性炭カラムに吸着させ、0.01N塩酸で洗滌
後、10%ピリジン−水で溶出し溶出液を乾固し
た。
発痘皮膚1KgからNSQを0.8〜1.5g得た。
元素分析値:C 42.3%
H 5.8%
O 32.9%
N 14.8%
さらに、これを微結晶セルロースカラムクロマ
トに付し、メタノール、イソプロパノール、ベン
ゼン及び水の混合溶媒を流した後、水で活性画分
を溶出精製した。
元素分析値:C 46.3%
H 6.4%
O 34.0%
N 12.1%
実施例 2
実施例1と同様にして得た吸着活性炭を、10%
ルチジン−水で溶出した。これをシリカゲルカラ
ムクロマトに付し、アセトニトリル−水で精製活
性画分を得た。
発痘皮膚1KgからNSQを1.0〜1.6g得た。
元素分析値:C 42.7%
H 7.2%
O 36.8%
N 11.9%
本発明NSQの薬理作用を以下に示す。
急性毒性試験
一群10匹のマウスを用いて、NSQの急性毒性
試験を行つた。結果を第1表に示す。
The present invention relates to a novel physiologically active substance (hereinafter referred to as NSQ), its production method, and a pharmaceutical containing the substance as an active ingredient. The present inventor inoculated various poxviruses,
As a result of research on medicinal active substances extracted by processing various animal tissues (excluding humans) that have been infected with pox, cultured cells or cultured tissues (hereinafter simply referred to as pox tissues), it has been found that they contain high concentrations of specific active ingredients. We succeeded in extracting and purifying the new physiologically active substance NSQ. NSQ includes various types of stress, such as biological stress such as viruses, bacteria, protozoa, and Rickettsia, oxygen deprivation, chemical stress such as drugs (ACTH, cortisone, etc.), physical stress such as cold, noise, radiation, fear, It acts on the body's homeostasis maintenance mechanism, which regulates and repairs distortions in the nervous system, secretory system, immune system, etc. that occur when the body's organic damage is caused by mental stress such as anxiety and mania. It has the effect of increasing natural healing power and normalizing biological functions. As described below, NSQ is not only useful as an analgesic, sedative, anti-stress, anti-ulcer, anti-hypertensive, anti-allergic, immunomodulating, anti-tumor drug, but also widely used in various diseases associated with various types of stress and autonomic nervous imbalance. In addition, when used in combination with other drugs, the side effects of the drugs can be reduced and a synergistic effect can be expected. According to the invention, NSQ grinds the pox tissue and
After adding an extraction solvent to this to remove protein, the extract is brought into contact with an adsorbent under acidic conditions, then the active ingredients are eluted using water or an organic solvent, and the insoluble materials are removed by dissolving this in water. It is produced by contacting it with an adsorbent under acidic conditions and then eluting it with a weakly basic organic solvent or a water mixture thereof. The method of the present invention will be described in more detail. In the present invention, variola tissue refers to virus-infected cultured tissue, cultured cells, and virus-infected inflamed tissue of various animals obtained by various inoculation methods or culture methods of poxviruses such as vaccinia virus, cowpox virus, and ectromelia virus. Or the chorioallantoic membrane of hatched chicken eggs. The pox tissue is collected aseptically and ground, and 1 to 5 times the amount of extraction solvent is added to make it milky. Distilled water, physiological saline, weakly acidic or weakly basic buffer solutions, or glycerin aqueous solutions can be used as the extraction solvent, and sterilization and sterilization may be performed as appropriate.
Phenol etc. may be added for preservative purposes. or,
At this time, the cell tissue can be destroyed by treatments such as freezing and thawing, ultrasound, cell membrane lytic enzymes, surfactants, etc. to make extraction easier. The resulting milky extract is filtered or centrifuged to remove tissue fragments and protein removal. Protein removal operation can be carried out by known physicochemical methods, such as heating, ultrasound, treatment with protein denaturants such as acids, bases, urea, guanidine, organic solvents, surfactants, etc., isoelectric precipitation, salting out, etc. method can be applied. Next, asbestos, Celite, Seitz filter plate, ultrafiltration,
Remove insoluble proteins using ion exchange resin, centrifugation, etc. The thus obtained extract containing the active ingredient is made weakly acidic using hydrochloric acid, sulfuric acid, hydrobromic acid, etc., and then adsorbed onto a suitable adsorbent. Kaolin, activated carbon, or ion exchange resin can be used as the adsorbent, and the active ingredients can be removed by passing the extract through a column packed with the adsorbent or by adding the adsorbent to the extract and stirring. Adsorption can be achieved. The adsorbent is water, methanol, ethanol,
Extract with an organic solvent such as isopropanol. At this time, when a weakly basic organic solvent or an aqueous mixture thereof, which will be described later, is used as the eluent, the following steps are not necessarily necessary. The obtained eluate is suitably neutralized and then evaporated to dryness or freeze-dried under reduced pressure to obtain an active ingredient-containing substance. Furthermore, 5 to 15 times the amount of water is added to the substance to remove water-insoluble substances, and then the substance is adsorbed onto an adsorbent under acidic conditions as described above. Next, it is eluted with a weakly basic organic solvent or a water mixture thereof. Particularly preferred weakly basic organic solvents include pyridine and lutidine. If desired, the obtained purified substance may be further purified by fractionation with water, methanol, acetonitrile, etc. by column chromatography using silica gel, microcrystalline cellulose, etc. NSQ extracted and purified by the method of the present invention is substantially free of inorganic substances, contains water-soluble organic active ingredients, and has the following physicochemical properties. Properties: Pale yellow-brown amorphous hygroscopic powder Solubility: Soluble in water and methanol Insoluble in benzene and ether PH: 6.5-7.5 Ultraviolet absorption: λ nax 265-275 nm Elemental analysis: C 41.4-47.0% H 5.4- 7.8% O 32.1-37.4% N 11.4-15.6% Ninhydrin reaction: positive Orsine-hydrochloric acid reaction: positive Color reaction by arsenic molybdate method: positive Various protein detection reactions: negative Next, an example of manufacturing NSQ will be shown. Example 1 The skin of a healthy adult rabbit was inoculated with vaccinia virus, the infected skin was aseptically removed and cut into small pieces, and then phenol-added glycerin water was added and ground with a homogenizer to form an emulsion. Obtained. This was then centrifugally filtered, and the resulting filtrate was adjusted to pH 4.8-5.5 with hydrochloric acid, heated to 100°C with flowing steam, and filtered. The filtrate was further filtered using a Seitz filter plate, adjusted to pH 9.2 with sodium hydroxide, heated to 100°C, and filtered. The filtrate was adjusted to pH 4.5 with hydrochloric acid, 1.5% activated carbon was added, stirred for 1 to 5 hours, filtered, water was added to the activated carbon, and adjusted to pH 9.4-10 with sodium hydroxide for 3 to 5 hours.
