JPH0429928A - Antiarrhythmic agent - Google Patents
Antiarrhythmic agentInfo
- Publication number
- JPH0429928A JPH0429928A JP13695290A JP13695290A JPH0429928A JP H0429928 A JPH0429928 A JP H0429928A JP 13695290 A JP13695290 A JP 13695290A JP 13695290 A JP13695290 A JP 13695290A JP H0429928 A JPH0429928 A JP H0429928A
- Authority
- JP
- Japan
- Prior art keywords
- arrhythmia
- salts
- antiarrhythmic
- esters
- amides
- 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.)
- Granted
Links
- 239000003416 antiarrhythmic agent Substances 0.000 title claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 150000001408 amides Chemical class 0.000 claims abstract description 5
- 150000002148 esters Chemical class 0.000 claims abstract description 5
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 claims description 17
- 239000004480 active ingredient Substances 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 4
- 206010003119 arrhythmia Diseases 0.000 abstract description 18
- 230000006793 arrhythmia Effects 0.000 abstract description 18
- -1 esters amides Chemical class 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 11
- 238000000034 method Methods 0.000 abstract description 7
- 208000010125 myocardial infarction Diseases 0.000 abstract description 7
- 208000003663 ventricular fibrillation Diseases 0.000 abstract description 7
- 241001465754 Metazoa Species 0.000 abstract description 3
- 238000004587 chromatography analysis Methods 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000000199 molecular distillation Methods 0.000 abstract description 2
- 208000031225 myocardial ischemia Diseases 0.000 abstract description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 abstract 1
- 238000002955 isolation Methods 0.000 abstract 1
- 230000002107 myocardial effect Effects 0.000 abstract 1
- 239000007924 injection Substances 0.000 description 18
- 238000002347 injection Methods 0.000 description 18
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 17
- 238000002474 experimental method Methods 0.000 description 14
- 235000020669 docosahexaenoic acid Nutrition 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 241000700159 Rattus Species 0.000 description 11
- 235000011187 glycerol Nutrition 0.000 description 8
- ITNKVODZACVXDS-YNUSHXQLSA-N ethyl (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate Chemical compound CCOC(=O)CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC ITNKVODZACVXDS-YNUSHXQLSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 229940090949 docosahexaenoic acid Drugs 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 6
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000006698 induction Effects 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 230000034994 death Effects 0.000 description 4
- 231100000517 death Toxicity 0.000 description 4
- 235000021323 fish oil Nutrition 0.000 description 4
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 235000021588 free fatty acids Nutrition 0.000 description 3
- 206010049993 Cardiac death Diseases 0.000 description 2
- 206010011906 Death Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000010775 animal oil Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 2
- 229960004194 lidocaine Drugs 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229960001404 quinidine Drugs 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- PIFNLEVPOVXBCF-UHFFFAOYSA-N CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O Chemical compound CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O.CCCC=CC(N)=O PIFNLEVPOVXBCF-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
- 208000001953 Hypotension Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 150000001218 Thorium Chemical class 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 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 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000005242 cardiac chamber Anatomy 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 235000018823 dietary intake Nutrition 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- UZBQIPPOMKBLAS-UHFFFAOYSA-N diethylazanide Chemical compound CC[N-]CC UZBQIPPOMKBLAS-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000013022 formulation composition Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 235000020978 long-chain polyunsaturated fatty acids Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- REQCZEXYDRLIBE-UHFFFAOYSA-N procainamide Chemical compound CCN(CC)CCNC(=O)C1=CC=C(N)C=C1 REQCZEXYDRLIBE-UHFFFAOYSA-N 0.000 description 1
- 229960000244 procainamide Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000009863 secondary prevention Effects 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、（ａｌｌ−ｚ） ４． ７．１０．１３．
１６．１９ドコサヘキサエン酸を有効成分として含有す
る抗不整脈薬に関するものである。DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention comprises (all-z) 4. 7.10.13.
