WO2011052765A1

WO2011052765A1 - Alleviator for renal disorders caused by administration of platinum-containing drug

Info

Publication number: WO2011052765A1
Application number: PCT/JP2010/069395
Authority: WO
Inventors: 純子山下; 幸史國場; 賢太梶原; 英樹堂本
Original assignee: 味の素株式会社
Priority date: 2009-10-27
Filing date: 2010-10-26
Publication date: 2011-05-05
Also published as: JPWO2011052765A1; JP6164719B2

Abstract

Renal disorders caused by the administration of a platinum-containing drug such as cisplatin can be alleviated. In association with the administration of a platinum-containing drug, moisture is loaded by using an infusion solution containing bicarbonate ion such as bicarbonate Ringer's solution.

Description

Relief for kidney damage by administration of platinum-containing drugs

The present invention relates to a preventive or alleviating agent for renal damage, which is a side effect caused by administration of a drug containing platinum represented by cisplatin (cis-diamine dichloroplatinum (II), CDDP). More specifically, the present invention relates to the prevention or alleviation of the renal injury by an infusion solution containing bicarbonate ions. In addition, the present invention relates to a preventive or alleviating agent for renal injury, in which N-acetylcysteine is further combined with an infusion solution containing bicarbonate ions.

Platinum-containing drugs represented by cisplatin are used as anticancer agents effective for testicular tumors, bladder cancer, renal pelvis / ureteral tumors and the like.
However, cisplatin is known to have serious side effects, particularly renal dysfunction, and this side effect greatly impairs its usefulness as a dose limiting factor for cancer treatment. Although the mechanism of renal dysfunction caused by cisplatin administration is still unclear and has not been clarified in detail, histopathologically it is proximal tubule injury and takes the form of acute tubular necrosis . Also, clinically, serum urea nitrogen and creatinine are increased in response to renal dysfunction, which is a major problem.
In order to reduce renal damage caused by cisplatin, forced diuresis by hydration using an appropriate infusion solution is generally used, and diuretics such as mannitol or furosemide may be used in combination. (Non-Patent Document 1). These treatments are thought to cause a decrease in cisplatin concentration in renal tissue and a decrease in contact time between cisplatin and tubular epithelium.
However, the main infusion used for the water load for reducing this cisplatin-induced drug-induced renal injury is a physiological saline, and the use of an infusion containing bicarbonate ions is not known.
Regarding the bicarbonate ion, Non-patent Document 2 shows that urine pH and urinary excretion of platinum after cisplatin administration are high in rats that had previously been given free drinking of sodium bicarbonate-containing water, but no improvement in renal damage was observed. It has been reported.
Regarding the relationship between platinum urinary excretion and renal injury reduction, Non-Patent Document 3 reports that the renal protection effect of diuretics against cisplatin administration, which is observed incompletely, is not the result of increased platinum urinary excretion. Has been. In general, the relationship between platinum urine excretion and kidney damage reduction is not clear.
On the other hand, although there are many drugs such as N-acetylcysteine (Non-patent Document 4), urinastatin (Patent Document 1), and an extract of Kamizo Harukasan (Patent Document 2), the effect of reducing renal damage by cisplatin has been reported. In addition, there are no drugs other than the above diuretics that are clinically used as a relieving agent for renal damage caused by cisplatin administration.
In addition, in order to reduce renal damage caused by cisplatin, N-acetylcysteine is used in combination with the above-mentioned water load treatment, contained in a water load infusion solution, or used in combination with an infusion solution containing bicarbonate ions. None have been reported.

JP 5-60813 JP-A 62-1098621

Development of a means for reducing renal damage caused by cisplatin administration is still extremely important clinically, and an object of the present invention is to provide a drug for reducing renal damage caused by a platinum-containing drug represented by cisplatin. It is.

