JP5777165B2 - Pelvic congestion model rat and production method thereof - Google Patents
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本発明は、骨盤うっ血モデルラットおよびその作製方法に関し、更に詳細には、頻尿や尿失禁などに有効な医薬品開発に利用しうる骨盤うっ血モデルラットおよびその作製方法に関する。 The present invention relates to a pelvic congestion model rat and a method for producing the same, and more particularly to a pelvic congestion model rat that can be used for developing a pharmaceutical effective for frequent urination, urinary incontinence, and the like, and a method for producing the rat.
***に関する疾患、例えば頻尿や尿失禁は重大な疾患とはいえないが、通常生活する上では、日々の買い物等の外出や、旅行等に対する制約になり、また精神的にも大きな負担となるため、生活のＱＯＬ（クオリティ・オブ・ライフ）を低下させるものである。日本においては、近年の高齢化に伴い、頻尿や、尿失禁の患者が増加しており、その治療法に関し関心が高まっている。 Diseases related to excretion, such as frequent urination and urinary incontinence, are not serious illnesses, but in daily life, going out of daily shopping, travel restrictions, etc. are also a great mental burden. Therefore, QOL (quality of life) of life is lowered. In Japan, with the recent aging of the population, the number of patients with frequent urination and urinary incontinence is increasing, and there is an increasing interest in the treatment methods.
このような頻尿や尿失禁は、尿意切迫感のある過活動膀胱の場合と、尿意切迫感のない頻尿の場合がある。尿意切迫感のあるときには通常は自分の意志では抑制できない膀胱収縮、つまり無抑制膀胱収縮が出現している。過活動膀胱には下部尿路自体に原因がある排尿筋過活動の場合と、中枢神経系に原因がある排尿筋過反射の場合がある。尿意切迫感のない頻尿の原因には膀胱のうっ血も挙げられており、それらは慢性前立腺炎の原因のひとつともいわれている。 Such frequent urination and urinary incontinence may be overactive bladder with urgency or frequent urination without urgency. When there is a sense of urgency, a bladder contraction that cannot normally be suppressed by one's will, that is, an unrestrained bladder contraction appears. Overactive bladder may be detrusor overactivity caused by the lower urinary tract itself, or detrusor hyperreflex caused by the central nervous system. The cause of frequent urination without a sense of urgency includes bladder congestion, which is said to be one of the causes of chronic prostatitis.
現在、頻尿や尿失禁の治療には、原因の如何に関わらず過活動膀胱治療薬が使用されており、その多くは抗コリン作用を主とする薬剤である。しかしながら、抗コリン作用を有する薬剤であっても尿意切迫感のない頻尿、つまり過活動膀胱ではない頻尿に対する効果は十分ではないことがあり、新たな、頻尿や尿失禁の治療に有効な医薬を開発するための手段の開発が求められている。 Currently, overactive bladder drugs are used for the treatment of frequent urination and urinary incontinence regardless of the cause, and many of them are drugs mainly having anticholinergic action. However, even drugs that have anticholinergic effects may not be effective against frequent urination without urinary urgency, that is, frequent urination that is not overactive bladder, and are effective in treating new urinary frequency and urinary incontinence There is a need for the development of a means for developing new medicines.
本発明は、患者が増加しつつある頻尿や尿失禁の治療に有効な医薬を開発するに当たり、有効なスクリーニング手段を提供することをその課題とするものである。 An object of the present invention is to provide an effective screening means in developing a medicine effective for treating frequent urination and urinary incontinence in which patients are increasing.
本発明者らは、頻尿や尿失禁等に有効な医薬に関し、検討を行っていたところ、過活動膀胱でない頻尿の原因のひとつが骨盤うっ血であることを知った。 The inventors of the present invention have been studying pharmaceuticals effective for frequent urination and urinary incontinence, and have found that pelvic congestion is one of the causes of frequent urination that is not overactive bladder.