16.19 This invention relates to an antiarrhythmic drug containing docosahexaenoic acid as an active ingredient.
（従来の技術）
現在使用されている速効性の抗不整脈薬としてはキニジ
ン、プロカインアミド、リドカインなどの合成医薬品が
その代表例として挙げられる。また心筋梗塞を起こして
から２４時間以内に死亡する例の大部分は不整脈である
とされ、中でも心室細動は最も危険な不整脈であり直接
心臓死に移行する。心筋梗塞の２次子防の研究として魚
油食が有効であることは、すてに幸し告されている。（
Ｒ，Ａ。(Prior Art) Synthetic drugs such as quinidine, procainamide, and lidocaine are representative examples of fast-acting antiarrhythmic drugs currently in use. Furthermore, most cases of death within 24 hours after myocardial infarction are said to be due to arrhythmia, and among these, ventricular fibrillation is the most dangerous arrhythmia and directly leads to cardiac death. It has been happily reported that fish oil diets are effective in research on secondary prevention of myocardial infarction. (
R, A.
Ｒｉｅｍｅｒｓａ ｅｔ ａｌ、 Ｊ、 Ｉｎ
ｔｅｒｎａｌ Ｍｅｄ、＋ ２２５＋ １１１（
発明が解決しようとする課題）
速効性の抗不整脈薬は効果が顕著である反面、副作用も
多く、例えば上記のキニジンは重篤な低血圧をまねくな
どの副作用が知られており、リドカインでは肝臓での代
謝が速く作用時間が短いなどの問題点を持っている。ま
た、魚油食による有益な作用が（ａｌｌ−ｚ） −４，
７，１０，１３，１６，１９ドコサヘキサエン酸の持つ
生理作用であることを直接証明する研究報告例は殆どな
く、本発明が提供する（ａｌｌ−ｚ）−４，７，１０，
１３，１６，１９−ドコサヘキサエン酸の抗不整脈効果
に関する報告例もない。魚油の食餌摂取は不整脈に対す
る防御効果を示すが、この効果が発現されるのは数週間
から数ケ月といった長期間にわたる投与の結果であり、
たった全心筋梗塞を起こした患者、あるいは心筋梗塞を
すくにも起こし得る患者に魚油を経口投与してもその効
果は期待できない。Riemersa et al., J. In.
internal Med, +225+111(
(Problems to be Solved by the Invention) Although fast-acting antiarrhythmic drugs have remarkable effects, they also have many side effects.For example, the above-mentioned quinidine is known to have side effects such as causing severe hypotension, and lidocaine has It has problems such as fast metabolism and short action time. In addition, the beneficial effects of fish oil diet are (all-z) -4,
7,10,13,16,19 There are few research reports that directly prove the physiological effects of docosahexaenoic acid, and the present invention provides (all-z)-4,7,10,
There are no reports regarding the antiarrhythmic effect of 13,16,19-docosahexaenoic acid. Dietary intake of fish oil shows a protective effect against arrhythmia, but this effect is only developed over a long period of time, from weeks to months;
Oral administration of fish oil to patients who have just had a complete myocardial infarction or who are at risk of having a myocardial infarction cannot be expected to be effective.
本発明の目的は上記のような事情のもとに心筋梗塞等の
虚血性心疾患などの際によく起こる不整脈に対して速効
性があり、作用時間が長く、しかも副作用の少ない抗不
整脈薬を提供するにある。The purpose of the present invention is to provide an antiarrhythmic drug that is fast-acting, has a long action time, and has few side effects against arrhythmias that often occur in ischemic heart diseases such as myocardial infarction. It is on offer.
（課題を解決するだめの手段）
本発明は、（ａｌｌ−ｚ） −４，７，１０，１３，１
６，１９ドコサヘキサエン酸並びに核酸の薬理的に許容
される塩、エステル、及びアミドの群から選ばれた少な
くとも１種を有効成分として含有することを特徴とする
抗不整脈薬である。(Means for solving the problem) The present invention provides (all-z) -4,7,10,13,1
The present invention is an antiarrhythmic drug characterized by containing as an active ingredient at least one member selected from the group of pharmacologically acceptable salts, esters, and amides of 6,19 docosahexaenoic acid and nucleic acids.