As a result of intensive studies by the present inventors to solve such problems, when using an infusion solution containing bicarbonate ions in a water load for reducing renal damage caused by cisplatin administration, physiological saline was used. As a result, the present inventors have found that renal damage is greatly reduced compared to the case.
That is, the present invention provides the following (1) to (12).
(1) An agent for reducing renal damage caused by administration of a platinum-containing drug, which is an infusion solution containing bicarbonate ions.
(2) The agent for reducing renal injury, wherein the platinum-containing drug is cisplatin.
(3) The above-mentioned renal injury reducing agent, which is an infusion solution for water load.
(4) The agent for reducing renal damage, which is an infusion solution further containing magnesium ions.
(5) The said renal disorder reducing agent which is an infusion which further contains sodium ion, chloride ion, potassium ion, and calcium ion.
(6) The above-mentioned renal injury reducing agent, which is an infusion solution having a bicarbonate Ringer's solution composition.
(7) The agent for reducing renal injury, which is an infusion solution further containing glucose.
(8) The above-mentioned renal injury reducing agent, which is an infusion solution having a bicarbonate ion concentration of 15 to 35 mEq / L.
(9) The agent for reducing renal damage, which is further combined with N-acetylcysteine.
(10) The renal injury reducing agent according to (9), which is an infusion solution containing bicarbonate ion and N-acetylcysteine.
(11) The agent for reducing renal injury according to the above (10), wherein the N-acetylcysteine concentration is 0.01 to 10 g / L.
(12) The agent for reducing renal damage according to any one of (9) to (11), wherein the substance amount of bicarbonate ion is 0.001 to 1.3 with respect to the substance amount 1 of N-acetylcysteine. .
The present invention also provides a method for reducing renal damage caused by administration of a platinum-containing drug, comprising administering the above-mentioned agent for reducing renal damage to a subject in need of reduction or prevention of renal damage caused by administration of the platinum-containing drug. .
The present invention also includes administration of an infusion solution containing bicarbonate ions to a subject in need of reduction or prevention of renal damage caused by administration of a platinum-containing drug, Provide mitigation methods.
The present invention also provides the use of an infusion solution containing bicarbonate ions for the manufacture of an agent for reducing renal damage caused by administration of a platinum-containing drug.

The agent for reducing renal damage caused by administration of a platinum-containing drug of the present invention, which is an infusion solution containing bicarbonate ions, remarkably reduces renal dysfunction, which is a side effect of a platinum-containing drug (particularly cisplatin). Moreover, the infusion solution characterized by containing bicarbonate ions further reduces the kidney damage more significantly by combining with N-acetylcysteine.

FIG. 3 shows plasma urea nitrogen in the rat model of cisplatin-induced drug-induced renal injury of Example 1. Day 0 indicates before water load, and

Day

4 and 5 indicate 4 and 5 days after cisplatin administration date, respectively. From the left, the results of 1 group (cisplatin, no water load), 2 groups (cisplatin + water load by physiological saline), and 3 groups (cisplatin + water load by bicarbon (registered trademark) infusion) are shown, respectively. (Same for FIG. 2) * p <0.05 Student's t-test FIG. 3 shows plasma creatinine in the rat model of cisplatin-induced drug-induced renal injury of Example 1. FIG. 3 is a diagram showing blood pH in a rat model of cisplatin-induced drug-induced renal injury of Example 1. Pre-hydration indicates before the start of moisture load, and Post-hydration indicates the end of moisture load. The results of group 1 (cisplatin, no water load), group 2 (cisplatin + water load with physiological saline), and group 3 (water load with cisplatin + bicarbon (registered trademark) infusion) are shown. * P <0.05 Student's t-test It is a figure which shows the renal tissue disorder level scored in the histopathological examination of Example 2. FIG. The tissue score indicates the scored renal tissue damage level, and the larger the value, the greater the damage to the kidney tissue. The results of Group 1 (cisplatin, no water load), Group 2 (water load by cisplatin + physiological saline), and Group 3 (water load by cisplatin + Bicarbon (registered trademark) infusion) are shown. * P <0.05 Wilcoxon t-test FIG. 4 shows plasma creatinine in the rat model of cisplatin-induced nephropathy of Example 3. Day 0 indicates before water load, and