そして、そのような骨盤うっ血の症状を有する動物を作製すれば、頻尿や尿失禁の治療手段を研究するために有効であると考え、ラットを用いて検討を行っていたところ、メスラットの両側総腸骨静脈と性腺静脈を結紮すれば、無菌性慢性膀胱炎を有する骨盤うっ血モデルラットが得られることを見出し、本発明を完成した。 And, if we made an animal with such pelvic congestion symptoms, we thought that it would be effective for studying treatments for pollakiuria and urinary incontinence. The present inventors have found that ligation between the common iliac vein and the gonadal vein can provide a pelvic congestion model rat having aseptic chronic cystitis.
すなわち本発明は、メスラットの両側総腸骨静脈と子宮静脈を結紮し、４週以上飼育することを特徴とする骨盤うっ血モデルラットの作製方法である。 That is, the present invention is a method for producing a pelvic congestion model rat characterized in that the bilateral common iliac vein and uterine vein of a female rat are ligated and reared for 4 weeks or more.
また本発明は、上記作製方法により作製される骨盤うっ血モデルラットである。 In addition, the present invention is a pelvic congestion model rat produced by the above production method.
更に本発明は、上記骨盤うっ血モデルラットに被験薬剤を投与し、その頻尿抑制程度を評価することを特徴とする頻尿治療薬のスクリーニング方法である。 Furthermore, the present invention is a method for screening a therapeutic drug for frequent urination, characterized in that the test drug is administered to the pelvic congestion model rat and the degree of frequent urination suppression is evaluated.
従来、頻尿や、尿失禁に有効な化合物のスクリーニングは、脳梗塞モデル、慢性期脊髄損傷モデル、閉塞膀胱モデルなどの動物が用いられていたが、これらは無排尿性膀胱収縮（臨床でいう無抑制膀胱収縮）を伴う過活動膀胱モデルであった。本発明の骨盤うっ血モデルラットは無排尿性膀胱収縮を伴わない頻尿モデルであり、過活動膀胱以外の頻尿に有効な化合物のスクリーニング試験を行うことが可能となった。 Conventionally, animals such as cerebral infarction model, chronic spinal cord injury model, obstructive bladder model, etc. have been used for screening for compounds that are effective for pollakiuria and urinary incontinence. This was an overactive bladder model with uninhibited bladder contraction. The pelvic congestion model rat of the present invention is a frequent urinary model not accompanied by non-urinary bladder contraction, and it has become possible to conduct a screening test for compounds effective in frequent urination other than overactive bladder.
本発明の骨盤うっ血モデルラットは、メスラットの両側総腸骨静脈と子宮静脈を結紮した後、これを４週以上飼育することにより作製される。 The pelvic congestion model rat of the present invention is prepared by ligating the bilateral common iliac vein and the uterine vein of a female rat and then rearing them for 4 weeks or more.
使用されるラットとしては、メスのラットであれば特に制約はなく、一般に動物実験に使用される各種系統のラットを挙げることができる。例えば、ＳＤラット、Ｆｉｓｈｅｒラット、Ｗｉｓｔａｒラット、Ｗｉｓｔａｒ Ｈａｎｎｏｖｅｒ／Ｒｃｃラット、Ｗｉｓｔａｒ／ＳＴラット、Ｄｏｎｒｙｕラット等を用いることができる。好ましいのは、排尿関連実験で使用頻度が多いという理由で、ＳＤラットである。 The rat used is not particularly limited as long as it is a female rat, and various types of rats generally used for animal experiments can be mentioned. For example, SD rat, Fisher rat, Wistar rat, Wistar Hanover / Rcc rat, Wistar / ST rat, Donryu rat and the like can be used. Preferred is the SD rat because it is frequently used in urination-related experiments.
また、このラットの両側総腸骨静脈と子宮静脈の結紮は、ラットをイソフルレン等による吸入麻酔下、下腹部を正中切開してから行われる。この結紮は、両側総腸骨静脈と子宮静脈の両者でなければならず、例えば、両側総腸骨静脈のみの場合は、試験に適した骨盤うっ血モデルラットとはならない。 Further, the ligation between the bilateral common iliac vein and the uterine vein of the rat is performed after a midline incision is made in the lower abdomen under inhalation anesthesia with isoflurane or the like. This ligation must be both bilateral common iliac vein and uterine vein. For example, bilateral common iliac vein alone is not a suitable pelvic congestion model rat for testing.
