JPS6157284B2 - - Google Patents
Info
- Publication number
- JPS6157284B2 JPS6157284B2 JP2986880A JP2986880A JPS6157284B2 JP S6157284 B2 JPS6157284 B2 JP S6157284B2 JP 2986880 A JP2986880 A JP 2986880A JP 2986880 A JP2986880 A JP 2986880A JP S6157284 B2 JPS6157284 B2 JP S6157284B2
- Authority
- JP
- Japan
- Prior art keywords
- cystine
- allyl
- sulfoxide
- administration
- administered
- 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
- 239000003814 drug Substances 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 7
- 208000019423 liver disease Diseases 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229940124597 therapeutic agent Drugs 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 38
- 238000002474 experimental method Methods 0.000 description 21
- 241000700159 Rattus Species 0.000 description 18
- MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 description 12
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 230000001225 therapeutic effect Effects 0.000 description 12
- 210000002966 serum Anatomy 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 206010067125 Liver injury Diseases 0.000 description 8
- 231100000234 hepatic damage Toxicity 0.000 description 8
- 230000008818 liver damage Effects 0.000 description 8
- 230000003449 preventive effect Effects 0.000 description 8
- 241000283973 Oryctolagus cuniculus Species 0.000 description 7
- 230000037396 body weight Effects 0.000 description 7
- 208000006454 hepatitis Diseases 0.000 description 7
- 210000004185 liver Anatomy 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 206010008909 Chronic Hepatitis Diseases 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000002075 main ingredient Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 3
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229960003067 cystine Drugs 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 150000003462 sulfoxides Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 108010088751 Albumins Proteins 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 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 2
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 2
- 239000004158 L-cystine Substances 0.000 description 2
- 235000019393 L-cystine Nutrition 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
- 241000700157 Rattus norvegicus Species 0.000 description 2
- 102000003929 Transaminases Human genes 0.000 description 2
- 108090000340 Transaminases Proteins 0.000 description 2
- 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 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229940102223 injectable solution Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010015719 Exsanguination Diseases 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 206010019133 Hangover Diseases 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 206010042220 Stress ulcer Diseases 0.000 description 1
- 206010043275 Teratogenicity Diseases 0.000 description 1
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 244000245420 ail Species 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 238000010876 biochemical test Methods 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 235000015115 caffè latte Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 238000012754 cardiac puncture Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 231100000132 chronic toxicity testing Toxicity 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 235000004611 garlic Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 230000006651 lactation Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 238000006213 oxygenation reaction Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 235000021055 solid food Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003375 sulfoxide group Chemical group 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000009182 swimming Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 231100000211 teratogenicity Toxicity 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本発明は、Ｓ−アリル−Ｌ−シスチン−（−）−