Day

4 and 5 indicate 4 and 5 days after cisplatin administration date, respectively. From left, 1 group (water load by cisplatin + physiological saline), 2 groups (water load by cisplatin + bicarbon (registered trademark) infusion), 3 groups (water load by cisplatin + N-acetylcysteine-containing physiological saline), The result of 4 groups (the water load by a cisplatin + N-acetylcysteine containing bicarbon (trademark) infusion solution) is represented. * P <0.05 Student's t-test It is a figure which shows the result of the oxidative stress degree measurement of Example 4. d-ROMs (U. CARR) indicates the d-ROMs test value in blood, which is an index of the degree of oxidative stress, in unit curl (U. CARR) unit, 1 group (water load by cisplatin + physiological saline) The results of Group 2 (water load by cisplatin + bicarbon (registered trademark) infusion) are shown. * P <0.05 Student's t-test

In the present invention, the platinum-containing drug is a platinum complex chemotherapeutic agent typified by cisplatin, and includes, for example, cisplatin, carboplatin, nedaplatin, and oxaliplatin, with cisplatin and nedaplatin being preferred, and cisplatin being particularly preferred.
The agent for reducing renal damage caused by administration of a platinum-containing drug includes a preventive or therapeutic agent for renal dysfunction caused by administration of a platinum-containing drug.
The water load (hydration) is water replenishment and is to perform a larger amount of infusion for securing urine volume than in the case of maintenance infusion. This is a method usually used for preventing or reducing renal damage caused by cisplatin administration, and the renal damage reducing agent of the present invention is preferably used for this water load.
The infusion solution containing bicarbonate ions (hereinafter also referred to as “infusion solution of the present invention”) preferably contains an electrolyte that supplies bicarbonate ions (HCO ₃ ⁻ , bicarbonate ions). Examples of the electrolyte that supplies bicarbonate ions include sodium bicarbonate (sodium bicarbonate), calcium bicarbonate, potassium bicarbonate, and ammonium bicarbonate. Sodium bicarbonate is particularly preferable.
The infusion solution of the present invention can further contain one or more different electrolytes as required. Examples of the electrolyte contained in the infusion solution of the present invention include sodium ion (Na ⁺ ), chloride ion (Cl ⁻ ), magnesium ion (Mg ²⁺ ), potassium ion (K ⁺ ), calcium ion (Ca ²⁺ ), Examples thereof include water-soluble salts that supply ions such as phosphate ions (more specifically, hydrogen phosphate ions (HPO ₄ ²⁻ ) or dihydrogen phosphate ions (H ₂ PO ⁴⁻ )).
Examples of water-soluble salts that supply sodium ions include sodium chloride, sodium acetate, sodium citrate, sodium lactate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium glycerophosphate, sodium sulfate, and sodium bicarbonate. Preferably, sodium chloride, sodium bicarbonate, and sodium citrate are mentioned.
Examples of water-soluble salts that supply chloride ions include sodium chloride, potassium chloride, calcium chloride, and magnesium chloride.
Examples of the water-soluble salt for supplying magnesium ions include magnesium sulfate, magnesium chloride, magnesium acetate, and preferably magnesium chloride.
Examples of water-soluble salts that supply potassium ions include potassium chloride, potassium iodide, potassium acetate, potassium citrate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium glycerophosphate, potassium sulfate, and potassium lactate. Preferably, potassium chloride is mentioned.
Examples of water-soluble salts that supply calcium ions include calcium chloride, calcium gluconate, calcium pantothenate, calcium lactate, calcium acetate, and preferably calcium chloride.
Examples of water-soluble salts for supplying phosphate ions include sodium dihydrogen phosphate, disodium hydrogen phosphate, magnesium monohydrogen phosphate, magnesium dihydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, Examples thereof include calcium monohydrogen phosphate and calcium dihydrogen phosphate.
In addition, as an electrolyte contained in the infusion solution of the present invention, a composition such as a hydrate can be used.
The infusion solution containing bicarbonate ions preferably further contains one or more ions selected from the group consisting of sodium ions, potassium ions, calcium ions, magnesium ions, and chloride ions.
Here, it is particularly preferable to contain magnesium ions, and it is more preferable to contain all of magnesium ions, sodium ions, and chloride ions. In this case, a higher diuretic effect can be expected and it can be suitable as an infusion solution for water load.
Moreover, it is preferable that the infusion solution of the present invention contains all sodium ions, chloride ions, potassium ions, and calcium ions. Furthermore, it is preferable to have a composition of bicarbonate Ringer's solution. Here, Ringer's solution refers to a physiological electrolyte solution having an ionic composition, osmotic pressure, and hydrogen ion concentration similar to that of an extracellular fluid that can be used for extracellular fluid replenishment. It is not limited to Ringer's solution described in Pharmacopoeia). The bicarbonate Ringer solution refers to a Ringer solution containing a bicarbonate as an alkalizing agent.
The infusion solution of the present invention preferably further contains glucose.
The infusion solution of the present invention may further contain a pH adjuster and the like. Examples of the pH adjuster include acids such as hydrochloric acid, acetic acid, lactic acid, malic acid, succinic acid, and citric acid, and alkalis such as sodium hydroxide and potassium hydroxide. You may mix | blend the acid and alkali of these pH adjusters as a water-soluble salt of the electrolyte which supplies ion. An example of such a water-soluble salt is sodium citrate.