このように両側総腸骨静脈および子宮静脈を結紮したラットは、結紮直後では骨盤うっ血状態が安定せず、頻尿の現象もまちまちであるので、結紮後４週間ほど飼育し、安定した骨盤うっ血状態となってからモデルラットとして使用する。 Rats ligated with bilateral common iliac veins and uterine veins are not stable in pelvic congestion immediately after ligation, and the frequency of frequent urination varies, so they are raised for about 4 weeks after ligation and stable pelvic congestion. Use it as a model rat after it is in condition.
この骨盤うっ血モデルラットを用いて、例えば、頻尿治療薬剤の候補となる化合物をスクリーニングするには、次の如くすれば良い。 In order to screen for compounds that are candidates for therapeutic drugs for frequent urination using the pelvic congestion model rat, for example, the following may be performed.
すなわち、骨盤うっ血に伴う頻尿の治療に有用である可能性がある化合物を、本モデルラットに投与した後、ラットの膀胱内圧測定を行い、それらを投与しない本モデルラット、または化合物の投与前に比べて、膀胱収縮間隔の有意な延長(頻尿の改善)があるかどうかを調べ、有意な延長が認められたものを、頻尿治療剤候補化合物として選び出すことができる。なお、本モデルラットへの化合物の投与は、餌に添加して与えたり、化合物を静脈投与したり、膀胱内投与したりして行うことができる。 That is, a compound that may be useful for the treatment of frequent urination associated with pelvic congestion is administered to this model rat, and then the rat's intravesical pressure is measured. In comparison with the above, it is examined whether there is a significant extension of the bladder contraction interval (improvement of frequent urination), and those in which a significant extension has been observed can be selected as candidate compounds for the treatment of frequent urination. In addition, administration of the compound to this model rat can be performed by adding to the diet, administering the compound intravenously, or administering intravesically.
次に実施例を挙げ、本発明を更に詳しく説明するが、本発明はこれら実施例に何ら製薬されるものではない。 EXAMPLES Next, although an Example is given and this invention is demonstrated in more detail, this invention is not pharmaceutical at all by these Examples.
実 施 例 １
骨盤うっ血モデルラットの作製：
ＳＤ系メスラットを用い、吸入麻酔下に下腹部正中切開して両側総腸骨静脈を結紮し、子宮静脈も両側結紮して骨盤うっ血群とした。一方、何ら操作しないラットをコントロール群とし、上記静脈の剥離操作のみで静脈結紮しないラットをシャム群とした。
Example 1
Preparation of pelvic congestion model rat:
Using SD female rats, a midline incision in the lower abdomen was performed under inhalation anesthesia, the bilateral common iliac veins were ligated, and the uterine veins were also ligated on both sides to form a pelvic congestion group. On the other hand, rats that were not operated at all were used as a control group, and rats that were not subjected to vein ligation only by the above-described vein peeling operation were used as a sham group.
静脈処理の２日後、１週後、２週後および４週後にウレタン浅麻酔拘束下で連続膀胱内圧測定を行い、開腹して下部尿路の状態を観察し、骨盤うっ血群とコントロール群の２群間と、骨盤うっ血群とシャム群の２群間で比較した。また、頻尿となる術後週数で自発運動量を測定して痛みの間接的評価を行った。 2 days, 1 week, 2 weeks, and 4 weeks after intravenous treatment, continuous intravesical pressure measurement was performed under urethane superanesthetic restraint, the abdomen was opened, the state of the lower urinary tract was observed, and pelvic congestion group and control group 2 Comparison was made between the two groups, the pelvic congestion group and the sham group. Indirect evaluation of pain was performed by measuring the amount of spontaneous exercise at the number of weeks after surgery that resulted in frequent urination.
この結果を表１に示すが、コントロール群に比べて、骨盤うっ血群では静脈処理２日後には連続膀胱内圧測定上、排尿間隔（膀胱収縮間隔）が短縮するラットと延長するラットがいて一定せず、表１に示すように静脈結紮１週後ではコントロール群より有意に延長したが、２週後には差はなくなり、４週後には逆に有意に短縮した。また、膀胱基線圧や最大膀胱収縮圧には群間差がなかった。 The results are shown in Table 1. Compared with the control group, in the pelvic congestion group, the urinary interval (bladder contraction interval) was shortened and extended in the continuous bladder pressure measurement 2 days after the venous treatment. As shown in Table 1, it was significantly extended from the control group after 1 week of venous ligation, but there was no difference after 2 weeks, and it was significantly shortened after 4 weeks. In addition, there was no difference between groups in bladder baseline pressure and maximum bladder contraction pressure.