スルホキシドを主成分とし、若くはＳ−アリル−
Ｌ−シスチン−（−）（＋）−スルホキシドの混合
物を主成分として製剤される肝疾患治療および疲
労回復用薬剤に関するものである。
Ｓ−アリル−Ｌ−シスチン−（＋）−スルホキシ
ドは天然産の大蒜（にんにく）から抽出すること
ができるが、本発明において主成分として使用す
るＳ−アリル−Ｌ−シスチン−（−）−スルホキシ
ドは自然界に存在しないジアステレオマーで、人
為的に合成することによつて得ることができる
が、その合成方法は、ジエツセ、Ｐ・グリーンス
テイルとミルトン、ウエニツとの共著になる「ケ
ミストリーオブジアミノアシツヅ（Chemistry
of Amino Acids、by TesseP.Greenstein and
Milton Winitz、John Wiley and Sons、
lnc.1961）の2662ページ乃至2664に記載されてい
る下記手段によつて得ることができる。
即ち、Ｌ−シスチン24ｇを500mlの水に溶解
し、これに25ｇのアリルブロマイドを加え、200
mlになるまで水を飛ばし、冷しながらPH5.0に調
整し、80％エタノールを混じ、Ｓ−アリル−Ｌ−
シスチンを取り出すが、合成過程においてＳ−ア
リル−Ｌ−シスチン−（＋）と（−）−スルホキシ
ドが略等量含まれており、この中からＳ−アリル
−Ｌ−シスチン−（−）−スルホキシドのみを取り
出すが、収量が1/3程度になる。
このＳ−アリル−Ｌ−シスチン−（−）−スルホ
キシドを使用するのがより効果があるが、合成過
程において得られるＳ−アリル−Ｌ−シスチン−
（＋）と（−）−スルホキシドを略等量混合した物
質を用いても略同じ治療効果および疲労回復効果
は殆んど変わらず、前者の物質を主成分として
も、後者の混合物を主成分としても大きな効能の
差異なく使用することができる。
本発明は、このようにして得られるＳ−アリル
−Ｌ−シスチン−（−）−スルホキシド及びＳ−ア
リル−Ｌ−シスチン−（−）（＋）−スルホキシド
が再生肝、創傷治癒、疲労等に際して、細胞を活
性にし、そして細胞増殖を旺盛にすることを慢性
肝炎の患者または中高年者に服用させ、また動物
実験の結果からも、さらに組織培養の結果から立
証し、細胞増殖と活性を旺盛にする密接な関係を
有することを見出し、このＳ−アリル−Ｌ−シス
チン−（−）−スルホキシドを主成分とし、若くは
Ｓ−アリル−Ｌ−シスチン−（−）（＋）−スルホ
キシド混合物を主成分として散剤、カプセル剤、
錠剤及び注射用液剤等に製剤し、肝疾患治療およ
び疲労回復用薬剤として提供するものである。
以下、これらの製造を具体例に基き述べること
とする。
先ず、散剤はＳ−アリル−Ｌ−シスチン−
（−）−スルホキシド若くはＳ−アリル−Ｌ−シス
チン−（−）（＋）−スルホキシドを乳糖或はブド
ウ糖に混合し、１回量５〜50mgとし、１日２回、
即ち１日10〜100mg服用させる。この散剤は１日
量1100mg程度投与しても人体に副作用は認められ
ない。
カプセル剤は散剤と同様に主成分を乳糖或はブ
ドウ糖に混合し、１カプセル中に５mg含有させ１
回量２〜10錠を１日３回、即ち１日量５〜100mg
服用させる。
錠剤は散剤、カプセル剤と同様の組成にさらに
炭酸カルシウム、澱粉等を加えて成型したもの
で、１錠中に含まれる主成分量は５mg、服用量は
散剤と同じである。
さらに注射用液剤は、主成分を生理的食塩水に
溶解したものを１mlアンプル中に10mg含有させ、
１日２回、即ち１日量は主成分を５〜100mg筋肉
内または皮下注射して投与する。
次に、本発明に係わる肝疾患治療剤の有効性に
ついて述べる。
先ず、発明者は、四塩化炭素及びＤ−ガラクト
サミンを用いてラツテに肝障害を起こさせて治療
実験をし、また、四塩化炭素及びＤ−ガラクトサ
ミンで肝障害を起こさせる前にＳ−アリル−Ｌ−
シスチン−（−）−スルホキシドまたは、Ｓ−アリ
ル−Ｌ−シスチン−（−）（＋）−スルホキシドを
投与する予備実験により血液学的、血清の生化学
的及び病理組織学的に炎症反応や肝障害の著しい
改善がみられ、本発明の有効性の実証を行なつ
た。
以下に四塩化炭素による予防及び治療実験、四
塩化炭素による治療実験、Ｄ−ガラクトサミンに
よる実験を投与ラツテ及び家兎について、さらに
慢性肝炎患者による治療実験の順に実験結果の詳
細を説明する。
実験例 １
四塩化炭素による予防及び治療実験
試験動物は体重150ｇ±10ｇ前後の雌雄ウイス
ター系ラツテを使用した。飼育室は温度22℃±１
℃、温度は50〜60％に調節し、固型飼料と水を自
由に摂取させた。
Ｓ−アリル−Ｌ−シスチン−（−）−スルホキシ
ドまたはＳ−アリル−Ｌ−シスチン−（−）（＋）
−スルホキシドを1000γ/ml、500γ/ml、200γ/
ml、50γ/ml及び10γ/mlの濃度の溶液に調製し、
その１mlずつを５日間、20日間及び30日間毎日皮
下内投与し、投与１週間後、３日間にわたり１日
１回、計３回四塩化炭素を吸入させた。
四塩化炭素を吸入させた10日後に４匹、20日後
に３匹、30日後に３匹各群よりラツテを取出し放
血死させた後肝蔵を摘出し、湿重量を測定した後
10％ホルマリン及び無水アルコールにより固定し
て病理標本を作成した肝の組織学的検索にはＨ−
Ｅ染色、グリコーゲン染色及び脂肪染色を行なつ
て観察した。また、各群については３日おきに体
重を測定し、体重曲線を求めた。
なお、四塩化炭素の吸入については各ラツテの
吸入程度を同一にするため、ガラス容器中に１匹
ずつ入れて四塩化炭素の吸入を確実に行なわせ
た。
この実験の結果、Ｓ−アリル−Ｌ−シスチン−
（−）−スルホキシドまたはＳ−アリル−Ｌ−シス
チン−（−）（＋）−スルホキシドを投与した群は
投与量の多いほど体重の増加がよく、また四塩化
炭素のみの投与群は体重増加が最も悪い結果を得
た。
Ｓ−アリル−Ｌ−シスチン−（−）−スルホキシ
ド投与による肝障害の治療結果は次の通りであ
る。
The present invention provides S-allyl-L-cystine-(-)-
The main component is sulfoxide, and young ones are S-allyl-
The present invention relates to a drug for treating liver diseases and relieving fatigue, which is formulated with a mixture of L-cystine-(-)(+)-sulfoxide as the main ingredient. S-allyl-L-cystine-(+)-sulfoxide can be extracted from naturally produced garlic, but S-allyl-L-cystine-(-)-sulfoxide used as the main component in the present invention is a diastereomer that does not exist in nature and can be obtained by artificial synthesis, but its synthesis method is described in the book "Chemistry of Diamino Acids" co-authored by Jietzse and P. Greenstehl and Milton and Uenitz. Tsuzu (Chemistry
of Amino Acids, by Tesse P. Greenstein and
Milton Winitz, John Wiley and Sons,
lnc.1961), pages 2662 to 2664. That is, 24g of L-cystine was dissolved in 500ml of water, 25g of allyl bromide was added thereto, and 200g of L-cystine was dissolved in 500ml of water.