After stirring for an hour, it was filtered. PH7.0− of the filtrate with hydrochloric acid
7.2 and dried under reduced pressure. Water was added thereto, dissolved, and insoluble matter was filtered. The filtrate was adjusted to pH 4.0 with hydrochloric acid and adsorbed onto an activated carbon column. After washing with 0.01N hydrochloric acid, it was eluted with 10% pyridine-water and the eluate was dried. . 0.8-1.5 g of NSQ was obtained from 1 kg of pox skin. Elemental analysis values: C 42.3% H 5.8% O 32.9% N 14.8% Furthermore, this was subjected to microcrystalline cellulose column chromatography, and after flowing a mixed solvent of methanol, isopropanol, benzene, and water, the active fraction was separated with water. It was purified by elution. Elemental analysis values: C 46.3% H 6.4% O 34.0% N 12.1% Example 2 Adsorption activated carbon obtained in the same manner as Example 1 was mixed with 10%
Eluted with lutidine-water. This was subjected to silica gel column chromatography to obtain an active fraction purified with acetonitrile-water. 1.0 to 1.6 g of NSQ was obtained from 1 kg of infected skin. Elemental analysis values: C 42.7% H 7.2% O 36.8% N 11.9% The pharmacological action of the NSQ of the present invention is shown below. Acute toxicity test An acute toxicity test of NSQ was conducted using 10 mice per group. The results are shown in Table 1.
【表】
薬理試験
以下の動物実験に用いられたSARTストレス
動物は、喜多らの方法〔日薬理誌、71,195−210
(1970)〕に従つて飼育した。該方法によつて飼育
したSARTストレス動物は強度のストレス状態
を示し、体重減少、心拍数増加、QRS時間の延
長がみられるなど、環境の変化によつて惹起され
る人間の自律神経失調症様状態をあらわす動物モ
デルとみることができる。
(1) ストレス動物における体重減少抑制作用
一群15匹のマウスをSARTストレス条件下
で飼育し、NSQ5mg/Kg/日投与群と非投与群の
体重変化を比較した。なお、正常環境条件下で飼
育したマウスの体重変化も同時に測定した。
結果を第2表に示す。[Table] Pharmacological test The SART stressed animals used in the following animal experiments were prepared using the method of Kita et al. [Japan Pharmacological Journal, 71 , 195-210]
(1970)]. SART-stressed animals raised using this method exhibit severe stress, exhibiting weight loss, increased heart rate, and prolonged QRS duration, similar to human autonomic imbalance caused by environmental changes. It can be seen as an animal model that represents the state. (1) Suppressive effect on weight loss in stressed animals Groups of 15 mice were raised under SART stress conditions, and changes in body weight were compared between the NSQ 5mg/Kg/day administration group and the non-administration group. At the same time, changes in body weight of mice raised under normal environmental conditions were also measured. The results are shown in Table 2.
【表】
(2) ストレス動物における呼吸数、心拍数の増加
及びQRS時間の延長に対する作用
一群10匹のマウスにSARTストレスを5日間
負荷し、呼吸数、心拍数、QRS時間に対する
NSQの効果を調べた。NSQを15mg/Kg/日腹腔
内投与すると、第3表に示すとおり、SARTス
トレスによつてひき起こされる呼吸数、心拍数の
増加及びQRS時間の延長を有意に抑制した。[Table] (2) Effects on increased respiration rate, heart rate, and prolongation of QRS time in stressed animals A group of 10 mice was subjected to SART stress for 5 days, and the effects on respiration rate, heart rate, and QRS time were
We investigated the effects of NSQ. As shown in Table 3, intraperitoneal administration of NSQ at 15 mg/Kg/day significantly suppressed the increases in respiratory rate, heart rate, and QRS duration caused by SART stress.
【表】
(3) 摘出腸管におけるアセチルコリン(ACh)
感受性回復作用
SARTストレスを5日間負荷したマウスの腸
管におけるACh(10-7g/ml)の感受性に対する
NSQの効果を調べた。第4表に示すとおり、
NSQを20mg/Kg/日投与することにより、ACh
感受性がほぼ正常値にまで回復した。[Table] (3) Acetylcholine (ACh) in isolated intestinal tract
Sensitivity recovery effect on the sensitivity of ACh (10 -7 g/ml) in the intestinal tract of mice subjected to SART stress for 5 days
We investigated the effects of NSQ. As shown in Table 4,
By administering 20mg/Kg/day of NSQ, ACh
Sensitivity returned to almost normal values.
【表】
(4) 鎮静作用
(4.1) 自発運動抑制作用
マウスにNSQを腹腔内投与し、50分後に15分
間の自発運動量を測定した。対照群には生理食塩
水25ml/Kgを投与した。
(4.2) 探索行動抑制作用
前記と同様にして、NSQ腹腔内投与50分後に
15分間の探索行動量を測定した。
これらの結果を第5表に示す。[Table] (4) Sedative effect (4.1) Locomotor activity suppression effect NSQ was intraperitoneally administered to mice, and 50 minutes later, locomotor activity was measured for 15 minutes. The control group received 25 ml/Kg of physiological saline. (4.2) Inhibitory effect on exploratory behavior In the same manner as above, 50 minutes after intraperitoneal administration of NSQ.
