JPH06116166A - Agent for preventing and treating cerebrovascular contraction - Google Patents
Agent for preventing and treating cerebrovascular contractionInfo
- Publication number
- JPH06116166A JPH06116166A JP4270150A JP27015092A JPH06116166A JP H06116166 A JPH06116166 A JP H06116166A JP 4270150 A JP4270150 A JP 4270150A JP 27015092 A JP27015092 A JP 27015092A JP H06116166 A JPH06116166 A JP H06116166A
- Authority
- JP
- Japan
- Prior art keywords
- agent
- preventing
- combination
- present
- treating cerebrovascular
- 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.)
- Withdrawn
Links
- 230000008602 contraction Effects 0.000 title abstract 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 7
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 claims abstract description 6
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 claims abstract description 6
- 229960005356 urokinase Drugs 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims description 17
- 208000001286 intracranial vasospasm Diseases 0.000 claims description 15
- 108090000932 Calcitonin Gene-Related Peptide Proteins 0.000 claims description 12
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 8
- 239000008103 glucose Substances 0.000 claims description 8
- 230000003449 preventive effect Effects 0.000 claims description 6
- 229940124597 therapeutic agent Drugs 0.000 claims description 6
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 5
- 229920001184 polypeptide Polymers 0.000 claims description 4
- 102000004414 Calcitonin Gene-Related Peptide Human genes 0.000 claims description 3
- 230000000968 intestinal effect Effects 0.000 claims description 2
- 230000002227 vasoactive effect Effects 0.000 claims description 2
- 108010003205 Vasoactive Intestinal Peptide Proteins 0.000 abstract description 11
- 102400000015 Vasoactive intestinal peptide Human genes 0.000 abstract description 11
- 239000004480 active ingredient Substances 0.000 abstract description 10
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 abstract description 6
- 108060001064 Calcitonin Proteins 0.000 abstract 1
- 229940079593 drug Drugs 0.000 description 11
- 238000012360 testing method Methods 0.000 description 10
- 102100038518 Calcitonin Human genes 0.000 description 9
- 210000004204 blood vessel Anatomy 0.000 description 9
- 241000283973 Oryctolagus cuniculus Species 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 239000008280 blood Substances 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 238000002583 angiography Methods 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- 208000005392 Spasm Diseases 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 229940105631 nembutal Drugs 0.000 description 3
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 230000000304 vasodilatating effect Effects 0.000 description 3
- 210000002385 vertebral artery Anatomy 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 210000001841 basilar artery Anatomy 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 2
- 210000003703 cisterna magna Anatomy 0.000 description 2
- 239000003527 fibrinolytic agent Substances 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 210000000103 occipital bone Anatomy 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 229960000103 thrombolytic agent Drugs 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 102000014702 Haptoglobin Human genes 0.000 description 1
- 108050005077 Haptoglobin Proteins 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 241000283977 Oryctolagus Species 0.000 description 1
- 108010064719 Oxyhemoglobins Proteins 0.000 description 1
- 206010067171 Regurgitation Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 206010047163 Vasospasm Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 125000004925 dihydropyridyl group Chemical class N1(CC=CC=C1)* 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 238000002594 fluoroscopy Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003629 gastrointestinal hormone Substances 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- OWMZNFCDEHGFEP-NFBCVYDUSA-N secretin human Chemical group C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(N)=O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)C1=CC=CC=C1 OWMZNFCDEHGFEP-NFBCVYDUSA-N 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 1
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- -1 triene compound Chemical class 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、クモ膜下出血後に発症
する脳血管攣縮を予防または治療するための医薬製剤に
関する。TECHNICAL FIELD The present invention relates to a pharmaceutical preparation for preventing or treating cerebral vasospasm that develops after subarachnoid hemorrhage.