In an infusion solution containing bicarbonate ions, the bicarbonate ion concentration is preferably 15 to 35 mEq / L, particularly preferably 20 to 30 mEq / L, and the pH is preferably 6 to 8, particularly 6.8 to 7.8. . In these cases, high chloroacidosis can be suitably prevented, which is preferable from the viewpoint of safety.
When the infusion solution containing bicarbonate ions has the Ringer's solution composition, sodium ions 125 to 145 mEq / L, potassium ions 2 to 6 mEq / L, chlorine ions (chloride ions) 90 to 130 mEq / L, calcium ions 2 to 5 mEq / L, containing 0.5 to 2.5 mEq / L of magnesium ions. Here, it is preferable to further contain citrate ions 0 to 7 mEq / L and glucose 0 to 5 g / L.
More specifically, the following compositions and properties are preferred for the infusion of the present invention:
Sodium ion: 128 to 143 mEq / L, preferably 130 to 140 mEq / L.
Potassium ion: 3 to 5 mEq / L, preferably 3.5 to 4.5 mEq / L.
Calcium ion: 2 to 4.5 mEq / L, preferably 2 to 4 mEq / L.
Magnesium ion: 0.5 to 2 mEq / L, preferably 0.5 to 1.5 mEq / L.
Chlorine ion: 100 to 125 mEq / L, preferably 103 to 123 mEq / L.
Bicarbonate ion: 15 to 30 mEq / L, preferably 18 to 28 mEq / L.
Citrate ion (Citrate ^3- ): 3 to 7 mEq / L, preferably 4 to 6 mEq / L.
pH: 6 to 8, preferably 6.8 to 7.8.
Osmotic pressure ratio (ratio to physiological saline): 0.9 to 2.0, preferably 0.9 to 1.0.
As the renal injury reducing agent of the present invention, an infusion solution containing the above-described bicarbonate ion combined with N-acetylcysteine is preferred. In this case, the effect of reducing kidney damage is particularly enhanced. N-acetylcysteine includes D-form, L-form, and mixtures thereof, and L-form is preferred.
Here, the renal injury reducing agent may be, for example, a kit comprising a drug containing N-acetylcysteine and an infusion solution containing bicarbonate ion, but contains bicarbonate ion and N-acetylcysteine. An infusion form is preferred.
In the above combination, the amount of bicarbonate ion is preferably 0.001 to 1.3, and more preferably 0.001 to 0.13, relative to the amount of N-acetylcysteine.
In the case of an infusion solution containing bicarbonate ion and N-acetylcysteine, the N-acetylcysteine concentration is preferably 0.01 to 10 g / L in consideration of maintaining the anticancer effect of cisplatin, etc. 5 g / L is preferred.
When the infusion solution containing bicarbonate ions further contains other electrolytes, etc., preparation at the time of use, a combination of two solutions of bicarbonate ion-containing solution and other electrolyte solutions, or a preparation filled with these in a two-chamber container In particular, the one-component type is preferable from the viewpoint of convenience during use.
Such an infusion preparation can be produced, for example, according to the methods described in JP-A-9-124491 and JP-A-10-279488. Commercial products can also be purchased and used.
When N-acetylcysteine becomes a separate preparation from an infusion containing bicarbonate ions, the form is not particularly limited, and is mixed as it is or with a pharmaceutically acceptable carrier, for example, a solid preparation such as a tablet, It can be administered orally or parenterally as a liquid agent such as an internal solution or an injection solution. Of these, intravenous administration as an injection solution is preferred. The preparations of these dosage forms can be produced according to known preparation methods in the field using conventional preparation materials.
The agent for reducing renal injury of the present invention is used by being administered to a subject in connection with administration of a platinum-containing drug. More specifically, it is used as an infusion before administration of the platinum-containing drug, as a medium at the time of administration of the platinum drug, or as an infusion after administration of the platinum-containing drug to prevent or reduce renal damage. Preferably, renal damage is prevented or reduced by administration as a fluid load infusion in connection with cisplatin administration. The dose and method vary depending on the age, weight, symptom level, etc. of the administration subject. Specifically, when the subject is an adult, for example, it is used as follows.
(1) Before administration of cisplatin, 1,000 to 2,000 mL of the renal injury reducing agent of the present invention is administered over 4 hours or more.
(2) At the time of cisplatin administration, it is mixed with 500 to 1,000 mL of physiological saline, glucose-saline solution or the renal alleviation agent of the present invention, and intravenously infused over 2 hours or more.
(3) After completion of cisplatin administration, 1,000 to 2,000 mL of the renal injury reducing agent of the present invention is administered over 4 hours or more.
(4) During cisplatin administration, pay attention to securing urine volume and administer diuretics such as mannitol and furosemide as necessary.
Here, as described above, N-acetylcysteine may be included in the infusion solution of the present invention, or may be separately administered orally or parenterally in connection with the infusion solution or cisplatin administration of the present invention. Good. The dose varies depending on the age, weight, symptom level, etc. of the administration subject, and for example, in the case of oral administration, it is 0.0001 mg / kg to 5 g / kg.
Hereinafter, the present invention will be more specifically disclosed with reference to examples, but the present invention is not limited thereto.