本発明において、有効成分の１つとして用いる（ａｌｌ
−ｚ）−４７，１０，１３，１６，１９−ドコサヘキサ
エン酸は代表的には水産動物油中にかなり含有されるも
のであり、これら水産動物より通常の方法、たとえば分
子蒸留法、向流分配法、クロマトグラフ法等により単離
可能であり、標準体として一部市販されている。しかし
実用的には、これらの水産動物からの上記高度不飽和酸
は、特に単離生成された純品である必要はなく、他の高
度不飽和酸等を若干含有する組成品であってもよい。ま
た」−配化合物は適当な出発原料を用いて有機合成され
たものであってもよい。In the present invention, it is used as one of the active ingredients (all
-z)-47,10,13,16,19-docosahexaenoic acid is typically contained in significant amounts in aquatic animal oils, and can be extracted from these aquatic animal oils by conventional methods such as molecular distillation, countercurrent partitioning, etc. It can be isolated by chromatography, etc., and some are commercially available as standards. However, for practical purposes, the above-mentioned highly unsaturated acids from these aquatic animals do not need to be particularly isolated and pure products, and even if they are compositions containing a small amount of other highly unsaturated acids, etc. good. Furthermore, the compound may be organically synthesized using appropriate starting materials.
本発明においては、また上記化合物の薬理的に許容され
る塩、エステル及びアミドとしては、代表的なものとし
てすトリウム塩、カリウム塩、カルシウム塩、アルミニ
ウム塩などのアルカリ金属、アルカリ土類金属、その他
の金属塩、アンモニウム塩、モルボリン、ピペラジン、
トリメチルアミン、ジエチルアミン等のアミン塩、及び
メチルエステル、エチルエステル等の低級アルコールエ
ステル、グリセロールのモノエステル、グリセロールの
ジエステル、グリセロールのトリエステル、ジメチルア
ミド、ジエチルアミド等を例示できる。In the present invention, typical pharmacologically acceptable salts, esters and amides of the above compounds include alkali metal salts, alkaline earth metal salts such as thorium salts, potassium salts, calcium salts, and aluminum salts; Other metal salts, ammonium salts, morboline, piperazine,
Examples include amine salts such as trimethylamine and diethylamine, lower alcohol esters such as methyl ester and ethyl ester, glycerol monoester, glycerol diester, glycerol triester, dimethylamide, and diethylamide.
本発明の抗不整脈薬は有効成分を化合物単独でも投与し
得るが、通常、製剤的担体と共に製剤組成物の形態で投
与される。製剤組成物の投与即位形態としては、各種の
形態を目的に応じて選択でき１、その代表的なものとし
て、錠剤、乳剤、散剤、液剤、懸濁液、乳剤、顆粒剤、
カプセル剤、坐剤、注射剤（液剤、懸濁剤）等を例示で
きるが、速効性のある抗不整脈薬としては注射剤が好ま
しい。Although the antiarrhythmic drug of the present invention can be administered as an active ingredient alone, it is usually administered in the form of a pharmaceutical composition together with a pharmaceutical carrier. As the administration form of the pharmaceutical composition, various forms can be selected depending on the purpose.1 Typical examples include tablets, emulsions, powders, solutions, suspensions, emulsions, granules,
Examples include capsules, suppositories, injections (solutions, suspensions), etc., but injections are preferred as fast-acting antiarrhythmic drugs.
注射剤として調製される場合には、液剤および懸濁剤は
殺菌されかつ血液と等張であることが好ましく、これら
液剤、乳剤及び懸濁剤の形態に形成するのに際しては、
希釈液としては例えば水、エチルアルコール、大豆レシ
チン、卵黄レシチン、プロピレングリコール、エトキシ
化イソステアリルアルコール、ポリオキシ化イソステア
リルアルコール、ポリオキシエチレンソルビソト、ソル
ビタンエステル等を使用できる。なおこの場合等張性の
溶液を調製するに充分な量の食塩、ブドウ糖あるいはグ
リセリンを、製剤中に含有せしめてもよい。When prepared as injections, solutions and suspensions are preferably sterilized and isotonic with blood; when forming these solutions, emulsions and suspensions,
As the diluent, for example, water, ethyl alcohol, soybean lecithin, egg yolk lecithin, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbisoto, sorbitan ester, etc. can be used. In this case, the preparation may contain a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution.
製剤組成成分中に含有させるべき有効成分化合物の量は
特に限定されず、広範囲に適宜選択されるが、通常、全
組成成分中２重量％以上とされ、乳剤を例にとれば、遊
離脂肪酸換算重量基準で、１００ ｍ！あたりほぼ２〜
２０ｇの有効成分化合物が含有される。The amount of the active ingredient compound to be contained in the formulation composition is not particularly limited and can be appropriately selected within a wide range, but it is usually 2% by weight or more in the total composition, and in the case of emulsions, for example, in terms of free fatty acids. Based on weight, 100 m! Approximately 2~
Contains 20g of active ingredient compound.
