JP2007238466A - Agent for suppressing visceral disorder caused by ischemic reperfusion - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an agent effective for suppressing visceral disorder caused by ischemic reperfusion. <P>SOLUTION: The agent for suppressing visceral disorder caused by ischemic reperfusion contains an agonist of histamine H<SB>4</SB>receptor. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a drug for suppressing visceral damage caused by ischemia / reperfusion.

  When the internal organs are damaged due to trauma or serious illness and recovery by surgery or drugs cannot be expected, organ transplantation may be performed. For example, organ transplantation such as liver, kidney, lung, small intestine, heart and pancreas is actually performed.

  However, in organ transplantation, in addition to rejection due to an immune response, problems caused by reperfusion of blood flow become a problem. That is, a cadaver or an organ removed from a living body for transplantation is perfused with a protective solution or cooled and stored for a short time, or is immediately transplanted to a patient. After transplantation, the organ is reperfused with the blood of the patient. This reperfusion generates free radicals such as active oxygen and directly damages the organ. In addition, various cytotoxic cytokines such as TNF-α are produced, causing an inflammatory reaction and causing organ damage.

  This ischemia-reperfusion injury can sometimes be fatal, and similar problems can occur after a temporary cessation of blood circulation, such as cardiac or large blood vessel surgery, or after cardiac arrest. It can occur in organs throughout the body after successful resuscitation and later resumption of blood flow. Thus, various solutions for this failure are being investigated, but there are no effective solutions yet.

By the way, Patent Document 1 discloses a technique that employs a compound that reduces active oxygen against general oxidative damage to hepatocytes and liver tissue. Examples of such compounds include histamine and histamine H ₂ receptor agonists, and the effects of histamine on liver damage caused by alcohol and the like have been experimentally demonstrated.
JP-T-2005-510501 (Claims, paragraphs [0006] and [0067], Examples)

  As described above, although a technique for suppressing visceral damage due to ischemia / reperfusion is required, a sufficiently effective means has not yet been found. In addition, histamine is known as one that is not directly related to ischemia-reperfusion injury but is effective in treating liver injury caused by alcohol or the like.

  However, histamine has side effects of inducing allergic reactions, anaphylactic reactions, asthma attacks, and shocks, and there are many problems in using histamine as a medicine.

  Therefore, a problem to be solved by the present invention is to provide a drug effective in suppressing visceral damage caused by ischemia / reperfusion.

Various studies were conducted on drugs that can suppress visceral damage caused by ischemia-reperfusion. As a result, the inventors have found that a histamine H ₄ receptor agonist is effective against such a disorder and completed the present invention.

That is, the visceral injury inhibitor according to the present invention is an agent for suppressing visceral injury due to ischemia / reperfusion, and contains an agonist of histamine H ₄ receptor.

Dimaprit is preferred as the H ₄ receptor agonist. In addition, the visceral disorder inhibitor according to the present invention is preferably used for the suppression of liver damage due to ischemia reperfusion. This is because these effects have been demonstrated in Examples to be described later.

  The visceral disorder inhibitor according to the present invention is preferably administered multiple times or continuously. This is because the occurrence and progression of the disorder can be suppressed by maintaining the drug concentration in the target viscera.

  Inhibitors of visceral injury due to ischemia-reperfusion according to the present invention are reperfusions that occur when blood flow is resumed after temporary blood flow interruption due to cardiac arrest or the like in organ transplantation surgery or other major surgery The disorder can be improved prophylactically or therapeutically. Therefore, the visceral disorder inhibitor according to the present invention is extremely useful as an agent that can effectively improve the built-in ischemia-reperfusion disorder, which has been a problem in the past.

The visceral disorder inhibitor according to the present invention is a drug for suppressing visceral damage due to ischemia / reperfusion, and contains an agonist of histamine H ₄ receptor.

  The subject of the drug of the present invention is visceral damage due to ischemia reperfusion. This temporary ischemia can occur in the liver, kidney, lung, small intestine, heart, pancreas, etc., transplanted by organ transplantation, and after resuscitation after cardiac or large blood vessel surgery or after cardiac arrest. It occurs in the internal organs when reperfused following a temporary stop. That is, when blood flow is resumed, necrosis and inflammation occur in the internal organs due to free radicals and inflammatory reactions. The present invention aims to improve these obstacles.

  The “disorder” of the present invention includes any damage to the internal organs caused by ischemia / reperfusion such as morphological disorder or functional disorder.