Bicarbon (registered trademark) infusion (Ajinomoto Co., Inc.) used in the following examples is an infusion containing bicarbonate ions (extracellular fluid replenisher, Ringer's solution), has the following composition, and has a pH of 6.8. 7.8 and osmotic pressure ratio of 0.9 to 1.0.
[composition]
In 500 mL contain:
Sodium chloride 3.07g
Potassium chloride 0.15g
Calcium chloride hydrate 0.11g
Magnesium chloride 0.051g
Sodium bicarbonate 1.05g
Sodium citrate hydrate 0.245g
The electrolyte concentration (mEq / L) is as follows:
Na + 135
K + 4
Ca2 + 3
Mg2 + 1
Cl-113
HCO3-25

Citrate

^3- 5
Example 1
In this example, in a rat model of cisplatin-induced nephropathy, the effect of bicarbon (registered trademark) infusion, which is an infusion containing bicarbonate ions, on the progression of nephropathy was verified in comparison with physiological saline. did.
(1) Group structure Group 1: Cisplatin (5 mg / kg, iv), n = 4, no water load Group 2: Cisplatin (5 mg / kg, iv), n = 8, with physiological saline Water load 3 groups: Cisplatin (5 mg / kg, iv), n = 8, water load by bicarbon (registered trademark) infusion (2) Test method 7 weeks old male SD rats were pentobarbital after quarantine habituation After anesthesia with sodium (Somnopentyl (registered trademark), Kyoritsu Pharmaceutical Co., Ltd.), remove the hair on the right side of the neck and the upper back and operate with an external disinfectant (Isodyne (registered trademark) solution, Meiji Seika Co., Ltd.) Steiger et al. (Steiger E., Vars HM and Dudrick S. J .: A technique for long-term intraven The catheter (central venous catheter: CVC) was inserted from the right external jugular vein according to the method of us feeding in unrestrained rats.Arch.Surg.104 (3): 330-332, 1972), and placed at the origin of the right upper aorta. .
The surgical site was sutured after a small amount of antibiotics (penicillin G potassium, 20 units, Meiji Pharmaceutical Co., Ltd.) was dropped. The catheter placement date was set to the third day. Animals were housed in a post-operative metabolic cage (Natsume Seisakusho) and habituated. On the 3rd day after the start of the study (day 0), the body weight was measured, grouped using the body weight as an index, cisplatin 5 mg / kg was administered as a single intravenous dose from CVC, and 1 hour before administration A 3-hour physiological saline solution (group 2) or Bicarbon (registered trademark) infusion solution (group 3) up to 2 hours later was continuously infused from the CVC at a constant rate of 30 mL / kg / h to obtain a water load (hydration). From the start of the study to the fifth day, the effects on general symptoms, body weight and food intake, and kidney function were examined.
Blood was collected from CVC before the water load on the first day of the test and 4 or 5 days after the day of cisplatin administration, where the deterioration of renal dysfunction reached a peak, and plasma urea nitrogen and plasma creatinine were measured. It was. Further, the pH of urine was measured immediately before the end of the water load, and blood was collected at the end of the water load to measure the blood pH.
(3) Results 1) Urea nitrogen in plasma (UN in plasma)
The results are shown in FIG.
There was no significant difference between the test groups on the test start day, but the highest value was shown on the 4th day of the test start, 63.5 ± 18.5 mg / dL per group, 21.9 ± 9. 8 mg / dL, 3 groups 38.0 ± 7.8 mg / dL, 3 groups (water load by cisplatin + bicarbon (registered trademark) infusion) were significantly more than 2 groups (water load group by cisplatin + physiological saline) A low value was shown (* p <0.05 Student's t-test). Moreover, although the significant difference was not recognized, the 3rd group of the 5th day showed the low value tendency.
2) Plasma creatinine (plasma Cre)
The results are shown in FIG.
There was no significant difference between the test groups on the test start day, but the highest value was shown on the fourth day of the test, 15.5 ± 0.5 mg / dL per group, 1.2 ± 0. Although 3 group / dL and group 3 0.9 ± 0.2 mg / dL were not significantly different, group 3 showed a lower trend than group 2 (p = 0.06 Student's t -Test).
3) Urine pH
Measured with pH test paper. The urine pH at the end of the water load was significantly higher in group 3 (8.2 ± 0.2) than in group 2 (7.3 ± 0.1) (* p <0.05 Student's t-test), Group 3 urine was alkaline.