【０００２】[0002]
【従来の技術】クモ膜下出血後、４〜１０日をピークと
して発症する脳血管攣縮は、虚血性合併症を誘発し、予
後を大きく左右するものであり、患者の約５０％に起こ
ることが知られている。しかしながら、その原因がいま
だ解明されていないこともあり、いろいろな観点から治
療および／または予防法の開発が試みられている。Cerebral vasospasm, which develops at the peak of 4 to 10 days after subarachnoid hemorrhage, induces ischemic complications and greatly affects the prognosis, and it occurs in about 50% of patients. It has been known. However, the cause thereof has not yet been clarified, and development of treatment and / or prevention methods has been attempted from various viewpoints.
【０００３】現在までに試みられている手法としては、
例えば、脳血管攣縮誘発物質をオキシヘモグロビン等の
ポリペプチドと推定し、その作用の阻害物質として血漿
ハプトグロビンを使用するもの（特開昭５２−１２８２
０５号公報）、および特定の大環状トリエン化合物を使
用するもの（特開昭５９−１２２４２７号公報）などが
挙げられる。また、別の観点から提案されている手法と
しては、血管拡張作用のある化合物、例えば、スタウロ
スポリン（特開平２−９８１９号公報）、ジヒドロピリ
ジン誘導体（特開平２−１８０８２６号公報）およびプ
ロスタグランジンＥ1 （特開昭６３−１４５２３０号公
報）などを使用するものが知られている。The techniques that have been tried so far are:
For example, one in which the cerebral vasospasm inducer is presumed to be a polypeptide such as oxyhemoglobin, and plasma haptoglobin is used as an inhibitor of its action (Japanese Patent Laid-Open No. 521282).
No. 05), and those using a specific macrocyclic triene compound (JP-A-59-122427). Further, as a method proposed from another viewpoint, a compound having a vasodilatory action, for example, staurosporine (JP-A-2-9819), dihydropyridine derivative (JP-A-2-180826) and prostaglandin It is known to use gin E 1 (JP-A-63-145230).
【０００４】[0004]
【発明が解決しようとする課題】これらの中には、所期
の目的をある程度達成するものもあるが、いまだ臨床上
有効な手段とはなりえていない。そこで、本発明の目的
は臨床上の使用に耐えうる脳血管攣縮予防または治療剤
を提供することにある。Although some of these achieve the intended purpose to some extent, they have not yet become clinically effective means. Therefore, an object of the present invention is to provide a preventive or therapeutic agent for cerebral vasospasm that can withstand clinical use.
【０００５】[0005]
【課題を解決するための手段】本発明者らは、上記と異
なる観点から有効な脳血管攣縮予防または治療剤を提供
すべく研究を重ねた結果、それ自体公知の血管拡張作用
を有する特定のペプチド類と血栓溶解剤として臨症的に
も広範囲に使用されているウロキナーゼを組み合わせて
使用すると、それら相互の作用に悪影響を及ぼすことな
く脳血管攣縮に対して所望の作用を示すことを見い出し
本発明に至った。Means for Solving the Problems As a result of repeated studies to provide an effective preventive or therapeutic agent for cerebral vasospasm from a viewpoint different from the above, the present inventors have identified a specific vasodilatory effect known per se. It has been found that when peptides and urokinase, which are widely used as a thrombolytic agent, are used in combination, they show a desired effect on cerebral vasospasm without adversely affecting the interaction between them. Invented.
【０００６】従って、本発明は、有効成分として、カル
シトニン遺伝子関連ペプチド（以下、「ＣＧＲＰ」とも
記載する）およびバソアクティブ・インテスティナル・
ポリペプチド（以下、「ＶＩＰ」とも記載する）から選
ばれる少なくとも１種とウロキナーゼ（以下、「ＵＫ」
とも記載する）とが組み合わさった脳血管攣縮予防また
は治療剤を提供することにより上記目的を達成する。Therefore, the present invention provides, as active ingredients, a calcitonin gene-related peptide (hereinafter also referred to as "CGRP") and a vasoactive intestinal.
At least one selected from a polypeptide (hereinafter, also referred to as “VIP”) and urokinase (hereinafter, “UK”)
The above object is also achieved by providing a preventive or therapeutic agent for cerebral vasospasm in combination with
【０００７】本発明の好ましい態様では、上記組み合わ
せの他に、グルコースをさらに組み合わせた脳血管攣縮
予防または治療剤を提供する。A preferred embodiment of the present invention provides a preventive or therapeutic agent for cerebral vasospasm, which further comprises glucose in addition to the above combination.