The histamine H ₄ receptor was cloned relatively recently in 2000 and is said to be involved in immune responses, but details are not clear at this time. In the drug of the present invention, a histamine H ₄ receptor agonist is used. Here, although the mechanism of action by which the histamine H ₄ receptor agonist ameliorates visceral injury due to ischemia / reperfusion is not clear, the effect is demonstrated by the examples described later.

Examples of the histamine H ₄ receptor agonist used in the present invention include dimaprit and clozapine, and dimaprit can be preferably used. This is because the effect has been demonstrated in Examples described later.

The dosage form and administration form of the inhibitor according to the present invention are not particularly limited. For example, tablets and the like may be administered orally before organ transplantation to prevent visceral damage prophylactically. However, in order to effectively suppress visceral damage, it is necessary to maintain the concentration of histamine H ₄ receptor agonist in the target organ immediately after ischemia / reperfusion and continuously thereafter. It is preferable. In that case, as the solvent, physiological saline adjusted with pH, pure water, distilled water, sterilized water, or the like can be used.

As shown in Examples described later, when a 15 mg / kg clozapine and 3 or 10 mg / kg dimaprit were administered twice to a rat having a body weight of about 300 g, a remarkable inhibitory effect on visceral damage caused by ischemia reperfusion was gotten. In view of such results, the dose to humans can be about 0.05 to 5 mg / kg of histamine H ₄ receptor agonist per dose. However, the dose of the histamine H ₄ receptor agonist should be appropriately changed depending on the age and sex of the patient, the severity of the disease, etc., and continuous administration by infusion should be considered.

Also, histamine H ₄ receptor agonist of the present invention is preferably administered multiple times. This is because the histamine H ₄ receptor agonist concentration is maintained not only immediately after ischemia / reperfusion but also continuously to suppress the inflammatory reaction of the viscera to be treated and the re-occlusion of blood vessels. From this point of view, it is also a preferred embodiment that the histamine H ₄ receptor agonist is continuously administered by infusion or the like using the drug of the present invention as an injection.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited by the following examples, but may be appropriately modified within a range that can meet the purpose described above and below. It is also possible to implement, and they are all included in the technical scope of the present invention.

Example 1 Improvement experiment of liver ischemia / reperfusion injury with H ₄ agonist Twelve male Wistar rats (obtained from Charles River, Japan) weighing about 300 g were divided into 6 control groups and 6 clozapine administration groups. . These Wistar rats were anesthetized with a 50:50 gas mixture of oxygen-nitrous oxide containing 2% halothane. A semiconductor thermometer probe was inserted into the rectum, the body was warmed with a lamp, and the rectal temperature was maintained at 37.5 ° C. After the start of anesthesia with the mixed gas, the halothane concentration was reduced to 1 to 1.5% during the operation. A transverse incision was made in the upper abdomen to expose the left portal vein. Heparin (100 IU) was injected subcutaneously, and blood flow in the left portal vein was blocked with a vascular clip for 30 minutes. This treatment caused ischemia in the liver except the right two lobes. After 30 minutes of ischemic loading, the clip was removed and the incision site was sutured. Immediately thereafter, clozapine 15 mg / kg suspended in 0.5% Polysorbate 80 or 0.5% Polysorbate 80 was injected subcutaneously. Rats recovered from anesthesia were returned to their cages and given food and water ad libitum. Furthermore, 6 hours after reperfusion, Polysorbate 80 or clozapine was injected subcutaneously in the same amount.

  Twenty-four hours after reperfusion, pentobarbital sodium was administered intraperitoneally, and a blood sample was collected from the abdominal aorta. Plasma concentrations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which are hepatocyte-derived enzymes, in the blood sample were measured by a general blood test (JSCC compliant method). The results are shown in FIG. In addition, the value in a figure shows an average +/- standard deviation, and "*" shows the case where a significant difference is recognized by p <0.05 with respect to the control group by t-test.

As shown in FIG. 1, in the control group, hepatocytes were destroyed by ischemia-reperfusion injury of the liver, and hepatocyte-derived enzymes were released into the blood. In contrast, administration of clozapine, an H ₄ agonist, suppressed this release. This result indicates that clozapine suppressed hepatocyte destruction and improved liver damage.

Example 2 Demonstration of Improvement Effect of H ₄ Agonist on Hepatic Ischemia / Reperfusion In order to prove that the improvement of hepatic ischemia / reperfusion injury according to the present invention is due to activation of histamine H ₄ receptor. In addition, the following experiment was conducted.