The amount of exploratory behavior was measured for 15 minutes. These results are shown in Table 5.
【表】
(5) 鎮痛作用
以下の鎮痛試験に用いたSARTストレスマウ
スは、ストレスを4日間負荷したものを用いた。
(5.1) 酢酸法
0.7%酢酸加生理食塩水をマウスに0.1ml/10g
腹腔内投与し、投与15分後から15分間に発現する
ライジング回数を測定した。効果判定は、NSQ
を皮下投与したマウスのライジング回数が、対照
群の50%以下に減少した場合を効果ありとし、そ
のマウスの割合で示した。
(5.2) フエニルキノン法
5%エタノール溶液に溶解した0.075%フエニ
ルキノン溶液を0.1ml/10g宛マウスに腹腔内投
与し、投与5分後から20分間に発現するライジン
グ回数を測定した。効果判定は、前記酢酸法の場
合と同様に行つた。
これらの結果を第6表に示す。[Table] (5) Analgesic effect The SART stress mice used in the following analgesic test were subjected to stress for 4 days. (5.1) Acetic acid method 0.1ml/10g of 0.7% acetic acid-added saline to a mouse
The drug was administered intraperitoneally, and the number of writhing events occurring for 15 minutes from 15 minutes after administration was measured. Effect judgment is NSQ
An effect was defined as the number of writhing mice subcutaneously administered was reduced to 50% or less of that of the control group, and the results are expressed as a percentage of the mice. (5.2) Phenylquinone method A 0.075% phenylquinone solution dissolved in a 5% ethanol solution was intraperitoneally administered to a mouse at 0.1 ml/10 g, and the number of writhing events occurring in 20 minutes from 5 minutes after administration was measured. The effectiveness was evaluated in the same manner as in the acetic acid method. These results are shown in Table 6.
【表】
(5.3) ダムル・スミス(D′Amour−Smith)
法
電熱線をマウスの尾根部に15秒間を限度として
照射し、逃避反応を示すまでの時間を測定した。
効果判定は、NSQ腹腔内投与後30,60,90及び
120分における反応時間の平均値が、投与前の値
の2倍以上に延長されていた場合を効果ありと
し、そのマウスの割合で示した。
結果を第7表に示す。[Table] (5.3) D'Amour-Smith
Method: We irradiated the ridge of a mouse with a heating wire for a maximum of 15 seconds, and measured the time it took for it to show an escape response.
Efficacy was evaluated at 30, 60, 90 and 30 days after intraperitoneal administration of NSQ.
When the average reaction time at 120 minutes was extended to more than twice the value before administration, it was considered effective and expressed as a percentage of mice. The results are shown in Table 7.
【表】
(5.4) 尾圧法
ランダール・セリツト(Randall−Selitto)式
圧刺激測定装置を用いてマウス尾根部に刺激を加
え、逃避反応を示すまで加圧を増加させた。
NSQ腹腔内投与後30,60,90及び120分後の加圧
重量の平均値を投与前の値で除し、この値を鎮痛
係数として表わした。
結果を第8表に示す。
SARTストレスマウスに対するNSQのED1.5は
1.5mg/Kgであつた。[Table] (5.4) Tail pressure method Stimulation was applied to the mouse ridge using a Randall-Selitto pressure stimulation measuring device, and the pressure was increased until the mouse exhibited an escape response.
The average value of the pressurized weight at 30, 60, 90, and 120 minutes after intraperitoneal administration of NSQ was divided by the value before administration, and this value was expressed as an analgesic coefficient. The results are shown in Table 8. ED 1.5 of NSQ for SART stress mice
It was 1.5mg/Kg.
【表】
(6) ストレス潰瘍抑制作用
雄性ラツトを24時間絶食させた後、拘束水浸ス
トレス(25℃,20時間)を負荷して胃体部にでき
た潰瘍の程度を観察した。NSQは、絶食開始前
とストレス負荷前に計10回腹腔内投与した。対照
群には生理食塩水3ml/Kg/回を投与した。
結果を第9表に示す。
ストレスによる潰瘍像は、胃体部全体の激しい
出血性びらん症状と粘膜欠損がみられた。これに
対して、NSQ投与により出血がほとんど認めら
れず、欠損やびらんも有意に減少した。[Table] (6) Stress ulcer suppressive effect After fasting male rats for 24 hours, restraint water immersion stress (25°C, 20 hours) was applied and the degree of ulcers formed in the stomach body was observed. NSQ was administered intraperitoneally 10 times in total before the start of fasting and before stress loading. The control group received 3 ml/Kg/times of physiological saline. The results are shown in Table 9. The stress-induced ulcer showed severe hemorrhagic erosion and mucosal defects throughout the gastric body. In contrast, with NSQ administration, almost no bleeding was observed, and defects and erosions were significantly reduced.
【表】
(7) 血圧正常化作用
ウイスター(Wistar)系ラツトと高血圧自然
発症ラツト(SHR)を用い、NSQ腹腔内投与90
分後の血圧を投与前のそれと比較した。
第10表から明らかなように、NSQは正常血圧
に対しては影響を与えず、高血圧に対しては正常
レベルまで降圧するのがわかる。[Table] (7) Blood pressure normalization effect Intraperitoneal administration of NSQ90 using Wistar rats and spontaneously hypertensive rats (SHR)
The blood pressure after minutes was compared with that before administration. As is clear from Table 10, NSQ has no effect on normal blood pressure, but lowers hypertension to a normal level.