製剤の投与量は、投与方法、患者の症状等に応じて適宜
選択され、−船釣には有効成分化合物を遊離脂肪酸換算
重量で２５〜１０００ｍｇ／体重ｋｇ／ｄａｙ程度であ
り、好ましくは５０−５００ｍｇ／体重ｋｇ／ｄａｙ程
度とされ、これは通常１日に１〜２回にわけであるいは
持続投与される。The dosage of the preparation is appropriately selected depending on the administration method, patient's symptoms, etc. - For boat fishing, the amount of active ingredient compound is about 25 to 1000 mg/kg body weight/day in terms of free fatty acid, preferably 50 - The dose is approximately 500 mg/kg body weight/day, which is usually administered once or twice a day or continuously.
（発明の効果）
本発明の（ａｌｌ−ｚ） ４．、 ７．１．０．１３
．１６．１９ドコサヘキナエン酸を有効成分として含む
抗不整脈剤によれば、心筋梗塞でよく出現する心室細動
を抑え、不整脈による心臓死を防くことができる。(Effects of the invention) (all-z) of the invention 4. , 7.1.0.13
．． 16.19 An antiarrhythmic agent containing docosahekinaenoic acid as an active ingredient can suppress ventricular fibrillation, which often occurs in myocardial infarction, and prevent cardiac death due to arrhythmia.
（実施例） 以下、実施例につき本発明を具体的に説明する。(Example) Hereinafter, the present invention will be specifically explained with reference to Examples.
予備実験１
予備実験とは（ａｌｌ−ｚ） ４． ７．１０．１３
．１６１９−ドコサヘキサエン酸エチル＜Ｊｄ下、ＤＨ
Ａ、：Ｉ：チルエステルと略記する）の薬効を試験する
ために行った予備実験であり、詳細は以下のとおりであ
る。Preliminary experiment 1 What is preliminary experiment (all-z) 4. 7.10.13
．． 1619-Ethyl docosahexaenoate <Jd, DH
This is a preliminary experiment conducted to test the medicinal efficacy of A, :I: abbreviated as thyl ester), and the details are as follows.
即ち、ウィスターラット１１匹を１年間にわたり市販の
スタンダード脱脂粉末飼料に長鎖多価不飽和脂肪酸が殆
ど含まれていない肝脂を１０重量％加えた食餌で飼育し
、以下の実施例、比較例に記載した不整脈誘発実験に供
した。That is, 11 Wistar rats were raised for one year on a commercially available standard defatted powdered diet supplemented with 10% by weight of liver fat, which contains almost no long-chain polyunsaturated fatty acids. It was subjected to the arrhythmia induction experiment described in .
実施例１
■ＤＨＡエチルエステル注射液の調製
９０重量％のＤＨＡエチルエステルを乳濁性注射液の製
法に従って、下記の手法で調製した。乳濁性注射液中の
９０重量％ＤＨＡエチルエステルの含量は１０％（Ｗ／
Ｖ）であり、乳化剤として卵黄レシチン１．２％（Ｗ／
Ｖ）を、また、乳濁性注射液の浸透圧をグリセリンで生
体と等張となるように調製した。Example 1 (1) Preparation of DHA ethyl ester injection 90% by weight of DHA ethyl ester was prepared by the following method according to the method for producing an emulsified injection. The content of 90% by weight DHA ethyl ester in the emulsified injection solution is 10% (W/
V) and egg yolk lecithin 1.2% (W/
In addition, the osmotic pressure of the emulsified injection solution was adjusted with glycerin so that it was isotonic with the living body.