【０００８】以下、本発明をより具体的に説明する。本
発明におけるＣＧＲＰとしては、例えば、Ｓ．Ｄ．Ｂｒ
ａｉｎらの、Ｎａｔｕｒｅ，Ｖｏｌ．３１３（１９８
５）５４〜５６ページに記載されるような血管拡張作用
を示すペプチドであり、本発明の目的を達成できるもの
であれば、その起源（例えば、ヒトおよびラット、な
ど）、調製方法（例えば、特定細胞からの抽出物および
化学合成品、など）の如何を問わず使用することがで
き、その上、これらと同様に作用するものであればそれ
らの類縁体も使用できる。The present invention will be described in more detail below. Examples of CGRP in the present invention include S. D. Br
ain et al., Nature , Vol. 313 (198
5) A peptide having a vasodilatory action as described on pages 54 to 56, and its source (for example, human and rat) and its preparation method (for example, as long as the object of the present invention can be achieved). It can be used regardless of whether it is an extract from a specific cell or a chemically synthesized product, and further, an analog thereof can be used as long as it acts in the same manner.
【０００９】ＶＩＰは、いわゆる消化管ホルモンのセク
レチン群に属するポリペプチドであって、小腸粘膜から
抽出、精製されたものや、対応する遺伝子の組換え法を
利用して産生されたものや、場合によって化学合成され
たもののいずれであってもよい。無論、本発明の目的に
使用できる限り、それらがヒトまたはブタなどのいずれ
の起源に由来するものであってもよい。VIP is a polypeptide belonging to the secretin group of so-called gastrointestinal hormones, which has been extracted and purified from the small intestinal mucosa, produced by the recombinant method of the corresponding gene, or in some cases. It may be any of those chemically synthesized by. Of course, they may be of any origin, such as human or porcine, so long as they can be used for the purposes of the present invention.
【００１０】また、本発明で使用できるＵＫとしては、
血栓溶解剤として臨床に応用されているものを始め、そ
れらと同等またはそれら以上の血栓溶解作用を示す特定
の酵素変性処理が施されたものが挙げられる。Further, as the UK which can be used in the present invention,
Examples include thrombolytic agents that have been clinically applied, and those that have been subjected to a specific enzyme denaturation treatment that exhibits a thrombolytic action equivalent to or higher than those.
【００１１】以上の説明から理解できるように、本発明
にいう「ＣＧＲＰ」、「ＶＩＰ」および「ＵＫ」の語
は、特定の１種の化合物を意味するのでなく、本発明の
使用目的上悪影響を及ぼすことなく、それぞれの活性を
示す化合物群を総称するものとして使用している。As can be understood from the above description, the terms "CGRP", "VIP" and "UK" in the present invention do not mean one specific compound, but have a bad influence on the purpose of use of the present invention. The compound group showing each activity without exerting is used as a generic term.
【００１２】本発明によれば、ＣＧＲＰおよびＶＩＰ
は、その少なくとも１種がＵＫと組み合わせて使用され
るが、３者を組み合わせて使用してもよい。「組み合わ
せて」の語は、それらを単一の医薬製剤に含める場合だ
けでなく、個別に製剤化して使用するが、脳血管攣縮に
連携して作用する態様を包含する概念で使用されてい
る。According to the present invention, CGRP and VIP
Is used in combination with at least one of them, but may be used in combination with three. The term “in combination” is used not only in the case of including them in a single pharmaceutical preparation but also in the case where they are individually formulated and used, but is used in a concept including a mode of acting in cooperation with cerebral vasospasm. .
