JPH0952831A - Acute renal insufficiency treating and preventing agent - Google Patents

Abstract

(57) [Summary] [Solution] 3-Methyl-1-phenyl-2-pyrazoline-5-
A prophylactic / therapeutic agent for acute renal failure (for example, warm ischemic acute renal failure) containing ON or a physiologically acceptable salt thereof as an active ingredient. [Effect] It is useful for the prevention and / or treatment of warm ischemic acute renal failure, which is caused when the blood flow is temporarily lowered under physiological temperature.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical useful for treating or preventing acute renal failure.

[0002]

2. Description of the Related Art Among acute renal failure, warm ischemic acute renal failure caused by a temporary decrease or stop of blood flow under physiological temperature is stored by cooling with complete blood flow interruption or exsanguination. It is understood that the mechanism of development and the progression of symptoms are different from acute renal failure (renal injury due to cold preservation and acute renal failure as ischemic reperfusion injury after transplantation) that occurs when transplanted isolated kidneys. ing. Various factors are involved in the pathogenesis of warm ischemic acute renal failure, for example, depletion of energy metabolites and reduction of production capacity during ischemia,
There is a possibility that the increase of intracellular calcium concentration or damage of cell membrane due to active oxygen generated after resumption of blood flow is involved.

In order to prevent warm ischemic acute renal failure, it is known to attempt prophylactic administration of superoxide dismutase (SOD), desferrioxamine (DFO), xanthine oxidase inhibitor and the like (kidney). And dialysis, 36 (2), pp.191-308, 1994). It has also been suggested that certain organogermanium compounds are also useful in the prevention of warm ischemic acute renal failure (Kumano Kumao et al., 17th Germanium Study Group). However, the effects of these preventive agents are not always satisfactory, and the emergence of more effective agents has been awaited.

[0004]

An object of the present invention is to provide a pharmaceutical useful for the prevention and / or treatment of warm ischemic acute renal failure.

[0005]

The present inventors have made diligent efforts to solve the above problems, and as a result, 3-methyl-1-phenyl
-2- A drug containing pyrazolin-5-one as an active ingredient,
We have found that it is useful for maintaining the physiological function of the kidney by significantly preventing the occurrence of warm ischemic acute renal failure in the kidney whose blood flow is temporarily stopped under physiological temperature. The present invention has been completed based on these findings.

That is, the present invention relates to 3-methyl-1-phenyl
It is intended to provide a preventive and / or therapeutic agent for acute renal failure, which comprises pyrazolin-5-one or a physiologically acceptable salt thereof as an active ingredient. As a preferred embodiment of the present invention, there is provided the above medicament, wherein the acute renal failure is warm ischemic acute renal failure.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION 3- which is an active ingredient of the medicine of the present invention
Methyl-1-phenyl-2-pyrazolin-5-one is a known compound and can be easily produced, for example, by the method described in the synthesis example in JP-B-5-31523, column 7. As for the use of this compound, as a medicinal use, brain function normalizing action (Japanese Patent Publication No. 5-31523), lipid peroxide production inhibitory action (Japanese Patent Publication No. 5-35128, compound of Example 1), anti-ulcer action ( JP-A-3-215425) and a blood glucose elevation suppressing effect (JP-A-3-215426) are known. However,
None of these publications suggests or teaches the nephroprotective effect of the above compounds on warm ischemic acute renal failure.

As the active ingredient of the medicament of the present invention, in addition to the above-mentioned compounds in free form, physiologically acceptable salts thereof can be used. Moreover, you may use those arbitrary hydrates or arbitrary solvates. The above compound has tautomers as shown in the chemical structural formula in the upper part of column 5, column 5 of Japanese Examined Patent Publication No. 5-31523. However, the active ingredient of the medicament of the present invention contains these tautomers. It goes without saying that all are included.