【表】
(8) 免疫調整作用
(8.1) 溶血斑形成細胞(HPFC)産生試験
シクロフオスフアミド(CP)25mg/Kgを2日
間腹腔内投与したマウスをヒツジ赤血球で免疫し
たのち、NSQを腹腔内投与して、CPによる
HPFC産生抑制に対する回復作用を調べた。
第1図に示したとおり、NSQはCPにより減少
した抗体産生能を有意に回復させた。
(8.2) IgE産生に及ぼす影響
ブタ回虫(ascaris suum)の抽出物にジニト
ロフエニル基を結合させたDNP−Asと百日咳ワ
クチンでラツトを免疫し、NSQ又はCPを5日間
腹腔内投与した後、9日目の血清中のIgE量を48
時間ホモロガスPCA反応により測定した。
第11表に示したとおり、NSQはIgE産生に影響
を及ぼさないことがわかつた。[Table] (8) Immunomodulatory effect (8.1) Hemolytic plaque-forming cell (HPFC) production test Mice that had been intraperitoneally administered with cyclophosphamide (CP) at 25 mg/Kg for 2 days were immunized with sheep red blood cells, and then NSQ was administered intraperitoneally. Administer intravenously and by CP
The recovery effect against suppression of HPFC production was investigated. As shown in FIG. 1, NSQ significantly restored the antibody production ability decreased by CP. (8.2) Effect on IgE production Rats were immunized with DNP-As, which is an extract of Ascaris suum bound to a dinitrophenyl group, and pertussis vaccine, and NSQ or CP was administered intraperitoneally for 5 days, followed by intraperitoneal administration for 9 days. Increases the amount of IgE in the eye serum by 48
Time was measured by homologous PCA reaction. As shown in Table 11, it was found that NSQ had no effect on IgE production.
【表】
(8.3) SHRの免疫能回復作用
SHR及び対照としてWKAラツトを用いて、武
市らの方法〔医学のあゆみ、第111巻、第6号、
376−378頁(1979)〕に準じて、ロゼツト形成試
験、溶血斑形成試験、リンパ球幼若化反応を行つ
た。
NSQ及び市販の抗悪性腫瘍性蛋白多糖体は、
それぞれ10mg/Kg、300mg/Kg一週間腹腔内投与
した。
第12表にロゼツト形成率、脾臓細胞106個中の
溶血斑形成細胞数及びフイトヘマグルチニン
(PHA)、コンカナバリンA(Con A)に対する
幼若化反応をとり込んだ3H−チミジンの放射能
カウント数として示した。NSQは、SHRの免疫
能、殊にT細胞機能の低下を有意に回復させた。[Table] (8.3) Immune ability recovery effect of SHR Using SHR and WKA rats as a control, the method of Takeichi et al. [Igaku no Ayumi, Vol. 111, No. 6,
376-378 (1979)], a rosette formation test, a hemolytic plaque formation test, and a lymphocyte blastogenesis reaction were performed. NSQ and commercially available antineoplastic protein polysaccharides are
10 mg/Kg and 300 mg/Kg were administered intraperitoneally for one week, respectively. Table 12 shows the radioactivity of 3 H-thymidine, which incorporates the rosette formation rate, the number of hemolytic plaque-forming cells in 106 spleen cells, and the rejuvenation reaction to phytohemagglutinin (PHA) and concanavalin A (Con A). Shown as counts. NSQ significantly restored the immunocompetence of SHR, especially the decline in T cell function.
【表】
(8.4) 抗腫瘍作用
メチルコラントレン誘発SHR腫瘍細胞を5×
105個、一群10匹のSHRに皮下移植し、その後6
日間NSQ、前記蛋白多糖体、グルカン又はWKA
ラツト胸腺抽出液を投与した。
第13表に示すとおり、NSQ投与群では有意に
死亡数が減少し、又、死亡ラツトの生存日数も延
長した。[Table] (8.4) Antitumor effect Methylcholanthrene-induced SHR tumor cells 5x
10 Five cells were implanted subcutaneously into a group of 10 SHRs, and then 6
Daily NSQ, said protein polysaccharide, glucan or WKA
Rat thymus extract was administered. As shown in Table 13, the number of deaths was significantly reduced in the NSQ administration group, and the survival days of the dead rats were also prolonged.
【表】
(8.5) 放射能防禦作用
一群10匹のマウスに900Rの放射線を照射し、
その後のマウスの死亡率を調べた。被験薬はそれ
ぞれ7日間腹腔内投与した。
第14表に示したとおり、NSQは放射線によつ
て低下した免疫能を回復、増強させ、死亡率を有
意に減少させた。[Table] (8.5) Radiation protection effect A group of 10 mice was irradiated with 900R radiation.
The subsequent mortality rate of the mice was examined. Each test drug was administered intraperitoneally for 7 days. As shown in Table 14, NSQ restored and enhanced the immune function decreased by radiation and significantly reduced the mortality rate.
【表】
(9) 抗アレルギー作用
(9.1) PCA反応抑制作用
DNP−Asと百日咳ワクチンでラツトを免疫
し、得られた抗血清を用いたホモロガス(homo
−logous)PCAに対する効果を調べた。即ち、
ラツト背部皮内に抗DNP−As血清を注射し、48
時間後、抗原DNP−Asとエバンス・ブル−
(Evans blue)を静脈内注射して反応を誘発し
た。
NSQを反応誘発30分前に腹腔内投与した場合、
有意にPCA反応を抑制した。(第15表)[Table] (9) Antiallergic effect (9.1) PCA reaction suppression effect Homologous (homologous) immunization of rats with DNP-As and pertussis vaccine
-logous) effects on PCA were investigated. That is,
Anti-DNP-As serum was injected intradermally into the back of rats.