【００１３】本発明の好ましい態様では、上記の組み合
わせからなる剤に、さらにグルコースが組み合わせて使
用される。グルコース自体は、脳血管の拡散または血栓
そのものに直接作用するものでないが、驚くべきこと
に、ＣＧＲＰとＵＫ、ＶＩＰとＵＫ、またはＣＧＲＰ＋
ＶＩＰとＵＫの組み合わせ使用の効果を顕著に向上させ
る。理論に拘束されるものでないが、その機序は、関連
細胞の栄養補給にグルコースが有意に働くためであるも
のと推察される。In a preferred embodiment of the present invention, glucose is used in combination with the agent comprising the above combination. Glucose itself does not act directly on the diffusion of cerebral blood vessels or the thrombus itself, but surprisingly CGRP and UK, VIP and UK, or CGRP +
The effect of the combined use of VIP and UK is significantly improved. Without wishing to be bound by theory, it is speculated that the mechanism is due to glucose's significant role in feeding relevant cells.
【００１４】以上の有効成分の１回用量は、患者の状
態、疾病の程度、投与経路または使用目的（例えば、予
防的使用または治療的使用）、あるいは各成分の力価に
より最適量が変動しうるので限定されるものでない。し
かし、一般的に、ＣＧＲＰおよびＶＩＰでは、患者の体
重１kg当り１０-15 〜１０-8モル、好ましくは１０-12
〜１０-9モル使用し、ＵＫでは１〜１００００ユニッ
ト、好ましくは１０〜５００ユニット使用し、そしてグ
ルコースは、全有効成分が単一製剤として液状または懸
濁液状で使用される場合には、０．００１〜１０ｇ、好
ましくは０．０１〜１ｇの濃度で使用される。The single dose of the above active ingredients varies depending on the condition of the patient, the degree of disease, the route of administration or the purpose of use (for example, prophylactic use or therapeutic use), or the potency of each ingredient. It is not limited because it is possible. However, in general, for CGRP and VIP, 10 −15 to 10 −8 mol, preferably 10 −12 , per kg body weight of the patient.
It is used in an amount of -10 -9 mol, in the UK 1-10000 units, preferably 10-500 units, and glucose is 0 when all the active ingredients are used in liquid or suspension form as a single preparation. It is used at a concentration of 0.001 to 10 g, preferably 0.01 to 1 g.
【００１５】薬剤の形態としては、これらの有効成分
を、単に滅菌蒸留水や生理食塩水またはそれらの緩衝化
された溶液に上記各組み合わせからなる有効成分を溶解
または懸濁させて使用できるが、その他イオン強度調製
剤として各種無機塩や、その他の賦形剤、例えばデキス
トリン、乳糖、澱粉などを加えて製剤化してもよい。有
効成分ごとに個別に製剤化し、これらを同時にか、また
は一定の時間間隔をおいて使用する方法、有効成分と適
当なキャリヤを投与経路を変えて投与する方法もある
が、通常、同時に同一の投与経路から投与することが有
利である。As the drug form, these active ingredients can be used by simply dissolving or suspending the active ingredients consisting of the above combinations in sterile distilled water, physiological saline or a buffered solution thereof. In addition, various inorganic salts as an ionic strength adjusting agent and other excipients such as dextrin, lactose, starch and the like may be added to the preparation. There is also a method of individually formulating each active ingredient and using them at the same time or with a certain time interval, and a method of administering the active ingredient and a suitable carrier by changing the administration route. It is advantageous to administer via the route of administration.
【００１６】また、投与時期は、使用する剤形、投与経
路および使用目的（予防または治療）により最適時期は
異なるが、クモ膜下出血の術後直後〜１０日目に投与す
るのがよい。特に、脳血管攣縮の予防を目的とする場合
には、除放剤の剤形として、クモ膜下出血の外科手術的
に、例えば、大槽内へその製剤を埋込んでおいてもよ
い。The optimum time of administration depends on the dosage form used, the route of administration and the purpose of use (prevention or treatment), but it is preferable to administer the drug 10 to 10 days after the operation of subarachnoid hemorrhage. In particular, for the purpose of preventing cerebral vasospasm, the formulation of the sustained-release preparation may be implanted surgically for subarachnoid hemorrhage, for example, in the cisterna magna.