ml, adjust the pH to 5.0 while cooling, mix with 80% ethanol, and add S-Allyl-L-
Cystine is extracted, but S-allyl-L-cystine-(+) and (-)-sulfoxide are contained in approximately equal amounts during the synthesis process, and from this, S-allyl-L-cystine-(-)-sulfoxide is extracted. However, the yield will be about 1/3. Although it is more effective to use this S-allyl-L-cystine-(-)-sulfoxide, S-allyl-L-cystine-(-)-sulfoxide obtained in the synthesis process
Even if a substance containing approximately equal amounts of (+) and (-)-sulfoxide is used, the therapeutic effect and fatigue recovery effect are almost the same. It can also be used without significant difference in efficacy. The present invention provides that S-allyl-L-cystine-(-)-sulfoxide and S-allyl-L-cystine-(-)(+)-sulfoxide thus obtained are effective in regenerating liver, wound healing, fatigue, etc. The drug was administered to patients with chronic hepatitis or middle-aged and elderly people, and it was proven from animal experiments and tissue culture results that it activates cells and stimulates cell proliferation. It was discovered that S-allyl-L-cystine-(-)-sulfoxide is the main component, and in younger cases, S-allyl-L-cystine-(-)(+)-sulfoxide mixture is the main component. Ingredients include powders, capsules,
It is formulated into tablets and liquid injections, and is provided as a drug for treating liver diseases and recovering from fatigue. The production of these will be described below based on specific examples. First, the powder is S-allyl-L-cystine-
(-)-sulfoxide or S-allyl-L-cystine-(-)(+)-sulfoxide is mixed with lactose or glucose, and the dose is 5 to 50 mg, twice a day.
That is, the dose is 10 to 100 mg per day. This powder has no side effects on the human body even when administered at a daily dose of about 1,100 mg. Capsules are made by mixing the main ingredient with lactose or glucose in the same way as powders, and each capsule contains 5 mg.
2 to 10 tablets 3 times a day, i.e. 5 to 100 mg per day
Have them take it. Tablets are made by adding calcium carbonate, starch, etc. to the same composition as powders and capsules, and each tablet contains 5 mg of the main ingredient, and the dosage is the same as that of powders. Furthermore, the injectable solution contains 10 mg of the main ingredient dissolved in physiological saline in a 1 ml ampoule.
It is administered twice a day, ie, the daily dose is 5 to 100 mg of the main ingredient by intramuscular or subcutaneous injection. Next, the effectiveness of the liver disease therapeutic agent according to the present invention will be described. First, the inventor conducted a therapeutic experiment by causing liver damage in rats using carbon tetrachloride and D-galactosamine, and also conducted a treatment experiment using carbon tetrachloride and D-galactosamine to cause liver damage in rats. L-
Preliminary experiments in which cystine-(-)-sulfoxide or S-allyl-L-cystine-(-)(+)-sulfoxide were administered revealed hematological, serum biochemical, and histopathological effects on inflammatory reactions and liver disease. A remarkable improvement in the disability was observed, demonstrating the effectiveness of the present invention. Below, the details of the experimental results will be explained in the order of prevention and treatment experiment with carbon tetrachloride, treatment experiment with carbon tetrachloride, experiment with D-galactosamine on administered rats and rabbits, and treatment experiment on chronic hepatitis patients. Experimental Example 1 Prevention and Treatment Experiment with Carbon Tetrachloride The test animals used were male and female Wistar rats weighing approximately 150g±10g. The temperature of the breeding room is 22℃±1
The temperature was adjusted to 50-60%, and the animals were given free access to solid food and water. S-allyl-L-cystine-(-)-sulfoxide or S-allyl-L-cystine-(-)(+)
-Sulfoxide 1000γ/ml, 500γ/ml, 200γ/
ml, 50γ/ml and 10γ/ml solutions,
1 ml of the same was administered subcutaneously every day for 5, 20, and 30 days, and one week after administration, carbon tetrachloride was inhaled once a day for 3 days, a total of 3 times. After 10 days of carbon tetrachloride inhalation, 4 rats, 20 days after 3 rats, and 3 rats after 30 days were taken out from each group and killed by exsanguination.The liver was removed and the wet weight was measured.