After hours, antigen DNP-As and Evans blue
(Evans blue) was injected intravenously to induce the response. When NSQ was administered intraperitoneally 30 minutes before response induction,
It significantly suppressed the PCA reaction. (Table 15)
【表】
(9.2) 脱顆粒抑制作用
ラツト抗DNP−As血清をラツト腹腔内に注射
して受動的に感作し、48時間後に腸間膜を摘出し
た。タイロード液中インキユベートし、NSQを
加え、さらに抗原DNP−Asを加え15分後トルイ
ジン・ブルーで染色して脱顆粒率を測定した。
第16表に示したように、NSQは有意に脱顆粒
を抑制した。[Table] (9.2) Degranulation inhibitory effect Rat anti-DNP-As serum was intraperitoneally injected into rats to passively sensitize them, and 48 hours later, the mesentery was removed. The cells were incubated in Tyrode's solution, NSQ was added, and then the antigen DNP-As was added, and after 15 minutes, the degranulation rate was measured by staining with toluidine blue. As shown in Table 16, NSQ significantly inhibited degranulation.
【表】
(9.3) ヒスタミン遊離抑制作用
モルモツトの心臓内に、抗ベンジルペニシロイ
ル牛ガンマグロブリン(BPO−BGG)血清を注
射して受動的に感作し、24時間後肺を摘出、細切
した。タイロード液中、NSQ及びベンジルペニ
シロイル牛血清アルブミン(BPO−BSA)を加
えてインキユベートし、上清中のヒスタミン量を
測定した。
結果を第17表に示す。[Table] (9.3) Effect of suppressing histamine release Anti-benzylpenicilloyl bovine gamma globulin (BPO-BGG) serum was injected into the hearts of guinea pigs to passively sensitize them, and 24 hours later, the lungs were removed and cut into small pieces. . NSQ and benzylpenicilloyl bovine serum albumin (BPO-BSA) were added and incubated in Tyrode's solution, and the amount of histamine in the supernatant was measured. The results are shown in Table 17.
【表】
(9.4) 実験的喘息抑制作用
モルモツトの心臓内に抗BPO−BGG血清を注
射して受動的に感作し、48時間後気管を切開しト
ランスジユーサーに連結し、呼吸流量及び呼吸流
速から呼吸数と吸気時間に対する呼吸時間の比を
測定した。
NSQ20mg/Kgは、BPO−BSAの頚静脈内投与
に先立ち、4回に分けて腹腔内投与した。誘発18
分後、最も顕著に喘息状態を表わしたが、この時
点でもNSQは症状を有意に抑制した。第18表に
おいて、呼吸数、呼吸流量及び呼気/吸気は、そ
れぞれ誘発前の値を100として示した。[Table] (9.4) Experimental asthma suppressive effect Anti-BPO-BGG serum was injected into the hearts of guinea pigs to passively sensitize them. After 48 hours, the trachea was incised and connected to a transducer, and the respiratory flow rate and respiration were measured. The respiratory rate and the ratio of respiration time to inspiratory time were measured from the flow rate. 20 mg/Kg of NSQ was administered intraperitoneally in four divided doses prior to intrajugular administration of BPO-BSA. trigger 18
After a few minutes, the asthmatic state was most evident, and even at this point, NSQ significantly suppressed the symptoms. In Table 18, the respiratory rate, respiratory flow rate, and exhalation/inhalation are each shown with the pre-induction values set at 100.
【表】
(10) 肝障害抑制作用
(10.1) 肝硬変抑制作用
一群10匹のラツトを用いて、四塩化炭素を同量
のオリーブ油との混合物として10ml/Kg宛15週、
計30回皮下投与し、惹起される肝硬変に対する
NSQの抑制効果を調べた。
NSQを四塩化炭素と同時に20mg/Kg宛、週5
回腹腔内投与した場合、対照群にみられた肝硬変
の像は全く認められなかつた。
(10.2) 肝細胞癌抑制作用
一群10匹のラツトを用いて、3′−メチル−ジエ
チルアミノアゾベンゼン(DAB)による肝細胞
癌に対するNSQの作用を調べた。DABは飼料に
0.06%混入して与え、又、NSQは週5回腹腔内
投与した。
実験動物は次の各群に分けた。結果を第19表に
示す。
A群……DABのみを投与
B群……DABを12週、NSQ20mg/Kgを13〜26
週投与
C群……DABを12週、以降DABとNSQ20mg/
Kgを同時投与
D群……26週までDABとNSQ2.5mg/Kgを同時
投与[Table] (10) Hepatic damage inhibitory effect (10.1) Liver cirrhosis inhibitory effect Using a group of 10 rats, carbon tetrachloride was mixed with the same amount of olive oil at 10ml/kg for 15 weeks.
A total of 30 subcutaneous administrations were performed to treat induced liver cirrhosis.