【００１７】本発明の有効成分は、静脈内投与、動脈
内、特に椎骨動脈内投与することができるが、より直接
的な効果が期待できる点で、大槽穿刺により大槽内へ投
与することが好ましい。The active ingredient of the present invention can be administered intravenously or intraarterially, especially in the vertebral artery, but from the viewpoint that a more direct effect can be expected, it should be administered into the aorta by cisternal puncture. Is preferred.
【００１８】本発明の効果は、上記有効成分の組み合わ
せからなる製剤を患者に直接投与して確認できることは
もとより、例えば、Ａ．Ｓｐａｌｌｏｎｅらの、Ｓｕｒ
ｇＮｅｕｒｏｌ，３２（１９８９）４０８〜４１７ペー
ジに記載の方法に準じて脳血管攣縮を惹起したモデル動
物を使用して確認することができる。例えば、麻酔を施
したウサギの脳底動脈を血管造影法により撮影してお
き、次いで新鮮な動脈の血液を大槽内に注入した数日
後、血管攣縮を確認し、次いで被験薬剤を大槽穿刺によ
り大槽内へ注入した後、経時的に攣縮を起こした血管の
拡張を観察すればよい。こうして、被験薬剤で有意に上
記血管が拡張されるか否かにより、攣縮血管の改善の有
無を確認できる。The effects of the present invention can be confirmed not only by direct administration of a preparation comprising a combination of the above active ingredients to a patient, but also by, for example, A. Sparlone et al., Sur
It can be confirmed using a model animal in which cerebral vasospasm has been induced according to the method described in g Neurol , 32 (1989) pp. 408-417. For example, the basilar artery of anesthetized rabbits was imaged by angiography, and several days after injection of fresh arterial blood into the cistern, vasospasm was confirmed, and then the test drug was punctured in the cistern. After injection into the cisternae, the expansion of blood vessels that have undergone spasm may be observed over time. In this way, the presence or absence of improvement of the spasm blood vessel can be confirmed by whether or not the test agent significantly expands the blood vessel.
【００１９】[0019]
【実施例】以下、具体的な試験例を示し、本発明をさら
に説明する。EXAMPLES The present invention will be further described below by showing concrete test examples.
【００２０】例１ 脳血管攣縮モデル動物の作製 （１）麻酔 日本白ウサギ（雄、体重２〜３kg）を、その耳介静脈よ
りネンブタールを注入して全身麻酔を行った。ウサギを
動かないように保定した後、穿刺静脈の周囲を滅菌エタ
ノールで消毒し、静脈に留置針を刺し終わったとき、即
座に、片方の先端に生理食塩水入りの１０mLシリンジが
２方向に、そして残りの一方向にネンブタール入１０mL
シリンジが接続された３方コックを備えるシリコン製延
長チューブとその留置針とを接続した（血管が細い場合
には、指で血管を刺激し拡張させる）。接続後、生理食
塩水でフラッシュして静脈中にあることを確認し、次い
で、ゆっくりとネンブタールをウサギの体重１kg当り７
５mgとなるように注入した。このとき、１分以内に麻酔
下にはいるので、呼吸ができるように気道を確保してお
く。 Example 1 Preparation of Cerebral Vasospasm Model Animal (1) Anesthesia A Japanese white rabbit (male, body weight: 2 to 3 kg) was anesthetized by injecting Nembutal from its auricular vein. After keeping the rabbit immovable, disinfect the area around the punctured vein with sterile ethanol, and immediately after puncturing the indwelling needle into the vein, immediately use a 10 mL syringe containing physiological saline at one end in two directions, And 10 mL with Nembutal in the remaining direction
A silicone extension tube equipped with a three-way cock to which a syringe was connected was connected to the indwelling needle (when the blood vessel is thin, the blood vessel is stimulated and expanded with a finger). After connection, flush with physiological saline to confirm that it is in the vein, and then slowly add Nembutal to 7 per kg of rabbit body weight.
It was infused so as to be 5 mg. At this time, since you are under anesthesia within 1 minute, ensure an airway so that you can breathe.