H- for histological examination of livers fixed with 10% formalin and absolute alcohol to prepare pathological specimens
Observations were made using E staining, glycogen staining, and fat staining. In addition, the weight of each group was measured every 3 days, and a weight curve was obtained. Regarding inhalation of carbon tetrachloride, in order to make the inhalation level of each latte the same, each rat was placed in a glass container to ensure inhalation of carbon tetrachloride. As a result of this experiment, S-allyl-L-cystine-
In the group administered with (-)-sulfoxide or S-allyl-L-cystine-(-)(+)-sulfoxide, the higher the dose, the better the weight gain, and in the group administered only with carbon tetrachloride, the weight gain was lower. got the worst results. The results of treatment of liver damage by administration of S-allyl-L-cystine-(-)-sulfoxide are as follows.
【表】
上表において、対照の障害の程度を基準として
肝障害の病変を＋〜＋＋＋＋とした。障害は小葉
構造、肝細胞の配列、大小不同、壊死、混濁腫
脹、空胞変性、核の変化、遊走細胞の程度等によ
り決めた。
上表のように、四塩化炭素のみ投与群は障害程
度が強いのに反し、Ｓ−アリル−Ｌ−シスチン−
（−）−スルホキシドの100〓、500〓及び200〓投
与群は肝障害の程度が著しく軽減された。
また、血清中の生化学的所見としてGOT、
GPT（血清トランスアミナーゼ）は四塩化炭素
のみ投与群は1000前後の高い値を示すのに対し、
Ｓ−アリル−Ｌ−シスチン−（−）−スルホキシド
投与群は10日後が500、20日後が100前後の値を示
した。
このように肝炎治癒或は肝障害治癒の効果が認
められたが、このような治療効果及び予防効果は
Ｓ−アリル−Ｌ−シスチン−（−）（＋）−スルホ
キシドにおいても略同程度に観察された。
実験例 ２
四塩化炭素による治療効果
体重150ｇ前後の雌雄ウイスター系ラツテを恒
温、恒湿状態で飼育し、飼料と水は自由に摂取さ
せ、外見上健康と思われるものを本実験に使用し
た。
四塩化炭素を１日１回、３日間吸入させた。
Ｓ−アリル−Ｌ−シスチン−（−）−スルホキシ
ドは生理的食温水で溶解させ、各群とも１匹当た
り200γずつ毎日腹腔内投与、皮下内投与及び静
脈内投与を行なつた。静脈内投与はエーテル麻酔
後に行なつた。
四塩化炭素吸入及び薬物投与後ラツテの動態を
観察した。
、体重測定は四塩化炭素を吸収させる前日と、
吸収から３、６、10、13、16及び20日後に夫々行
なつた。
10日後及び20日後の投与終了後、即ち、11日目
と21日目にラツテを麻酔させ、放血致死させた
後、肝の湿重量を測定した。また、ラツテの血清
についてはGOT、GPT（血清トランアミナー
ゼ）ALP（アルカリフオスフアターゼ）、LDH
（血清乳酸化脱水素酸素）、BUN（尿素窒素）、総
蛋白及びアルブミン等いろいろの検査を行なつ
た。さらに主要臓器についてはホルマリン固定
後、病理組織標本を作成して鏡検した。
体重曲線の結果、体重の増加に対しては腹腔内
投与、皮下内投与及び静脈内投与とも何れも認め
られる異常はなかつた。
血清の生化学的検査においてはGPT、ALP、
LDH、BUN、総蛋白及びアルブミン等には何れ
も認められる差はなく、生理的な変動範囲であつ
たが、GOTについては下表に示すように若干の
差が認められた。[Table] In the above table, lesions of liver damage were classified as + to +++++ based on the degree of damage in the control. The damage was determined based on the lobular structure, hepatocyte arrangement, size irregularity, necrosis, opaque swelling, vacuolar degeneration, nuclear changes, degree of migrating cells, etc. As shown in the table above, the group administered only with carbon tetrachloride had a strong degree of impairment, while the S-allyl-L-cystine-
The degree of liver damage was significantly reduced in the (-)-sulfoxide administration groups of 100〓, 500〓, and 200〓. In addition, as biochemical findings in serum, GOT,
GPT (serum transaminase) showed a high value of around 1000 in the group receiving only carbon tetrachloride;
The S-allyl-L-cystine-(-)-sulfoxide administration group showed values of 500 after 10 days and around 100 after 20 days. In this way, the effect of curing hepatitis or liver damage was observed, but these therapeutic and preventive effects were also observed to approximately the same extent with S-allyl-L-cystine-(-)(+)-sulfoxide. It was done. Experimental Example 2 Therapeutic Effect of Carbon Tetrachloride Male and female Wistar rats weighing around 150 g were kept at constant temperature and humidity, allowed free access to feed and water, and were apparently healthy and used in this experiment. Carbon tetrachloride was inhaled once a day for 3 days. S-allyl-L-cystine-(-)-sulfoxide was dissolved in saline-warmed water, and 200 γ per animal in each group was administered intraperitoneally, subcutaneously, and intravenously every day. Intravenous administration was performed after ether anesthesia. The dynamics of the rats after carbon tetrachloride inhalation and drug administration were observed. , the weight was measured the day before carbon tetrachloride was absorbed,