（処方）
９０重量％ＤＨＡエチルエステル ５０．０ｇ卵黄レシ
チン ６．０ｇグリセリン
１２．５ ｇ注射用蒸留水
残量
全ｉｆ ５００ｍｊ！■不整脈
の誘発
予備実験で飼育したラットに、■で調製したＤＨＡエチ
ルエステル乳濁性注射液３慴！（ＤＨＡエチルエステル
０．３ｇを含む）を静注し、３時間後にラットを麻酔下
、人工呼吸管理下に開腹し、心臓を露出する。冠動脈前
下行技の下に絹糸を通し、心臓を心腔内に戻す。１５分
間の回復期間後、左前下行技を１５分間閉塞し、次に１
０分間再潅流する。(Formulation) 90% by weight DHA ethyl ester 50.0g egg yolk lecithin 6.0g glycerin
12.5 g distilled water for injection
Total remaining amount if 500mj! ■3 doses of the DHA ethyl ester emulsified injection prepared in ■ were given to rats raised in a preliminary experiment to induce arrhythmia! (containing 0.3 g of DHA ethyl ester) was intravenously injected, and 3 hours later, the rat's abdomen was opened under anesthesia and artificial respiration control to expose the heart. Pass the silk thread under the anterior descending coronary artery and return the heart to the heart chamber. After a 15-minute recovery period, the left anterior descending maneuver was occluded for 15 minutes, then 1
Reperfuse for 0 minutes.
この時、閉塞時と再潅流時の不整脈を心電図でモニター
する。以上の方法で不整脈の頻度、持続時間、死亡率を
測定した。At this time, monitor arrhythmias during occlusion and reperfusion using an electrocardiogram. The frequency, duration, and mortality rate of arrhythmia were measured using the above methods.
以上の実験の結果、表に示す如く、ＤＨＡエチルエステ
ル乳濁性注射液を静注したラットは、不整脈による心室
細動を全く起こさず、死亡例がなかった。また、重徳な
血圧低下等の副作用を起こしたラットはなかった。As a result of the above experiments, as shown in the table, rats to which the DHA ethyl ester emulsified injection solution was intravenously injected did not develop ventricular fibrillation due to arrhythmia, and there were no cases of death. Additionally, none of the rats developed serious side effects such as a drop in blood pressure.
実施例２
■（ａｌｌ−ｚ） ４． ７．１０．１３．１６．１
９−ドコサヘキサエン酸トリグリセリド（以下、ＤＨＡ
）リグリセリドと略記する）乳濁性注射液の調製５０
重量％のＤＨＡ）リグリセリドを実施例１と同様の方法
に従って、下記の処方で乳濁性注射液として調製した。Example 2 ■(all-z) 4. 7.10.13.16.1
9-docosahexaenoic acid triglyceride (hereinafter referred to as DHA)
) Preparation of emulsified injection solution (abbreviated as liglyceride) 50
DHA (% by weight) liglyceride was prepared as an emulsified injection solution according to a method similar to Example 1 with the following formulation.
（処方）
５０重量％ＤＨＡ）リグリセリド ５０．０ｇ卵黄レ
シチン ６．０ｇグリセリン
１２．５ ｇ全量
５００ｍ＃■不整脈の誘発
予備実験で飼育したラットに、■で調製した５０重量％
ＤＨＡ）リグリヤリド乳濁性注射液０．２ｄ（ＤＨＡを
遊離脂肪酸換算で０．１ｇ含む）を静注し、４時間後に
、実施例１と同様の方法で不整脈の誘発実験を行った。(Formulation) 50% by weight DHA) Liglyceride 50.0g Egg yolk lecithin 6.0g Glycerin
12.5 g total amount
500 m # ■ 50% by weight prepared in ■ to rats raised in a preliminary experiment for induction of arrhythmia.
0.2 d of DHA) Ligrialide emulsified injection solution (containing 0.1 g of DHA in terms of free fatty acid) was injected intravenously, and 4 hours later, an arrhythmia induction experiment was conducted in the same manner as in Example 1.
以上の実験の結果、表に示す如く、ＤＨＡトリグリセリ
ド乳濁性注射液を静注したラットは、不整脈による心室
細動を全く起こさず死亡例がなかった。また、重徳な血
圧低下等の副作用を起こしたラットはなかった。As a result of the above experiments, as shown in the table, rats injected intravenously with the DHA triglyceride emulsion injection did not develop ventricular fibrillation due to arrhythmia, and there were no deaths. Additionally, none of the rats developed serious side effects such as a drop in blood pressure.