【００２１】（２）カテーテル挿入（Ｓｅｌｄｉｎｇｅ
ｒ法） 大腿部切開により大腿部動脈を露出させ、露出部からガ
イドワイアーを用いカテーテルを透視下、椎骨動脈へ挿
入した。また、カテーテル挿入時の血栓生成を阻止する
ために０．２mLのヘパリンを注入した。(2) Catheter insertion (Seldinge)
Method r) The femoral artery was exposed by femoral incision, and the catheter was inserted into the vertebral artery under fluoroscopy using a guide wire from the exposed portion. In addition, 0.2 mL of heparin was injected to prevent thrombus formation during catheter insertion.
【００２２】（３）血管撮影（Ａｎｇｉｏｇｒａｐｈ
ｙ） 透視により血管撮影場所を決定し、頭部をしっかり固定
した後、血液の逆流（Ｂａｃｋ ｆｌｏｗ）を確認し、
０．８mLの造影剤を一定圧（２．３kg／cm2 ）で注入し
た。０．６mL注入したところで血管の写真撮影を行っ
た。(3) Angiography (Angiograph)
y) Fluoroscopically determine the angiographic location, firmly fix the head, and then check for blood backflow (Back flow),
0.8 mL of contrast agent was injected at constant pressure (2.3 kg / cm 2 ). When 0.6 mL was injected, the blood vessel was photographed.
【００２３】（４）大槽穿刺（Ｃｉｓｔｅｒｎａ ｐｕ
ｎｃｔｕｒｅ） この操作はウサギに血液および被験薬剤を注入する場合
に共通して行った。(4) Cisterna pu
This operation was commonly performed when blood and test drug were injected into rabbits.
【００２４】動物を俯せにし、水平面に対し、３０度下
方に頭部を傾けた。後頭骨を確認した後、第一頸椎を確
認し、その間に２６Ｇの翼状針を約６０度の角度で刺し
た。針が後頭骨にあたったところで９０度に針を立て、
さらに深く穿刺した。ここで、引圧にし脳髄液が出るこ
とを確認した。この針を介して新鮮な動脈の血液を１mL
／min の速度でウサギの体重１kg当り１mL注入した。注
入後、再び脳髄液の逆流を確認し、ウサギを１５分以上
そのままの状態で静置した。こうして、動物の脳血管に
ついて血液注入後３日目に撮影を行った。The animal was laid down and its head was tilted downward by 30 degrees with respect to the horizontal plane. After confirming the occipital bone, the first cervical vertebra was confirmed, and a 26 G winged needle was inserted at an angle of about 60 degrees between them. When the needle hits the occipital bone, raise the needle at 90 degrees,
I made a deeper puncture. Here, it was confirmed that the cerebrospinal fluid was released by applying a pressure. 1 mL of fresh arterial blood through this needle
1 mL / kg of rabbit body weight was injected at a rate of 1 / min. After the injection, regurgitation of the cerebrospinal fluid was confirmed again, and the rabbit was allowed to stand for 15 minutes or longer. Thus, the cerebral blood vessels of the animals were photographed 3 days after the blood injection.
【００２５】例２．被験薬剤の投与 （１）被験薬剤の投与 １群５匹のウサギを上記のように処置し、椎骨動脈との
分岐部より脳底動脈を３等分し、その中点の径をノギス
で測定して１８％以上攣縮が起ったウサギを使用し、血
液注入後３日目に表１〜３に示すような薬剤用量を、動
脈の血液に代えて被薬剤の蒸留水溶液各０．５mLを投与
したこと以外、上記例１（４）の大槽穿刺法を繰り返し
て、各動物の大槽内へ被験薬剤を投与した。なお、被験
薬剤として蒸留水、ならびにそれぞれ蒸留水に溶解した
ＶＩＰおよびＣＧＲＰ溶液を比較のために投与した。 Example 2. Administration of test drug (1) Administration of test drug Five rabbits per group were treated as described above, the basilar artery was divided into 3 equal parts from the bifurcation with the vertebral artery, and the midpoint diameter was measured with a caliper. Then, using a rabbit with 18% or more spasm, the drug doses as shown in Tables 1 to 3 on the third day after blood injection were replaced with 0.5 mL of distilled aqueous solution of the drug instead of arterial blood. The test drug was administered into the cisterna magna of each animal by repeating the cisterna puncture method of Example 1 (4) except that the test drug was administered. As test agents, distilled water and VIP and CGRP solutions respectively dissolved in distilled water were administered for comparison.