The tests were carried out 3, 6, 10, 13, 16 and 20 days after absorption, respectively. After 10 and 20 days of administration, that is, on the 11th and 21st days, the rats were anesthetized and exsanguinated to death, and the wet weight of the liver was measured. In addition, regarding rat serum, GOT, GPT (serum transaminase), ALP (alkaline phosphatase), LDH
Various tests were conducted including serum lactation, dehydrogenation, oxygenation, BUN (urea nitrogen), total protein, and albumin. Furthermore, after formalin fixation of the major organs, histopathological specimens were prepared and microscopically examined. As a result of the body weight curve, no abnormality was observed in the increase in body weight for either intraperitoneal administration, subcutaneous administration, or intravenous administration. In serum biochemical tests, GPT, ALP,
There was no discernible difference in LDH, BUN, total protein, albumin, etc., which were all within physiological fluctuation ranges, but slight differences were observed in GOT, as shown in the table below.
【表】【table】
【表】
上記表に示すようにＳ−アリル−Ｌ−シスチン
−（−）−スルホキシド投与群では、四塩化炭素に
よる肝障害治療実験成績において抜群であること
が明らかとなつた。
その他、四塩化炭素を用いた実験としてラツテ
の系統による治療効果の差異、投与方法と治療効
果、四塩化炭素吸入回数とその予防効果、投与方
法による予防効果、ラツテの種差による予防効
果、投与量と投与方法による治療効果並びに予防
効果について検討したが、Ｓ−アリル−Ｌ−シス
チン−（−）−スルホキシドの試験成績の予防成績
が優れていることが血清学的にも病理組織学的に
も立証することができた。
このような効果はＳ−アリル−Ｌ−シスチン−
（−）（＋）−スルホキシドにおいても証明され
た。
実験例 ３
Ｄ−ガラクトサミンによる実験成績−投与ラツ
テにおける影響
生理的食塩水に溶解したＤ−ガラクトサミンの
ラツテの体重１Kgにつき300mlの割で腹腔内に投
与し、さらにＳ−アリル−Ｌ−シスチン−（−）−
スルホキシドを500〓、200〓、100〓に区分し
夫々皮下内投与した。
Ｄ−ガラクトサミン投与24時間後に各実験群の
ラツテより得られた血清のGOT及びGPTを測定
し、また、各臓器について肉眼的に観察し、さら
に肝蔵を摘出し病理組織標本を作成した。[Table] As shown in the above table, it was revealed that the S-allyl-L-cystine-(-)-sulfoxide administration group had excellent experimental results for treating liver damage caused by carbon tetrachloride. Other experiments using carbon tetrachloride include differences in therapeutic effects depending on the rat strain, administration method and therapeutic effect, number of carbon tetrachloride inhalations and its preventive effect, preventive effect depending on administration method, preventive effect due to differences in rat species, and dosage. We investigated the therapeutic and preventive effects of S-allyl-L-cystine-(-)-sulfoxide depending on the administration method, and the test results showed that S-allyl-L-cystine-(-)-sulfoxide had excellent preventive results both serologically and histopathologically. I was able to prove it. This effect is due to S-allyl-L-cystine-
It was also demonstrated for (-)(+)-sulfoxide. Experimental Example 3 Experimental results with D-galactosamine - Effects on administered rats D-galactosamine dissolved in physiological saline was administered intraperitoneally at a rate of 300 ml per 1 kg of rat body weight, and S-allyl-L-cystine-( −)−
Sulfoxide was divided into 500〓, 200〓, and 100〓 and administered subcutaneously. 24 hours after administration of D-galactosamine, GOT and GPT of the serum obtained from the rats of each experimental group were measured, each organ was visually observed, and the liver was removed to prepare a histopathological specimen.
