JP5146946B2 - A preventive or therapeutic agent for acute renal failure - Google Patents

Description

  The present invention relates to a preventive or therapeutic agent for acute renal failure.

  Acute renal failure is a disease that often accompanies pathologies such as sepsis, respiratory failure, severe burns and trauma, surgical complications, or disseminated intravascular coagulation. The death rate of acute renal failure is high, and it is said that the mortality rate in adults exceeds 50%. Moreover, the frequency of acute renal failure in transplanted kidneys is very high, and when it occurs, delayed rejection occurs in about 30%. For these reasons, there is a strong clinical need for the development of a method for specifically treating acute renal failure. However, no definitive treatment has yet been found, and the current treatment has not progressed at all for 25 years.

  On the other hand, radicicol is a microbial metabolite. Radicicol or a derivative thereof is known to have useful effects such as an antitumor effect and an immunosuppressive effect (Patent Documents 1, 2 and 3). However, the relationship between radicicol and acute renal failure has not been studied so far.

Japanese Patent No. 3055967 International Publication WO 2002/015925 Pamphlet JP-A-62-298764

  An object of the present invention is to provide an effective therapeutic or preventive agent for acute renal failure.

  The present inventors have found that acute renal failure is significantly improved when radicicol is administered to a mouse in a model experimental system in which acute renal failure due to renal ischemia-reperfusion injury occurs in mice, and the present invention has been completed. It was. That is, the present invention relates to a preventive or therapeutic agent for acute renal failure containing radicicol as an active ingredient.

  The present invention makes it possible to prevent or treat acute renal failure.

Radicicol used in the present invention has the following structure:

  Radicicol is obtained by culturing Neocosmospora tenuicristata, Cylinderocarpon radicicola, or Penicillium spp. , A. 2006. PhD. Thesis. Swedish University of Agricultural Sciences, Uppsala, 41 PP., J. Natural Products, 42, 374 (1979)]. Commercially available radicicol may be used for the purposes of the present invention.

  Radicicol may be in the form of a hydrate with water or a solvate with a lower alcohol or the like. That is, within the scope of radicicol in the present invention, its hydrate or solvate form is also included.

  The scope of radicicol in the present invention also encompasses so-called prodrug compounds that are precursors of radicicol and are metabolized in vivo to be converted to radicicol.

  By administering radicicol, acute renal failure can be prevented or treated in the body of an animal belonging to a mammal (typically a human). Examples of subjects other than humans include non-human primates such as monkeys and chimpanzees, rodents such as mice, rats, and guinea pigs, dogs, cats, cows, and horses. That is, radicicol is useful as an active ingredient of a preventive or therapeutic agent for acute renal failure in animals belonging to mammals. Examples of the method of administering radicicol to a target animal include parenteral administration methods such as intravenous injection, subcutaneous injection, intramuscular injection, and suppository, or oral administration methods such as tablets, capsules, powders and granules. .

  In preparing the drug of the present invention containing radicicol, various forms can be adopted depending on the administration route. For example, it can be formulated into oral solid preparations, oral liquid preparations, injections, suppositories and the like. The agents of the present invention may include pharmaceutically acceptable carriers or excipients, or other additives.

  In the case of a solid preparation for oral use, after adding excipients, binders, disintegrants, lubricants, coloring agents, flavoring / flavoring agents, etc. to radicicol as necessary, tablets, fine granules are prepared by conventional methods. It can be formulated into solid preparations for oral use such as preparations, coated tablets, granules, powders, capsules, and dry syrups. When preparing oral liquid preparations, add a flavoring agent, buffering agent, stabilizer, flavoring agent, etc. to radicicol and formulate into oral liquid preparations such as oral liquids, syrups, elixirs, etc. by conventional methods. Can do. For injections, add pH regulators, buffers, stabilizers, tonicity agents, local anesthetics, etc. to radicicol, and inject subcutaneous, intramuscular and intravenous injections etc. by conventional methods. It can be formulated into an agent. As additives used for these formulations, additives generally used in the art can be used. Particularly preferred preparation forms include intravenous injections, subcutaneous injections, intramuscular injections, suppositories, tablets, capsules, powders, granules and the like.

  The amount of radicicol formulated in each of the above dosage unit forms should be appropriately determined according to the symptoms of the patient to which this is to be applied, or depending on the dosage form, etc., as long as it is a therapeutically or prophylactically effective amount. Can do. The dose of radicicol for adults varies depending on the target disease, administration route and number of administrations, period, etc., but usually 10 to 200 mg per day is administered once or divided into several times.

Experimental Procedure Acute renal failure was developed by renal ischemia reperfusion as outlined below.
A 7-week-old male ddy mouse was anesthetized with 75 mg / kg, ip of pentobarbital (Somnopentyl, Schering-Plough KK, NJ), then the midline laparotomy was performed, and the connective tissue around the bilateral hilar region was bluntly detached. Blood flow was blocked using a microvascular clip (RS-5426, Roboz Surgical Instrument Co., Inc., MD). After 35 minutes, the clip was removed and reperfusion was performed (renal ischemia reperfusion). Then, it was sutured and awakened from anesthesia. During the treatment, the body temperature was maintained at 36 ° C. to 38 ° C. by maintaining the mouse on a hot plate, and the circulating blood volume was maintained by intraperitoneal administration of 0.9% NaCl. Blood was collected before treatment and 24 hours after reperfusion. The blood was treated with heparin (Fuji Pharmaceutical, Tokyo) and centrifuged at 12,000 rpm for 10 minutes to separate plasma. In order to evaluate renal function, creatinine (Cr) and urea nitrogen (UNa) values were measured using plasma. For measurement of Cr value, Fuji Dry Chem Slide (CRE-P III, Fuji Photo Film Co., Ltd., Tokyo) was used. The Fuji dry chem slide (BUN-P II) was used for the measurement of UN value. The drug was dissolved in 50% DMSO + 50% saline and administered intraperitoneally 1 hour before anesthesia and immediately before suturing. The dose mentioned in the experimental results section is the total of these two doses.

  Data were expressed as mean ± standard error. For the test of significant difference, student's t-test was used, and significant difference was judged at P <0.05.

Experimental results In order to investigate the effect of radicicol on acute renal failure, blood was collected before renal IR treatment in the vehicle group, radicicol 40 mg / kg group, radicicol 120 mg / kg group, 24 hours after treatment, Cr value and UN The value was measured. The result is shown in FIG. Compared with the vehicle group, there was no significant difference in the radicicol 40 mg / kg group, but in the radicicol 120 mg / kg group, significant suppression of increase in Cr and UN levels was observed 24 hours after treatment. (P <0.05). * Indicates significant in vehicle group and P <0.05. (N) indicates the number of examples.

In the vehicle group, the radicicol 40 mg / kg group, and the radicicol 120 mg / kg group, the day before ischemia / reperfusion treatment (pre) and 24 hours after the ischemia / reperfusion treatment (24 hrs post IRI) Indicates creatinine (Cr) value. In the vehicle group, the radicicol 40 mg / kg group, and the radicicol 120 mg / kg group, the day before ischemia / reperfusion treatment (pre) and 24 hours after the ischemia / reperfusion treatment (24 hrs post IRI) Urea nitrogen (urea nitrogen, UN) value is shown.

Claims (2)

  A preventive or therapeutic agent for acute renal failure containing radicicol as an active ingredient. The preventive or therapeutic agent according to claim 1, wherein the acute renal failure is ischemic acute renal failure.

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