【００２６】（２）血管径の測定 被験薬剤の投与後、１５および３０分の経時で血管撮影
を行った。データの解析は、撮影されたＸ線フィルムを
３倍に拡大し、次いでプリントした後、各動物の血管の
直径を測定した。例１（３）の血管撮影（Ｄａｙ０）の
直径に対する相対的な大きさを、下記表１〜３にそれぞ
れ示す。(2) Measurement of blood vessel diameter Angiography was performed 15 and 30 minutes after the administration of the test drug. For analysis of the data, the x-ray film taken was magnified 3 times and then printed before measuring the vessel diameter of each animal. The relative sizes with respect to the diameter of the angiography (Day 0) of Example 1 (3) are shown in Tables 1 to 3 below.
【００２７】これらの結果から、ＶＩＰとＵＫ、ＣＧＲ
ＰとＵＫおよびＣＧＲＰとＵＫとグルコースの各組み合
わせが、脳血管攣縮に対して有意の治療効果を示すこと
がわかる。From these results, VIP, UK, CGR
It can be seen that each combination of P and UK and CGRP, UK and glucose shows a significant therapeutic effect on cerebral vasospasm.
【００２８】[0028]
【表１】 [Table 1]
【００２９】[0029]
【表２】 [Table 2]
【００３０】[0030]
【表３】 [Table 3]
【００３１】[0031]
【発明の効果】本発明は、クモ膜下出血後に発症する脳
血管攣縮を有効に予防または治療する薬剤の組み合わせ
を提供する。かかる薬剤の組み合わせとして、カルシト
ニン遺伝子関連ペプチドとウロキナーゼ、バソアクティ
ブ・インテスティナル・ポリペプチドとウロキナーゼ、
およびこれらの組み合わせにグルコースをさらに組み合
わせたものが提供される。The present invention provides a combination of agents for effectively preventing or treating cerebral vasospasm that occurs after subarachnoid hemorrhage. As a combination of such agents, calcitonin gene-related peptide and urokinase, vasoactive intestinal polypeptide and urokinase,
And further combinations of these with glucose are provided.
Claims (2)
連ペプチドおよびバソアクティブ・インテスティナル・
ポリペプチドから選ばれる少なくとも１種とウロキナー
ゼとが組み合わさった脳血管攣縮予防または治療剤。1. A calcitonin gene-related peptide and vasoactive intestinal
A preventive or therapeutic agent for cerebral vasospasm comprising at least one selected from polypeptides and urokinase in combination.
項１記載の予防または治療剤。2. The preventive or therapeutic agent according to claim 1, further comprising glucose.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4270150A JPH06116166A (en) | 1992-10-08 | 1992-10-08 | Agent for preventing and treating cerebrovascular contraction |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4270150A JPH06116166A (en) | 1992-10-08 | 1992-10-08 | Agent for preventing and treating cerebrovascular contraction |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH06116166A true JPH06116166A (en) | 1994-04-26 |
Family
ID=17482242
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4270150A Withdrawn JPH06116166A (en) | 1992-10-08 | 1992-10-08 | Agent for preventing and treating cerebrovascular contraction |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH06116166A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008102563A1 (en) | 2007-02-23 | 2008-08-28 | Next21 K.K. | Therapeutic or prophylactic agent for vasoconstriction |
-
1992
- 1992-10-08 JP JP4270150A patent/JPH06116166A/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008102563A1 (en) | 2007-02-23 | 2008-08-28 | Next21 K.K. | Therapeutic or prophylactic agent for vasoconstriction |
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