【表】【table】
【表】
上表に示すようにGOT、GPT値とも、Ｓ−ア
リル−Ｌ−シスチン−（−）−スルホキシド投与群
が最も低く、治療効果も500〓及び200〓投与群が
最も優れている結果が得られた。同様にＳ−アリ
ル−Ｌ−シスチン−（−）（＋）−スルホキシド投
与群においても効果の優れていることが証明され
た。
実験例 ４
Ｄ−ガラクトサミンによる実験成績
−投与家兎における影響
3.0Kg前後の雌家兎を用いて実験した。
実験はＳ−アリル−Ｌ−シスチン−（−）−スル
ホキシドを体重１Kgにつき50mgの割で腹腔内へ投
与し、対照として体重１Kgにつき250mlの割でＤ
−ガラクトサミンを腹腔内へ投与した家兎及び無
処置のものを各１匹ずつ用いた。
Ｓ−アリル−Ｌ−シスチン−（−）−スルホキシ
ド投与24時間後及び48時間後に耳静脈からヘパリ
ン処理注射器で採血し、赤血球、白血球、ヘモグ
ロビン量及びヘマトクリツト値を測定すると共に
心臓穿刺によつて得た血清を用いてGOT、GPT
値等13項目について生化学的性状を測定した。薬
液投与24時間後及び48時間後に肝臓を取出し、病
理組織学的に観察した。
その結果、Ｓ−アリル−Ｌ−シスチン−（−）−
スルホキシドはＤ−ガラクトサミンによる肝障害
を防御することがGOT、GPT値及び病理組織学
的検討結果から立証された。
その他、Ｄ−ガラクトサミンを腹腔内に投与
し、２時間及び４時間後にＳ−アリル−Ｌ−シス
チン−（−）−スルホキシドを皮下内、腹腔内及び
経口的に1000〓、500〓、200〓、100〓投与し、
投与22時間後に血清中のGOT、GPT値及び肝の
病理組織学的所見を検討し優れた治療結果を認め
た。
また、Ｓ−アリル−Ｌ−シスチン−（−）−スル
ホキシドを皮下内、腹腔内及び経口的に投与し、
投与２時間及び４時間後にＤ−ガラクトサミンを
投与し、22時間後に血清の生化学的性状、病理組
織学的観察を行ない、優れた予防効果のあること
を認めた。
以上に述べたように、Ｄ−ガラクトサミンにつ
いてもラツテ、家兎を用いての予防実験及び治療
実験の結果、有効性を認めた。
同様にＳ−アリル−Ｌ−シスチン−（−）（＋）
−スルホキシド投与群においても効果の優れてい
ることが証明された。
実験例 ５
慢性肝炎患者による治療実験
50〜60才の男性36例について、Ｓ−アリル−Ｌ
−シスチン−（−）−スルホキシドを毎食後１日２
〜３回、２カ月間続けて経口に腹用させた結果、
24例についてGOT、GPTの値の低下が認めら
れ、また全身状態の回復されることがわかつた。
前記GOT、GPTは200〜300程度であつたものが
50前後に低下した。
なお、残る２例は慢性肝炎よりも肝硬変が強い
のか、服用開始２カ月後においてGOT、GPT値
の若干の減少が認められたのみで有意差はなあつ
た。またＳ−アリル−Ｌ−シスチン−（−）（＋）
−スルホキシドを慢性肝炎患者14例に用い治療実
験を行なつたところ、全例にGOT、GPTの低下
が認められた。
次にＳ−アリル−Ｌ−シスチン−（−）−スルホ
キシド及びＳ−アリル−Ｌ−シスチン−（−）
（＋）−スルホキシドの安全性について、急性毒性
試験、３カ月間の亜急性通性試験、６カ月間の慢
性毒性試験、３代にわたる催奇性実験、一般薬理
学的実験及び特殊薬理学的実験を行なつてその安
全性を証明することができた。
また、マウスでは体重１Kgにつき2.5ｇの割で
１ラツテで体重１Kgにつき1.5ｇの割で経口投
与、皮下内投与及び腹腔内投与しても死亡は１例
も認められなかつた。
一方本発明に係る薬剤は疲労回復剤あるいは精
力剤としての効果を有することも判つた。このこ
とは本剤を中高年者の男女50〜100名を対象に１
カ月間服用させ、食欲、倦怠感、胃腸症状等種々
の項目についてチエツクしたところ本剤の服用者
において疲労回復が早く、精力の増強、二日酔が
なくなつたなどの訴えが多く認められたことから
言えるものである。また本剤を投与した者と投与
みなかつた者とでは体力テスト（水泳、懸垂）を
行うと、薬剤投与者群の方が定性的ではあるが持
続力を有し、しかも長い期間投与した者ほどその
持続力があることも認められた。またこれらはＳ
−アリル−Ｌ−シスチン−（＋）−スルホキシドよ
りもＳ−アリル−Ｌ−シスチン−（−）（＋）−ス
ルホキシド、またはこれよりもＳ−アリル−Ｌ−
シスチン−（−）−スルホキシドが回復剤、精力剤
として強く作用することを認めた。
またこれらは胃潰瘍にも効果のあることをスト
レス潰瘍などで証明した。
以上に詳述したようにＳ−アリル−Ｌ−シスチ
ン−（−）−スルホキシド若くはＳ−アリル−Ｌ−
シスチン−（−）（＋）−スルホキシド混合物を主
成分とする本発明の肝疾患治療および疲労回復用
薬剤は、ラツテや家兎による動物を用いての予防
実験並ひに治療実験および耐久力試験のみなら
ず、慢性肝炎患者による治療実験また中高年者に
おける回復率からも有効性が実証され、また、安
全性についても前述の各種実験結果からその安全
性を立証することができた。
そして投与手段として経口投与、皮下内投与、
静脈内投与は腹腔内投与の何れの手段を用いても
有効でしかも安全であり、また、散剤、カプセル
剤、錠剤或は注射用液剤として製剤することがで
きるために、疾患の症状や疲労度に適応した投与
手段を採ることができ、一層治療効果を増進する