4) Blood pH
The results are shown in FIG.
Immediately after the end of moisture loading, Group 3 showed a high-value trend, although no significant difference was observed compared to Group 2 (p = 0.07 Student's t-test). Immediately after the end of the water load and immediately after the end, only two groups showed significantly lower blood pH than before the end of the water load (* p <0.05 Student's t-test).
From the results of renal function indices (plasma UN and Cre), Bicarbon (registered trademark) infusion, which is an infusion containing bicarbonate ions, shows an excellent kidney injury-reducing effect compared to physiological saline, and kidneys caused by cisplatin administration It was found to be useful as a disorder reducing agent.
Example 2
Histopathological examination The kidney used in Example 1 above was removed on day 5 of the test, the kidney was excised, hematoxylin and eosin-stained sections of the kidney were prepared, pathological examination was performed, and the renal tissue injury level was scored as follows. Turned into. The results are shown in FIG.
Score 4 (advanced): Almost all (100%) of the extramedullary zone damaged by cisplatin is impaired. Score 3 (moderate): About 70% of the extramedullary zone is impaired. Score 2 (mild): 30 of the extramedullary zone. Disability is around 1% Score 1 (minor): Less than 10% of the outer medulla zone is disability Score 0 (no abnormality): No disability (0%)
In all groups examined, and in all animals, basophilic tubules, which are thought to be caused by tubular necrosis caused by cisplatin administration, were found mainly in the extramedullary zone, but bicarbon (registered trademark) 3) The group 3 that had been subjected to water load (hydration) by infusion had a milder degree of this basophilic tubule formation than the groups 1 and 2. Basotubular tubules are considered to be tubules that have been regenerated by necrosis of the tubules after administration of cisplatin. Therefore, tubule necrosis caused by cisplatin administration was significantly mild in the bicarbon (registered trademark) infusion group ( * P <0.05 Wilcoxon t-test).
From the results of this renal histological examination, Bicarbon (registered trademark) infusion, which is an infusion containing bicarbonate ions, has an extremely superior effect on reducing renal damage compared to physiological saline, and it is a renal damage reducing agent by administration of cisplatin. As useful.
Example 3
Combination with N-acetylcysteine In this example, it was verified what kind of influence the combination of an infusion solution containing bicarbonate ions and N-acetylcysteine (NAC) would have on the progression of renal damage.
(1) Group structure Group 1: Cisplatin (5 mg / kg, iv), n = 5, water load by physiological saline Group 2: Cisplatin (5 mg / kg, iv), n = 5, bicarbon Water load by (registered trademark) infusion Group 3: Cisplatin (5 mg / kg, iv), n = 5, water load by NAC-containing physiological saline Group 4: Cisplatin (5 mg / kg, iv), n = 5, water load by infusion of NAC-containing bicarbon (2) (2) Test method 1) Surgery for insertion of catheter for administration At the end of quarantine habituation (experimental day-3rd day), 7-week-old male SD rats were pent Anesthetize with barbital sodium (Somnopentyl (registered trademark): Kyoritsu Pharmaceutical Co., Ltd.), remove hair on right side of neck and upper back (around scapula), then erase with isodine (registered trademark) solution: manufactured by Meiji Seika Co., Ltd. And, methods such Steiger (Arch.Surg, 104:. 330-332,1972) Insert the catheter from the right external jugular vein according to indwelling catheters in the upper right vena cava proximal portion. The surgical site was sutured after a small amount of antibiotics (penicillin G potassium, 20 units, Meiji Pharmaceutical Co., Ltd.) was dropped. The catheter placement date was set to the third day. Animals were housed in a post-operative metabolic cage (Natsume Seisakusho) and habituated.