We investigated the inhibitory effect of NSQ. NSQ at the same time as carbon tetrachloride to 20mg/Kg, 5 times a week
When administered intraperitoneally, no signs of liver cirrhosis were observed in the control group. (10.2) Hepatocellular carcinoma inhibitory effect The effect of NSQ on hepatocellular carcinoma induced by 3'-methyl-diethylaminoazobenzene (DAB) was investigated using a group of 10 rats. DAB as feed
NSQ was administered intraperitoneally 5 times a week. Experimental animals were divided into the following groups. The results are shown in Table 19. Group A: Administer DAB only Group B: DAB for 12 weeks, NSQ 20mg/Kg for 13-26 weeks
Weekly administration Group C: DAB for 12 weeks, then DAB and NSQ 20mg/
Co-administration of Kg Group D: Co-administration of DAB and NSQ 2.5mg/Kg until 26 weeks
【表】
以上の薬理試験の結果から明らかなように、本
発明NSQは、その毒性が低く、かつ幅広い薬理
作用、特に各種ストレスに起因する生体機能の異
常を調節、修復し、生体恒常性維持に有用な生体
防禦調整物質である。従つてNSQは、鎮痛、鎮
静、抗潰瘍、血圧正常化、免疫調整、抗腫瘍、抗
アレルギーを目的とする薬剤として有用であるば
かりでなく、広く抗ストレス剤、自律神経調節剤
などの生体損傷時の修復剤として適用しうる。
NSQの適応疾患の一例を示せば、以下のごと
くである。
神経痛、腰痛、本態性高血圧症、低血圧症、胃
炎、消化性潰瘍、ストレス潰瘍、月経異常、肥満
症、糖尿病、夜尿症、皮膚掻痒症、メニエール症
候群等のストレス起因性疾患、心臓神経症、胃腸
神経症、呼吸神経症、頭痛、めまい、疲労感、不
眠、ふるえ、四肢冷感、動悸、息切れ、食欲不
振、便秘、下痢等の自律神経失調症、無ガンマグ
ロブリン血症、低ガンマグロブリン血症、ウイス
コツト・アルドリツヒ(Wiskott−Aldrich)症
候群、ルイス・バー(Louis−Bar)症候群、ジ
トリン(Gitlin)症候群、ネゼロフ(Nezelof)
症候群、デイ・ジヨルジー(DiGeorge)症候群、
リンパ腫、ホジキン病、白血病、ステロイド剤や
制癌剤による免疫不全症等の免疫不全症候群、各
種悪性腫瘍、気管支喘息、花粉症、アレルギー性
鼻炎、腸炎、潰瘍性大腸炎、結節性動脈周囲炎、
蕁麻疹、湿疹、接触性皮膚炎、アレルギー性結膜
炎、リウマチ様関節炎、エリテマト−デス等のア
レルギー性疾患、さらにインフルエンザ、赤痢、
破傷風、敗血症、その他各種感染症、放射線障
害。
NSQはこれら疾患に対し、予防剤、治療剤又
は治療補助剤として、単独で若しくは他の薬剤と
組み合わせて使用することができる。さらに、
NSQは他の薬剤と併用した場合には、他剤の副
作用低減、用量低減及び効果の増大なども期待で
きる。
本発明NSQを有効成分として含有する医薬組
成物としては、例えば錠剤、カプセル剤、顆粒
剤、液剤、注射剤、軟膏剤、坐剤、エアゾール剤
の他通常用いられる剤形に処方することができ
る。
錠剤、カプセル剤、顆粒剤等の製剤には、デン
プン、乳糖、マンニツト等の賦形剤の他、適宜、
結晶セルロース、アラビアゴム、トウモロコシデ
ンプン、ゼラチン、ポリエチレン、ポリビニルア
ルコール、ポリビニルピロリドン等の結合剤、カ
ルボキシメチルセルロース、ポリエチレングリコ
ール、バレイシヨデンプン等の崩壊剤、タルク、
ステアリン酸マグネシウム等の滑沢剤、グリセロ
ール等の湿潤剤、その他被覆剤、着色剤、矯味矯
臭剤を用いることができる。
注射剤の製剤には、注射用蒸留水、生理食塩
水、ブドー糖注射液、注射用植物油、プロピレン
グリコール、ポリエチレングリコール等の溶剤を
用いて殺菌された水性又は非水性の溶液、又は懸
濁液とすることができる。又、必要に応じてピロ
亜硫酸ナトリウム、硫化水素ナトリウム、1−ア
スコルビン酸、チオグリコール酸、クエン酸塩、
酢酸塩、リン酸塩等の安定剤、塩酸プロカイン、
ブドー糖等の無痛化剤、その他等張化剤、溶解補
助剤、保存剤、懸濁化剤、乳化剤等を加えること
ができる。この種の製剤には、殺菌した固体組成
物として、用時溶解して用いる剤形としてもよ
い。
軟膏剤には、脂肪油、パラフイン、ラノリン、
ワセリン、グリコール類、グリセリン、高級アル
コール、その他適当な基剤を用いて、また坐剤に
は、カカオ脂、マクロゴール、グリセロゼラチ
ン、ラノリン脂等の基剤を用いて製剤することが
でき、適宜界面活性剤、保存剤を添加してもよ
い。
さらに、液体若しくは微小粉体の形で、適当な
噴射剤と共にエアゾール剤とすることもでき、所
望により湿潤剤、分散剤等の助剤を添加する。
本発明NSQの投与量は、投与対象、投与方法
により変わるが、所望の効果を得るには、一般に
一日当たり1μgないし10mg/Kg投与するのが好
ましく、疾患、症状により適宜変更しうる。
以下に、本発明NSQを含有する医薬組成物の
処方例を示す。
錠剤
NSQ 50mg
乳 糖 125〃
結晶セルロース 20〃
ステアリン酸マグネシウム 5〃
計 200mg
カプセル剤
NSQ 10mg
乳 糖 160〃
バレイシヨデンプン 75〃
ステアリン酸マグネシウム 5〃
計 250mg
注射剤
NSQ 1mg
塩化ナトリウム 適量
注射用蒸留水 適量
坐剤
NSQ 10mg
カカオ脂 1990〃
計 2000mg
軟膏剤
NSQ 1g
乳化ワツクス 24〃
白色ワセリン 60〃
流動パラフイン 15〃
計 100g
エアゾール剤
NSQ 0.1重量%
レシチン 0.9 〃
ジクロロジフルオロメタン 39 〃
ジクロロテトラフルオロエタン 60 〃
100 重量%[Table] As is clear from the results of the above pharmacological tests, the NSQ of the present invention has low toxicity and a wide range of pharmacological effects, particularly regulating and repairing abnormalities in biological functions caused by various stresses, and maintaining biological homeostasis. It is a useful biodefense regulator. Therefore, NSQ is not only useful as a drug for analgesia, sedation, anti-ulcer, normalization of blood pressure, immune regulation, anti-tumor, and anti-allergy, but also widely used as an anti-stress agent, autonomic nerve regulator, etc. It can be applied as a time repair agent. Examples of diseases for which NSQ is applicable are as follows. Neuralgia, low back pain, essential hypertension, hypotension, gastritis, peptic ulcer, stress ulcer, menstrual abnormality, obesity, diabetes, nocturnal enuresis, skin pruritus, stress-induced diseases such as Meniere's syndrome, cardiac neuropathy, gastrointestinal Neurosis, respiratory neurosis, headache, dizziness, fatigue, insomnia, trembling, cold extremities, palpitations, shortness of breath, anorexia, constipation, autonomic dysfunction such as diarrhea, agammaglobulinemia, hypogammaglobulinemia , Wiskott-Aldrich syndrome, Louis-Bar syndrome, Gitlin syndrome, Nezelof