As the salt of the above compound, an acid addition salt or a base addition salt can be used. Mineral salts such as, for example, hydrochlorides, sulphates, hydrobromides or phosphates;
Organic acid salts such as methane sulfonate, paratoluene sulfonate, acetate, oxalate, citrate, malate or fumarate; sodium salt, potassium salt,
Alternatively, a metal salt such as a magnesium salt; an ammonium salt; or an organic amine salt such as ethanolamine or 2-amino-2-methyl-1-propanol can be used, provided that they are physiologically acceptable. The type of salt is not particularly limited.

The drug of the present invention acts as a preventive agent for preventing warm ischemic acute renal failure and as a therapeutic agent for restoring the normal physiological function of the kidney causing warm ischemic renal failure. Have In the present specification, warm ischemic acute renal failure refers to, among acute renal failure caused by various causes, acute dysfunction of the kidney that occurs when blood flow is temporarily reduced or stopped at physiological temperature. I mean. This term should be interpreted in its broadest sense as long as it is consistent with the above definition, and should not be construed in the context of different disease names. Whether or not the disease corresponds to warm ischemic acute renal failure can be easily diagnosed by a skilled doctor.

The administration route of the medicament of the present invention is not particularly limited, and it can be administered orally or parenterally. For example, it is preferable to prophylactically administer the medicament of the present invention by intravenous, intraarterial, or intracardiac injection to a patient who has suffered a large amount of bleeding or acute circulatory failure due to an accident or the like.
If a significant amount of bleeding is expected during surgery,
It is preferable that the medicament of the present invention is orally administered prophylactically prior to surgery, or prophylactically during or before and after surgery by parenteral administration such as injection or drip. For patients who develop warm ischemic acute renal failure, the purpose is to prevent the deterioration of symptoms or reduce symptoms.
It is preferably administered intravenously, intraarterially, or intracardially by injection.

As the medicament of the present invention, one or more of the above-mentioned compounds as active ingredients or salts thereof may be directly administered to a patient, but preferably the active ingredient and pharmacologically and pharmaceutically acceptable It should be administered as a formulation in the form of a pharmaceutical composition containing possible additives. The pharmacologically and pharmaceutically acceptable additives include, for example, excipients, disintegrants or disintegration aids, binders, lubricants, coating agents,
Dyes, diluents, bases, solubilizers or solubilizers, isotonic agents, pH adjusters, stabilizers, propellants, adhesives and the like can be used. Examples of formulations suitable for oral administration include
For example, tablets, capsules, powders, fine granules, granules, liquids, syrups and the like can be mentioned. Examples of suitable formulations for parenteral administration include injections, drip infusions, and suppositories. Can be mentioned.

For the preparation suitable for oral administration, as an additive, for example, an excipient such as glucose, lactose, D-mannitol, starch or crystalline cellulose; a disintegrating agent such as carboxymethyl cellulose, starch or carboxymethyl cellulose calcium or Disintegration aid; Binder such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or gelatin;
Lubricants such as magnesium stearate or talc; Coating agents such as hydroxypropylmethylcellulose, sucrose, polyethylene glycol or titanium oxide; Vaseline, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, or bases such as hard fat Agents can be used. Formulations suitable for injection or infusion include, for example, distilled water for injection, physiological saline, and solubilizers or solubilizers that can compose aqueous or injection-soluble injections such as propylene glycol; glucose, sodium chloride, D-mannitol. , Isotonic agents such as glycerin; pharmaceutical additives such as pH adjusting agents such as inorganic acids, organic acids, inorganic bases or organic bases can be used.

The dose of the pharmaceutical agent of the present invention can be appropriately selected depending on the purpose of prevention or treatment of warm ischemic acute renal failure, and the age and condition of the patient, etc. On the other hand, about 0.1 to 100 mg / kg is preferably administered by injection or infusion, or about 0.1 to 100 mg / kg is orally administered. When administered by injection, for example,
It is preferable to use the injections described in JP-A-63-132833. The above-mentioned compound, which is an active ingredient of the medicament of the present invention, has high safety (intraperitoneal administration to mice LD
₅₀ 2012 mg / kg; Oral administration to rats LD ₅₀ 3,500 mg / kg: Re
gistry of ToxicEffects of Chemical Substances, 198
1-1982), it has also been proved non-carcinogenic (Nation
al Cancer Institute Report, 89, 1978).