ことができる。[Table] As shown in the above table, the S-allyl-L-cystine-(-)-sulfoxide administration group had the lowest GOT and GPT values, and the 500〓 and 200〓 administration groups had the best therapeutic effect. was gotten. Similarly, excellent effects were demonstrated in the S-allyl-L-cystine-(-)(+)-sulfoxide administration group. Experimental Example 4 Experimental results with D-galactosamine - Effects on administered rabbits Experiments were conducted using female rabbits weighing approximately 3.0 kg. In the experiment, S-allyl-L-cystine-(-)-sulfoxide was intraperitoneally administered at a rate of 50 mg per 1 kg of body weight, and as a control, D was administered at a rate of 250 ml per 1 kg of body weight.
- One rabbit each received intraperitoneal administration of galactosamine and one untreated rabbit. 24 hours and 48 hours after administration of S-allyl-L-cystine-(-)-sulfoxide, blood was collected from the ear vein using a heparinized syringe, and red blood cells, white blood cells, hemoglobin levels, and hematocrit levels were measured and obtained by cardiac puncture. GOT, GPT using serum
Biochemical properties were measured for 13 items including values. The liver was removed 24 and 48 hours after administration of the drug solution and histopathologically observed. As a result, S-allyl-L-cystine-(-)-
It was proven from GOT, GPT values and histopathological examination results that sulfoxide protects against liver damage caused by D-galactosamine. In addition, D-galactosamine was administered intraperitoneally, and 2 and 4 hours later, S-allyl-L-cystine-(-)-sulfoxide was administered subcutaneously, intraperitoneally, and orally at 1000〓, 500〓, 200〓, 100〓 administered,
22 hours after administration, serum GOT and GPT values and histopathological findings of the liver were examined, and excellent therapeutic results were found. In addition, S-allyl-L-cystine-(-)-sulfoxide is administered subcutaneously, intraperitoneally and orally,
D-galactosamine was administered 2 and 4 hours after administration, and 22 hours later, serum biochemical properties and histopathological observations were performed, and it was found that it had an excellent preventive effect. As mentioned above, D-galactosamine was also found to be effective as a result of preventive and therapeutic experiments using rats and rabbits. Similarly, S-allyl-L-cystine-(-)(+)
- It was proven that the effect was excellent even in the sulfoxide administration group. Experimental example 5 Treatment experiment with chronic hepatitis patients. S-allyl-L was used in 36 male patients aged 50-60.
- Cystine-(-)-sulfoxide 2 days a day after every meal
As a result of oral and abdominal administration 3 times for 2 months,
In 24 cases, a decrease in GOT and GPT values was observed, and it was also found that the general condition improved.
The GOT and GPT mentioned above were about 200 to 300.