First, H ₂ / H using Jimapuritto is ₄ agonist, a 31 male Wistar rats, 7 animals in the control group, 6 animals 1 mg / kg Jimapuritto administration group, Nine 3 mg / kg Jimapuritto administration group, and 9 The experiment was conducted in the same manner as in Example 1 except that the group was divided into 10 mg / kg dimaprit administration groups and physiological saline or a predetermined amount of dimaprit was administered twice. The plasma concentration of ALT is shown in FIG. 2 (1), and the plasma concentration of AST is shown in FIG. 2 (2). In the figure, “*” indicates the case where the Bonferroni test was significant at p <0.05 relative to the control group, and “**” indicates the case where it was significant at p <0.01.

As shown in FIG. 2, it was found that administration of dimaprit, an H ₂ / H ₄ agonist, improved liver damage in a dose-dependent manner.

  Next, in the above experiment, various histamine receptor antagonists were used in combination, and the effect of dimaprit on whether liver damage was improved was examined.

47 male Wistar rats were divided into 6 control groups, 7 3 mg / kg mepyramine (H ₁ antagonist) combined administration group, 8 5 mg / kg famotidine (H ₂ antagonist) combined administration group, 6 5 mg / Kg famotidine twice combined administration group, 8 10 mg / kg ranitidine (H ₂ antagonist) twice combined administration group, 6 5 mg / kg thioperamide (H ₃ / H ₄ antagonist) twice combined administration group, and 6 The mice were divided into 15 mg / kg thioperamide double administration groups. After hepatic ischemia, 3 mg / kg dimaprit was administered to all rats, and in addition, physiological saline or predetermined amounts of various histamine receptor antagonists were administered in combination. Otherwise, the experiment was performed in the same manner as in Example 1 above. Dimaprit was administered twice immediately after reperfusion and 6 hours after reperfusion, and the histamine antagonist was administered twice only just after reperfusion or in the same manner as dimaprit.

  The plasma concentration of ALT is shown in FIG. 3 (1), and the plasma concentration of AST is shown in FIG. 3 (2). “Sal” is a control administered only with physiological saline and dimaprit, “M” is mepyramine combination, “F” is famotidine combination, “R” is ranitidine combination, “T” is thioperamide combination, The number on the side indicates the dose (unit: mg / kg). Further, “*” in the figure indicates a case where the Bonferroni test was significant at p <0.05 with respect to the control group.

As shown in FIG. 3, when dimaprit, which is an H ₂ / H ₄ agonist, was used in combination with an H ₁ antagonist or an H ₂ antagonist, the improvement results of liver damage were almost unchanged. On the other hand, when thioperamide, which is an H ₃ / H ₄ antagonist, was used in combination, the improvement effect by dimaprit was clearly reduced. As described above, it was demonstrated that the improvement of ischemia / reperfusion injury in the liver according to the present invention is due to the activation of histamine H ₄ receptor.

When treated with clozapine histamine H ₄ receptor agonist is a diagram showing an improvement of liver injury by ischemia-reperfusion. (1) shows the plasma concentration (IU / L) of ALT, a liver cell-derived enzyme, and (2) shows the plasma concentration (IU / L) of AST. A lower plasma concentration of these enzymes indicates that liver dysfunction is suppressed. In the case of administration of Jimapuritto histamine H ₄ receptor agonist is a diagram showing an improvement of liver injury by ischemia-reperfusion. (1) shows the plasma concentration of ALT (IU / L), and (2) shows the plasma concentration of AST (IU / L). It is a figure which shows the improvement effect of a liver disorder at the time of using together an antagonist of a dimaprit and various histamine receptors. (1) shows the plasma concentration of ALT (IU / L), and (2) shows the plasma concentration of AST (IU / L). In particular, when thioperamide, which is an H ₃ / H ₄ antagonist, is administered in combination, it can be seen that the improvement effect of dimaprit has been reduced. From the results, it was proved that the improvement of ischemia / reperfusion injury of the liver according to the present invention was due to the activation of histamine H ₄ receptor.

Claims (5)

A drug for suppressing visceral damage caused by ischemia / reperfusion, comprising a histamine H ₄ receptor agonist. The visceral disorder inhibitor according to claim 1, wherein the H ₄ receptor agonist is dimaprit.   The inhibitor of visceral damage according to claim 1 or 2, which is for suppressing liver damage due to ischemia reperfusion.   4. The visceral disorder inhibitor according to any one of claims 1 to 3, which is administered multiple times.   The visceral disorder inhibitor according to any one of claims 1 to 3, which is administered continuously.