[0015]

The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited to the following examples. Example 1 A rat (male, Sprague Dawley system, body weight around 300 g) was anesthetized with Nembutal (50 mg / kg, intraperitoneal injection), and a midline laparotomy was performed, and the left renal artery was clamped with a brain surgical clip for 45 minutes. A reversible warm ischemic acute renal failure model was created. The right kidney was removed immediately before the clamp. 3-Methyl-1-phenyl-2-pyrazolin-5-one (3 mg / kg), which is the active ingredient of the medicament of the present invention, was administered by one-shot immediately before clamping and immediately before unclamping. Saline (0.5 ml) was similarly administered to the control group.

Rats were placed in metabolic cages at 24-48 hours and 48-72 hours after unclamping, and urine was collected for 24 hours each. Blood was collected at 24 and 48 hours, blood was collected at 72 hours, and then sacrificed, and histopathological examination of the kidney was performed. For urine, urine volume (ml / day), creatinine (mg / d
l) and sodium content (mEq / l) were calculated, and the sodium excretion rate (FENa: Fraction Excretiti) was used as an index of tubular function.
on of Na,%), and creatinine as an index of renal function.
Clearance (μl / day) was calculated. For blood, creatinine (mg / dl) and sodium content (m
Eq / l) was calculated. The results are shown in Table 1 below. From these results, it is clear that the medicament of the present invention reduced the onset of warm ischemic acute renal failure.

[0017]

[Table 1] ───────────────────────────────── Evaluation item Item comparison group Drug administration group ─── ────────────────────────────── Urine collection (24-48 h) Urine volume (ml / day) 8.89 ± 6.91 5.56 ± 0.980 Creatinine (mg / dl) 168 ± 86.5 218 ± 43.4 Sodium (mEq / l) 0.575 ± 0.399 0.613 ± 0.391 Creatinine clearance (μl / day) 1170 ± 491 1300 ± 352 Sodium excretion rate (%) 0.225 ± 0.299 0.0753 ± 0.489 Urine collection (48-72 h) Urine volume (ml / day) 7.53 ± 5.56 5.76 ± 1.13 Creatinine (mg / dl) 198 ± 91.7 229 ± 45.2 Sodium (mEq / l) 0.275 ± 0.158 0.375 ± 0.175 Creatinine clearance (μl / day) 1140 ± 262 1500 ± 214 ^* Na excretion rate (%) 0.0615 ± 0.0844 0.0448 ± 0.0269 Serum (24 hours after unclamping ) Creatinine (mg / dl) 1.28 ± 0.489 1.04 ± 0.262 Sodium (mEq / l) 148 ± 5.53 147 ± 2.25 Serum (after 48 hours) Creatinine (mg / d l) 0.963 ± 0.177 0.888 ± 0.253 Sodium (mEq / l) 145 ± 2.19 148 ± 1.77 Serum (72 hours later) Creatinine (mg / dl) 0.900 ± 0.107 0.863 ± 0.130 Sodium (mEq / l) 148 ± 1.07 147 ± 0.707 ───────────────────────────────── ^* p <0.05 (vs control group)

[0018]

INDUSTRIAL APPLICABILITY The medicament of the present invention is useful for the prevention and / or treatment of warm ischemic acute renal failure.

Claims (4)

[Claims] 1. 3-Methyl-1-phenyl-2-pyrazoline-5
A prophylactic / therapeutic agent for acute renal failure containing ON or a physiologically acceptable salt thereof as an active ingredient. 2. 3-Methyl-1-phenyl-2-pyrazoline-5
A prophylactic / therapeutic agent for warm ischemic acute renal failure containing ON or its physiologically acceptable salt as an active ingredient. 3. The preventive / therapeutic agent according to claim 2, which is used for preventing warm ischemic acute renal failure. 4. 3-Methyl-1-phenyl-2-pyrazoline-5
A preventive agent for warm ischemic acute renal failure containing ON or a physiologically acceptable salt thereof as an active ingredient.