2) Evaluation of renal dysfunction due to cisplatin administration On the day of the study, CVC was administered intravenously to 5 mg / kg of cisplatin, 3 hours physiological saline (1 group) from 1 hour before administration to 2 hours after administration, Bicarbon (registered trademark) infusion (group 2), N-acetylcysteine-containing physiological saline (group 3), or N-acetylcysteine-containing bicarbon (registered trademark) infusion (group 4) at a constant rate of 30 mL / kg / h Continuous infusion from CVC continued. In addition, N-acetylcysteine was blended at a concentration such that it was continuously infused at 30 mg / kg / 3 h in the water load solutions of the third group and the fourth group.
Thereafter, body weight, food intake, and urine volume were measured daily until 5 days after cisplatin administration. Blood was collected from CVC before water load (hydration) on the first day of the test and 4 or 5 days after the day of cisplatin administration, which was considered to have peaked the worsening of renal dysfunction, and plasma urea nitrogen and plasma creatinine The quantity was measured.
(3) Results 1) Plasma creatinine (plasma Cre)
The results are shown in FIG.
The plasma creatinine levels were normal in all groups before cisplatin administration, but there were differences between the test groups on the 4th and 5th day after administration, compared to the physiological saline group (1 group). In the NAC-containing bicarbonate Ringer's solution (bicarbon (registered trademark) infusion solution) administration group (group 4), the value was significantly low (* p <0.05 Dunnett-test).
Based on the results of this kidney function index (Cre), bicarbon (registered trademark) infusion, which is an infusion containing bicarbonate ions, can be used together with NAC to provide an unprecedented superior kidney injury-reducing effect when administered alone. And was found to be particularly preferable as an agent for reducing renal damage by administration of cisplatin.
Example 4
Oxidative stress measurement In a rat model of cisplatin-induced drug-induced nephropathy, what effect bibicarbonate (registered trademark) infusion containing bicarbonate ions has on the oxidative stress associated with the progression of nephropathy, The d-ROMs (Diacron-Reactive Oxygen Metabolites) test value was used as an index indicating the degree of oxidative stress, and was evaluated in comparison with physiological saline. The d-ROMs test value can be used as an index for comprehensive evaluation of the oxidative stress state. For example, biological sample analysis Vol. 32, no. 4, p. 301_306, 2009.
(1) Group structure Group 1: Cisplatin (5 mg / kg, iv), n = 8, water load by physiological saline Group 2: Cisplatin (5 mg / kg, iv), n = 8, bicarbon (2) Water load by infusion (2) Test method Similar to the test method shown in Example 1, cisplatin 5 mg / kg was administered as a single intravenous dose from CVC, and 1 hour before the administration and 2 hours after the administration. For 3 hours until later, physiological saline solution (Group 1) or Bicarbon (registered trademark) infusion solution (Group 2) was continuously infused from CVC at a constant rate of 30 mL / kg / h, and water load (hydration) was continued.
Blood was collected from the CVC before the water load at the start of the test and on the 4th and 5th day from the day of cisplatin administration, which was considered to reach the peak of deterioration in renal dysfunction, and the reagents for the d-ROMs test (R1 reagent, R2 Reagents; Wismer Co., Ltd.) and an active oxygen / free radical measuring device (device name; FRAS4, Wismer Co., Ltd.) were used to evaluate d-ROMs.
(3) Results The results are shown in FIG.
The d-ROMs test value indicating the degree of oxidative stress increased with time from the test start date, and showed the highest value on the fifth day of the test start. There was no significant difference between the test groups on the start date of the test, but on the 4th and 5th days of the start of the test, 2 groups (cisplatin + bicarbon (registered trademark) fluid load group) were 1 group (cisplatin). The value was significantly lower than that in the group (water load group with physiological saline) (* p <0.05 Student's t-test).
From this result, it was found that when Bicarbon (registered trademark) infusion was used, oxidative stress in the blood was significantly less than that of physiological saline. Renal dysfunction due to cisplatin administration is known to be associated with oxidative stress, and this result is considered to further support the excellent renal dysfunction-reducing effect of Bicarbon (registered trademark) infusion.