実施例３
■（ａｌｌ−ｚ）−４，７，１０，１３，１６，１９−
ドコサヘキサエン酸アミド（以下、ＤＨＡアミドと略記
する）乳濁性注射液の調製
９０重量％のＤ ＨＡアミドを実施例１と同様の方法に
従って、下記の処方で乳濁性注射液として調製した。Example 3 ■(all-z)-4,7,10,13,16,19-
Preparation of emulsified injection solution of docosahexaenoic acid amide (hereinafter abbreviated as DHA amide) 90% by weight of DHA amide was prepared as an emulsified injection solution according to the following formulation in the same manner as in Example 1.
（処方）
９０重ｔ％ Ｄ ＨＡ ７ ミｔ’ ３０．
０ ｇ卵黄レシチン ６．０ｇグリセ
リン １２．５ｇ全量
５０（１ｍ［■不整脈の誘発
予備実験で飼育したラットに、■で調製した９０重量％
ＤＨＡアミド乳濁性注射液３．０ｍ１． （Ｄ ＨＡア
ミド０．１６ ｇを含む）を静注し、４時間後に、実施
例１と同様の方法で不整脈の誘発実験を行った。(Formulation) 90 wt% D HA 7 mit' 30.
0 g egg yolk lecithin 6.0 g glycerin 12.5 g total amount
50 (1 m [■ 90% by weight prepared in ■
DHA amide emulsified injection solution 3.0ml. (containing 0.16 g of D HA amide) was intravenously injected, and 4 hours later, an arrhythmia induction experiment was conducted in the same manner as in Example 1.
以上の実験の結果、表に示す如く、ＤＨＡアミド乳濁性
注射液を静注したラットは、不整脈による心室細動を全
く起こさず死亡例がなかった。また、重徳な血圧低下等
の副作用を起こしたラットはなかった。As a result of the above experiments, as shown in the table, rats injected intravenously with the DHA amide emulsion injection did not develop ventricular fibrillation due to arrhythmia, and there were no deaths. Additionally, none of the rats developed serious side effects such as a drop in blood pressure.
比較例１
予備実験で飼育したラットを無処理のまま、実施例１と
同様の方法で不整脈誘発実験を行った。Comparative Example 1 An arrhythmia induction experiment was conducted in the same manner as in Example 1 using untreated rats raised in the preliminary experiment.
以上の実験の結果、表に示す如く、無処理の第一群ラッ
トでは７匹中５例で心室細動が起き、５匹とも死亡した
。As a result of the above experiment, as shown in the table, ventricular fibrillation occurred in 5 out of 7 untreated rats in the first group, and all 5 died.
表 ＊ ｐ ＜０．０２５table *p<0.025
Claims (1)
コサヘキサエン酸並びに該酸の薬理的に許容される塩、
エステル、及びアミドの群から選ばれた少なくとも１種
を有効成分として含有することを特徴とする抗不整脈薬
。(all-z)-4,7,10,13,16,19-docosahexaenoic acid and pharmacologically acceptable salts of the acid,
An antiarrhythmic drug characterized by containing at least one member selected from the group of esters and amides as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13695290A JP2893866B2 (en) | 1990-05-25 | 1990-05-25 | Antiarrhythmic drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13695290A JP2893866B2 (en) | 1990-05-25 | 1990-05-25 | Antiarrhythmic drugs |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0429928A true JPH0429928A (en) | 1992-01-31 |
| JP2893866B2 JP2893866B2 (en) | 1999-05-24 |
Family
ID=15187346
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13695290A Expired - Lifetime JP2893866B2 (en) | 1990-05-25 | 1990-05-25 | Antiarrhythmic drugs |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2893866B2 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5576349A (en) * | 1995-11-30 | 1996-11-19 | The General Hospital Corporation | Retionoic acid treatment of cardiac arrhythmia |
| WO1996040106A3 (en) * | 1995-06-07 | 1997-03-13 | Martek Biosciences Corp | Methods for controlling highly unsaturated fatty acid content in various tissues |
| JP2003146874A (en) * | 2001-11-12 | 2003-05-21 | Quatex Nv | Use of polyunsaturated fatty acid for primary prevention of major cardiovascular event |
| US7462643B1 (en) | 1999-02-17 | 2008-12-09 | Pfizer Italia S.R.L. | Essential fatty acids in the prevention of cardiovascular events |
| WO2008063323A3 (en) * | 2006-10-13 | 2008-12-31 | Reliant Pharmaceuticals Inc | Treatment with antiarrhythmics and omega-3 fatty acids and a combination product thereof |
| JP2014058575A (en) * | 2002-07-17 | 2014-04-03 | Avanir Pharmaceuticals | Pharmaceutical compositions comprising dextromethorphan and quinidine for treatment of neurological disorders |