更に、静脈処理の４週後のシャム群と骨盤うっ血群の比較でも、表２に示すように、骨盤うっ血群の膀胱収縮間隔は有意に短縮していたが、膀胱基線圧や最大膀胱収縮圧には群間差がなかった。 Furthermore, in comparison between the sham group and the pelvic congestion group after 4 weeks of venous treatment, as shown in Table 2, the bladder contraction interval of the pelvic congestion group was significantly shortened, but the bladder baseline pressure and the maximum bladder contraction pressure There was no difference between groups.
なお、膀胱をそのままの状態およびエバンスブルーで着色した状態を目視で観察した結果では、骨盤うっ血群の骨盤内静脈は拡張し、膀胱は静脈結紮後一貫して浮腫状で肥厚していた。血管透過性の指標としての膀胱壁からのエバンスブルー漏出量は、シャム群（１．１±０．１ｍｇ／ｍｌ）に比べて骨盤うっ血群（１．３±０．２ｍｇ／ｍｌ）で有意（P＜０．０５）に増加していた。また、痛みの間接的評価としての自発運動量の評価では、ラットの活動期である暗期の自発運動量は、シャム群（１７４５６±１７０２カウント）に比べて骨盤うっ血群（１４９７９±２１４１カウント）で有意（P＜０．０５）に低下していた。ラットの睡眠期である明期の自発運動量には群間差がなかった。 As a result of visually observing the state of the bladder as it was and colored with Evans blue, the pelvic veins of the pelvic congestion group were dilated, and the bladder was consistently edematous and thickened after vein ligation. The amount of Evans blue leakage from the bladder wall as an indicator of vascular permeability is significant in the pelvic congestion group (1.3 ± 0.2 mg / ml) compared to the sham group (1.1 ± 0.1 mg / ml) ( P <0.05). In addition, in the evaluation of the spontaneous exercise amount as an indirect evaluation of pain, the spontaneous exercise amount in the dark period, which is the active period of the rat, is more significant in the pelvic congestion group (14979 ± 2141 count) than in the sham group (17456 ± 1702 count). (P <0.05). There was no difference between the groups in the locomotor activity during the light period of the rat.
この結果、メスラットの両側総腸骨静脈と子宮静脈を結紮し、４週経過後には頻尿の骨盤うっ血モデルラットが作製できることがわかった。 As a result, it was found that bilateral common iliac veins and uterine veins were ligated in female rats, and urinary pelvic congestion model rats could be prepared after 4 weeks.
実 施 例 ２
骨盤うっ血モデルラットの頻尿に対する薬剤の静脈内投与の影響：
実施例１で得たメスの骨盤うっ血モデルラット（１群６匹）に、ウレタン麻酔下、経尿道的にカテーテルを膀胱に挿入し、連続膀胱内圧測定を行なった。
Example 2
Effects of intravenous drug administration on frequent urination in pelvic congestion model rats:
The catheter was inserted into the bladder transurethrally under urethane anesthesia to the female pelvic congestion model rats (6 rats per group) obtained in Example 1, and continuous intravesical pressure measurement was performed.
公知の頻尿治療薬であるプロピベリン塩酸塩１ｍｇ／ｋｇを大腿静脈から投与し、頻尿の抑制状況を、膀胱収縮間隔を用いて測定した。比較としては、骨盤うっ血モデルラットのプロピベリン塩酸塩１ｍｇ／ｋｇ投与前の膀胱収縮間隔を用いた。この結果を表３に示す。 Propiverine hydrochloride 1 mg / kg, which is a known therapeutic agent for frequent urination, was administered from the femoral vein, and the suppression of frequent urination was measured using the bladder contraction interval. As a comparison, the bladder contraction interval before administration of propiverine hydrochloride 1 mg / kg in pelvic congestion model rats was used. The results are shown in Table 3.