It dropped to around 50. In the remaining two cases, perhaps due to liver cirrhosis being more severe than chronic hepatitis, only a slight decrease in GOT and GPT values was observed two months after the start of treatment, and there was no significant difference. Also, S-allyl-L-cystine-(-)(+)
- When a treatment experiment was conducted using sulfoxide on 14 patients with chronic hepatitis, a decrease in GOT and GPT was observed in all patients. Then S-allyl-L-cystine-(-)-sulfoxide and S-allyl-L-cystine-(-)
Regarding the safety of (+)-sulfoxide, we conducted an acute toxicity test, a 3-month subacute facultative test, a 6-month chronic toxicity test, a teratogenicity test over 3 generations, a general pharmacological test, and a special pharmacological test. We were able to prove its safety. Furthermore, in mice, no death was observed even when administered orally, subcutaneously, or intraperitoneally at a rate of 2.5g per kg of body weight per rat at a rate of 1.5g per kg of body weight. On the other hand, it was also found that the drug according to the present invention has an effect as a fatigue-relieving agent or an energizing agent. This means that this drug was administered to 50 to 100 middle-aged and elderly men and women.
After taking the drug for a month and checking various items such as appetite, fatigue, and gastrointestinal symptoms, many patients who took this drug complained of faster recovery from fatigue, increased energy, and no hangovers. This can be said from this. In addition, when physical fitness tests (swimming, pull-ups) were conducted between those who received the drug and those who did not receive the drug, the drug-administered group had qualitatively better endurance, and moreover, those who did not receive the drug for a long period of time had better endurance. It was also recognized that it has a long lasting power. Also, these are S
S-allyl-L-cystine-(-)(+)-sulfoxide than -allyl-L-cystine-(+)-sulfoxide, or S-allyl-L-
Cystine-(-)-sulfoxide was found to have strong effects as a restorative and energizing agent. They have also proven that they are effective against stomach ulcers, such as stress ulcers. As detailed above, S-allyl-L-cystine-(-)-sulfoxide or S-allyl-L-
The drug for treating liver diseases and relieving fatigue of the present invention, which contains a mixture of cystine-(-)(+)-sulfoxide as a main component, has been tested in animal prevention experiments using rats and rabbits, as well as therapeutic experiments and durability tests. Not only that, its effectiveness was demonstrated through treatment experiments with chronic hepatitis patients and recovery rates among middle-aged and elderly patients, and its safety was also demonstrated through the results of the various experiments mentioned above. Oral administration, subcutaneous administration,
Intravenous administration is effective and safe regardless of whether intraperitoneal administration is used, and since it can be formulated as a powder, capsule, tablet, or injectable solution, it can reduce the symptoms of the disease and the degree of fatigue. It is possible to adopt an administration method that is suitable for the patient, and the therapeutic effect can be further enhanced.
Claims (1)
シド、若しくはＳ−アリル−Ｌ−シスチン−
（−）（＋）−スルホキシドの混合物を有効成分と
する肝疾患治療剤。 ２ Ｓ−アリル−Ｌ−シスチン−（−）−スルホキ
シド、若しくはＳ−アリル−Ｌ−シスチン−
（−）（＋）−スルホキシドの混合物を有効成分と
する疲労回復剤。[Claims] 1 S-allyl-L-cystine-(-)-sulfoxide, or S-allyl-L-cystine-
A liver disease therapeutic agent containing a mixture of (-)(+)-sulfoxides as an active ingredient. 2 S-allyl-L-cystine-(-)-sulfoxide, or S-allyl-L-cystine-
A fatigue relief agent containing a mixture of (-)(+)-sulfoxide as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2986880A JPS56127312A (en) | 1980-03-10 | 1980-03-10 | Drug for remedy of hepatic disease and recovery from fatigue |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2986880A JPS56127312A (en) | 1980-03-10 | 1980-03-10 | Drug for remedy of hepatic disease and recovery from fatigue |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS56127312A JPS56127312A (en) | 1981-10-06 |
| JPS6157284B2 true JPS6157284B2 (en) | 1986-12-06 |
Family
ID=12287942
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2986880A Granted JPS56127312A (en) | 1980-03-10 | 1980-03-10 | Drug for remedy of hepatic disease and recovery from fatigue |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS56127312A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0292030U (en) * | 1989-01-10 | 1990-07-20 |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102016117961A1 (en) | 2016-09-23 | 2018-03-29 | Dr. Ing. H.C. F. Porsche Aktiengesellschaft | Exhaust system of a combustion-powered motor vehicle with turbocharger |
-
1980
- 1980-03-10 JP JP2986880A patent/JPS56127312A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0292030U (en) * | 1989-01-10 | 1990-07-20 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS56127312A (en) | 1981-10-06 |
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