As described above, the present invention is useful for reducing renal damage caused by cisplatin administration, and can make cancer treatment with a platinum-containing drug typified by cisplatin more effective.

Claims

An agent for reducing renal damage caused by administration of a platinum-containing drug, which is an infusion solution containing bicarbonate ions.
The renal injury reducing agent according to claim 1, wherein the platinum-containing drug is cisplatin.
The agent for reducing renal damage according to claim 1 or 2, which is an infusion for water load.
The agent for reducing renal injury according to any one of claims 1 to 3, which is an infusion solution further containing magnesium ions.
The renal injury reducing agent according to any one of claims 1 to 4, which is an infusion solution further containing sodium ion, chloride ion, potassium ion, and calcium ion.
The renal failure reducing agent according to any one of claims 1 to 5, which is an infusion having a composition of bicarbonate Ringer's solution.
The agent for reducing renal damage according to any one of claims 1 to 6, which is an infusion solution further containing glucose.
The agent for reducing renal damage according to any one of claims 1 to 7, which is an infusion solution having a bicarbonate ion concentration of 15 to 35 mEq / L.
The agent for reducing renal damage according to any one of claims 1 to 8, further combined with N-acetylcysteine.
The agent for reducing renal injury according to any one of claims 1 to 9, which is an infusion solution containing bicarbonate ion and N-acetylcysteine.
The agent for reducing renal damage according to claim 10, wherein the N-acetylcysteine concentration is 0.01 to 10 g / L.
The agent for reducing renal damage according to any one of claims 9 to 11, wherein the substance amount of bicarbonate ions is 0.001 to 0.13 with respect to the substance amount 1 of N-acetylcysteine.