-
1990
- 1990-05-25 JP JP13695290A patent/JP2893866B2/en not_active Expired - Lifetime
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996040106A3 (en) * | 1995-06-07 | 1997-03-13 | Martek Biosciences Corp | Methods for controlling highly unsaturated fatty acid content in various tissues |
| EP1886679A3 (en) * | 1995-06-07 | 2008-05-28 | Martek Biosciences Corporation | Methods for controlling highly unsaturated fatty acid content in various tissues |
| US5576349A (en) * | 1995-11-30 | 1996-11-19 | The General Hospital Corporation | Retionoic acid treatment of cardiac arrhythmia |
| US7462643B1 (en) | 1999-02-17 | 2008-12-09 | Pfizer Italia S.R.L. | Essential fatty acids in the prevention of cardiovascular events |
| JP2003146874A (en) * | 2001-11-12 | 2003-05-21 | Quatex Nv | Use of polyunsaturated fatty acid for primary prevention of major cardiovascular event |
| JP4731789B2 (en) * | 2001-11-12 | 2011-07-27 | プロ・アパルツ・インベステイメントス・エ・コンサルトリア・リミターダ | Use of polyunsaturated fatty acids for primary prevention of major cardiovascular events |
| JP2014058575A (en) * | 2002-07-17 | 2014-04-03 | Avanir Pharmaceuticals | Pharmaceutical compositions comprising dextromethorphan and quinidine for treatment of neurological disorders |
| WO2008063323A3 (en) * | 2006-10-13 | 2008-12-31 | Reliant Pharmaceuticals Inc | Treatment with antiarrhythmics and omega-3 fatty acids and a combination product thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2893866B2 (en) | 1999-05-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1152755B1 (en) | Essential fatty acids in the prevention of cardiovascular events | |
| US7553870B2 (en) | Use of polyunsaturated fatty acid for the primary prevention of major cardiovascular events | |
| EP0347056B1 (en) | Essential fatty acid compositions | |
| US5436269A (en) | Method for treating hepatitis | |
| JPH0832230B2 (en) | Food composition | |
| JPS6296422A (en) | Manufacture of preventive or therapeutic composition for endometric proliferation and prevention or remedy therefor | |
| EP0321128A1 (en) | Fatty acid compositions | |
| JPWO2004069238A1 (en) | Prognostic agent for subarachnoid hemorrhage | |
| JPH0249723A (en) | Encephalon function improving composition, learning ability enhancing agent, memory enhancing agent, preventive and remedy for dementia or functional food having encephalon function improving effect | |
| DE3705549A1 (en) | USE OF PYRIDOXINE DERIVATIVES IN THE PROPHYLAXIS AND THERAPY OF HYPERLIPIDAEMIA AND ATHEROSCLEROSIS | |
| JPH0429928A (en) | Antiarrhythmic agent | |
| US9808437B2 (en) | Monounsaturated fatty acid compositions and use for treating atherosclerosis | |
| KR20190121752A (en) | Topical Anesthetic-containing Acid Emulsion Compositions | |
| JPH04244023A (en) | Omega,6-unsaturated fatty acid-containing medicine | |
| JPH0692848A (en) | Emulsion for treating diabetes | |
| DE60104693T2 (en) | TREATMENT OF SEPTIC SHOCK | |
| JPH01156922A (en) | Production of drug for treating brain disease and treatment compound | |
| JP2902459B2 (en) | Fat emulsion containing PAF antagonist | |
| JP3177686B2 (en) | Dysmenorrhea prevention or treatment agent and dysmenorrhea prevention functional food | |
| EP1147769A2 (en) | Use of polyunsaturated fatty acids, especially omega-3-fatty acids, for the treatment of enuresis and incontinence | |
| DE2411768B2 (en) | MEDICINAL PRODUCTS WITH LIPOPROTEIDS-REDUCING EFFECT | |
| JPH05148140A (en) | Malaria-treating medicine | |
| MXPA01008213A (en) | Essential fatty acids in the prevention of cardiovascular events |