syndrome, DiGeorge syndrome,
Lymphoma, Hodgkin's disease, leukemia, immunodeficiency syndromes such as immunodeficiency caused by steroids and anticancer drugs, various malignant tumors, bronchial asthma, hay fever, allergic rhinitis, enteritis, ulcerative colitis, periarteritis nodosa,
Allergic diseases such as urticaria, eczema, contact dermatitis, allergic conjunctivitis, rheumatoid arthritis, and lupus erythematosus, as well as influenza, dysentery,
Tetanus, sepsis, various other infectious diseases, and radiation damage. NSQ can be used alone or in combination with other drugs as a prophylactic agent, therapeutic agent, or therapeutic adjuvant for these diseases. moreover,
When NSQ is used in combination with other drugs, it can be expected to reduce the side effects of other drugs, reduce dosage, and increase efficacy. Pharmaceutical compositions containing the NSQ of the present invention as an active ingredient can be formulated into tablets, capsules, granules, liquids, injections, ointments, suppositories, aerosols, and other commonly used dosage forms. . In addition to excipients such as starch, lactose, and mannitrate, formulations such as tablets, capsules, and granules may contain, as appropriate,
Binder such as crystalline cellulose, gum arabic, corn starch, gelatin, polyethylene, polyvinyl alcohol, polyvinylpyrrolidone, disintegrant such as carboxymethyl cellulose, polyethylene glycol, potato starch, talc,
Lubricating agents such as magnesium stearate, wetting agents such as glycerol, other coating agents, coloring agents, and flavoring agents can be used. For the preparation of injections, aqueous or non-aqueous solutions or suspensions sterilized using solvents such as distilled water for injection, physiological saline, glucose injection, vegetable oil for injection, propylene glycol, polyethylene glycol, etc. It can be done. In addition, sodium pyrosulfite, sodium hydrogen sulfide, 1-ascorbic acid, thioglycolic acid, citrate,
Stabilizers such as acetates and phosphates, procaine hydrochloride,
A soothing agent such as glucose, other tonicity agents, solubilizing agents, preservatives, suspending agents, emulsifying agents, etc. can be added. This type of preparation may be in the form of a sterilized solid composition that is dissolved before use. Ointments contain fatty oils, paraffin, lanolin,
Suppositories can be formulated using petrolatum, glycols, glycerin, higher alcohols, and other suitable bases, and suppositories can be formulated using bases such as cacao butter, macrogol, glycerogelatin, lanolin fat, etc., as appropriate. Surfactants and preservatives may be added. Furthermore, it can be made into an aerosol in the form of a liquid or fine powder together with a suitable propellant, and if desired, auxiliary agents such as wetting agents and dispersants may be added. The dosage of the NSQ of the present invention varies depending on the subject and the method of administration, but in order to obtain the desired effect, it is generally preferable to administer 1 μg to 10 mg/Kg per day, and it can be changed as appropriate depending on the disease and symptoms. Examples of formulations of pharmaceutical compositions containing the NSQ of the present invention are shown below. Tablet NSQ 50mg Lactose 125〃 Crystalline cellulose 20〃 Magnesium stearate 5〃 Total 200mg Capsule NSQ 10mg Lactose 160〃 Potato starch 75〃 Magnesium stearate 5〃 Total 250mg Injection NSQ 1mg Sodium chloride Appropriate amount Distilled water for injection Appropriate amount Suppository NSQ 10mg Cocoa butter 1990〃Total 2000mg Ointment NSQ 1g Emulsified wax 24〃 White petrolatum 60〃 Liquid paraffin 15〃Total 100g Aerosol NSQ 0.1% by weight Lecithin 0.9 〃 Dichlorodifluoromethane 39 〃 Dichlorotetra Fluoroethane 60 〃 100 Weight %
第1図は、本発明物質NSQの免疫機能回復作
用を示すグラフである。
FIG. 1 is a graph showing the immune function recovery effect of the substance of the present invention, NSQ.