表３に示すように、プロピベリン塩酸塩１ｍｇ／ｋｇ投与により、骨盤うっ血モデルラットの膀胱収縮間隔はプロピベリン塩酸塩投与前より有意に延長し（７．９±１．０→１３．５±１．１分、P＜０．０５）、この薬剤により骨盤うっ血モデルラットでの頻尿が改善されることがわかった。 As shown in Table 3, administration of propiverine hydrochloride 1 mg / kg significantly increased the bladder contraction interval of pelvic congestion model rats before administration of propiverine hydrochloride (7.9 ± 1.0 → 13.5 ± 1. 1 min, P <0.05), this drug was found to improve frequent urination in pelvic congestion model rats.
実 施 例 ３
骨盤うっ血モデルラットの頻尿に対する薬剤の経口投与の影響：
実施例１で得た骨盤うっ血モデルラットに対し、結紮処理１日目から飲料水に混合した試験薬剤を４週間、継続的に投与した。投与した薬剤は、公知の血管透過性亢進抑制剤のカルバゾクロムスルホン酸ナトリウム（０．２５ｍｇ／ｍｌ）であった。
Example 3
Effects of oral administration of drugs on frequent urination in pelvic congestion model rats:
To the pelvic congestion model rat obtained in Example 1, the test drug mixed with drinking water was continuously administered for 4 weeks from the first day of ligation treatment. The administered drug was sodium carbazochrome sulfonate (0.25 mg / ml), which is a known vascular permeability enhancement inhibitor.
実施例２と同様に、骨盤うっ血モデルラットの膀胱内圧測定を行い、薬剤を投与していない（薬剤未投与）群と比較して、薬剤投与ラットの頻尿の改善を検討した。この結果を表４に示す。 In the same manner as in Example 2, the intravesical pressure of pelvic congestion model rats was measured, and improvement of frequent urination in drug-administered rats was examined as compared with the group not administered with drugs (no drug administration). The results are shown in Table 4.
表４に示すように、薬剤投与ラットの膀胱収縮間隔（１０．６±０．５分）は薬剤未投与群（７．９±１．０分）より有意（P＜０．０５）に延長し、カルバゾクロムスルホン酸の投与により、骨盤うっ血モデルラットでの頻尿が改善されることがわかった。 As shown in Table 4, the bladder contraction interval (10.6 ± 0.5 minutes) of drug-administered rats was significantly (P <0.05) longer than that of the drug-untreated group (7.9 ± 1.0 minutes). In addition, it was found that frequent urination in pelvic congestion model rats was improved by administration of carbazochrome sulfonic acid.
本モデルラットは、過活動膀胱でない頻尿のひとつの原因である骨盤うっ血を有する動物であるため、骨盤うっ血に関連する、例えば、頻尿等に対する治療法の開発に有効に利用することができる。例えば、この動物に頻尿治療薬剤の候補とされる化合物を投与し、当該化合物の有する頻尿抑制効果を公知の過活動膀胱治療薬剤と比較することで、頻尿や、尿失禁に有効な化合物をスクリーニングすることができる。
Since this model rat is an animal with pelvic congestion that is one cause of frequent urination that is not overactive bladder, it can be effectively used for the development of treatments related to pelvic congestion, such as frequent urination . For example, by administering a compound that is a candidate for frequent urination drug to this animal and comparing the frequent urinary inhibitory effect of the compound with known overactive bladder therapeutic drugs, it is effective for frequent urination and urinary incontinence. Compounds can be screened.
Claims (3)
A method for screening a therapeutic drug for frequent urination, comprising administering a test drug to the pelvic congestion model rat according to claim 2 and evaluating the degree of suppression of frequent urination.
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| WO2009088054A1 (en) * | 2008-01-11 | 2009-07-16 | Astellas Pharma Inc. | Model animal having both pain in testis or testis-related discomfort actions and frequent urination |
| JP5283424B2 (en) * | 2008-05-14 | 2013-09-04 | 三菱化学メディエンス株式会社 | Production method of animal model of stress urinary incontinence |
| JP2014079188A (en) * | 2012-10-16 | 2014-05-08 | Kimio Sugaya | Aseptic chronic prostatitis non-human model animal, frequent micturition non-human model animal, and method for evaluating test substance using the same |
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