Claims (1)
除蛋白した後、抽出液を酸性条件下で吸着剤と接
触せしめ、次いで水又は有機溶媒を用いて有効成
分を溶出し、さらにこれを水に溶かして不溶物を
除去し、酸性条件下で吸着剤と接触させた後、弱
塩基性有機溶媒若しくはその水混合液を用いて溶
出することにより得られる下記特性を有する新規
生理活性物質NSQ。 性状:淡黄褐色無定形の吸湿性粉末 溶解性:水、メタノールに可溶 ベンゼン、エーテルに不溶 PH:6.5〜7.5 紫外部吸収:λnax265〜275nm 元素分析:C 41.4〜47.0% H 5.4〜 7.8% O 32.1〜37.4% N 11.4〜15.6% ニンヒドリン反応:陽性 オルシン−塩酸反応:陽性 ヒ素モリブデン酸法による呈色反応:陽性 各種蛋白検出反応:陰性 2 発痘組織を磨砕し、これに抽出溶媒を加えて
除蛋白した後、抽出液を酸性条件下で吸着剤と接
触せしめ、次いで水又は有機溶媒を用いて有効成
分を溶出し、さらにこれを水に溶かして不溶物を
除却し、酸性条件下で吸着剤と接触させた後、弱
塩基性有機溶媒若しくはその水混合液を用いて溶
出することよりなる新規生理活性物質NSQの製
造方法。 3 NSQを有効成分として含有してなる抗スト
レス、自律神経調節剤。 4 NSQを有効成分として含有してなる鎮痛、
鎮静剤。 5 NSQを有効成分として含有してなる免疫調
整、抗アレルギー剤。 6 NSQを有効成分として含有してなる抗潰瘍
剤。 7 NSQを有効成分として含有してなる血圧調
整剤。 8 NSQを有効成分として含有してなる抗腫瘍
剤。[Claims] 1. After grinding the pox tissue and adding an extraction solvent to it to remove protein, the extract is brought into contact with an adsorbent under acidic conditions, and then the active ingredient is extracted using water or an organic solvent. The following properties can be obtained by eluting this, dissolving it in water to remove insoluble matter, contacting it with an adsorbent under acidic conditions, and then eluting it with a weakly basic organic solvent or its water mixture. NSQ, a new physiologically active substance with Properties: Pale yellow-brown amorphous hygroscopic powder Solubility: Soluble in water and methanol Insoluble in benzene and ether PH: 6.5-7.5 Ultraviolet absorption: λ nax 265-275 nm Elemental analysis: C 41.4-47.0% H 5.4- 7.8% O 32.1-37.4% N 11.4-15.6% Ninhydrin reaction: positive Orsine-hydrochloric acid reaction: positive Color reaction by arsenic molybdate method: positive Various protein detection reactions: negative 2 Grind the pox tissue and extract it After removing protein by adding a solvent, the extract is brought into contact with an adsorbent under acidic conditions, then the active ingredients are eluted using water or an organic solvent, and the insoluble matter is removed by dissolving this in water. A method for producing a novel physiologically active substance NSQ, which comprises contacting with an adsorbent under the following conditions and then eluting it using a weakly basic organic solvent or an aqueous mixture thereof. 3.An anti-stress and autonomic nerve regulator containing NSQ as an active ingredient. 4 Analgesic containing NSQ as an active ingredient,
Sedatives. 5. An immunomodulating and anti-allergic agent containing NSQ as an active ingredient. 6. An anti-ulcer agent containing NSQ as an active ingredient. 7. A blood pressure regulator containing NSQ as an active ingredient. 8. An antitumor agent containing NSQ as an active ingredient.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP55155486A JPS5777697A (en) | 1980-11-04 | 1980-11-04 | Physiologically active substance nsq |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP55155486A JPS5777697A (en) | 1980-11-04 | 1980-11-04 | Physiologically active substance nsq |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5777697A JPS5777697A (en) | 1982-05-15 |
JPS6325600B2 true JPS6325600B2 (en) | 1988-05-26 |
Family
ID=15607090
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP55155486A Granted JPS5777697A (en) | 1980-11-04 | 1980-11-04 | Physiologically active substance nsq |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5777697A (en) |
Families Citing this family (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2651674B2 (en) * | 1987-07-23 | 1997-09-10 | 日本臓器製薬 株式会社 | New physiologically active substance and method for producing the same |
DE68909100T2 (en) * | 1988-04-30 | 1994-01-13 | Nippon Zoki Pharmaceutical Co | Physiologically active substances, processes for their preparation and pharmaceutical compositions thereof. |
JP2588109B2 (en) * | 1993-03-19 | 1997-03-05 | 日本臓器製薬株式会社 | Painkillers |
JP3213832B2 (en) * | 1993-08-06 | 2001-10-02 | 日本臓器製薬株式会社 | Test substance activity measurement method |
JP3213831B2 (en) * | 1993-08-06 | 2001-10-02 | 日本臓器製薬株式会社 | Test substance activity measurement method |
JP2594222B2 (en) * | 1993-09-28 | 1997-03-26 | 日本臓器製薬株式会社 | New physiologically active substance-KF |
JP4033936B2 (en) * | 1997-01-08 | 2008-01-16 | 日本臓器製薬株式会社 | Nitric oxide production inhibitor |
KR19990044835A (en) | 1997-11-28 | 1999-06-25 | 고니시 진우에몬 | Herbal Extract |
CA2305825A1 (en) | 1999-04-15 | 2000-10-15 | Nippon Zoki Pharmaceutical Co., Ltd. | Novel bioactivating substance |
JP2001058949A (en) * | 1999-08-20 | 2001-03-06 | Fujimoto Brothers:Kk | Anti-shock agent |
CA2337484A1 (en) | 2000-02-18 | 2001-08-18 | Jin-Emon Konishi | Fatty acid-containing composition |
US6913900B2 (en) | 2001-08-29 | 2005-07-05 | Nippon Zoki Pharmaceutical Co., Ltd. | Plasma prekallikrein activation and kallikrein production assay |
KR101307999B1 (en) | 2004-12-01 | 2013-09-12 | 니폰 조키 세야쿠 가부시키가이샤 | Dried material and method for the manufacture thererof |
US20060134646A1 (en) | 2004-12-17 | 2006-06-22 | Ansari Aftab A | Method for treatment of HIV infection |
CA2909234C (en) | 2013-04-30 | 2023-03-14 | Nippon Zoki Pharmaceutical Co., Ltd. | Extracts and preparation thereof from inflamed skins of rabbits inoculated with vaccinia virus |
WO2015120317A1 (en) * | 2014-02-07 | 2015-08-13 | Neurocrine Biosciences, Inc. | Pharmaceutical compositions comprising an antipsychotic drug and a vmat2 inhibitor and uses thereof |
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EA201991784A1 (en) | 2017-01-27 | 2021-09-23 | Нейрокрин Байосайенсиз, Инк. | METHODS OF ADMINISTRATION OF SOME VMAT2 INHIBITORS |
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US10993941B2 (en) | 2017-10-10 | 2021-05-04 | Neurocrine Biosciences, Inc. | Methods for the administration of certain VMAT2 inhibitors |
US20200230127A1 (en) | 2017-10-10 | 2020-07-23 | Neurocrine Biosciences, Inc. | Methods for the Administration of Certain VMAT2 Inhibitors |
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-
1980
- 1980-11-04 JP JP55155486A patent/JPS5777697A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS5777697A (en) | 1982-05-15 |
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