Medicine for treating acute pyelonephritis and application thereof

Abstract

The invention relates to a medicine for treating acute pyelonephritis and application thereof. The medicine comprises piperacillin sodium and sophocarpidine as active pharmaceutical ingredients, and the sophocarpidine enhances the treatment effect of piperacillin sodium on nephropathy, especially acute pyelonephritis, releases the drug effect of piperacillin sodium and plays a synergistic role. The method is very helpful for developing more pharmaceutical combination forms of piperacillin sodium.

Description

Technical Field

[0001] The present invention relates to the field of medicines, and in particular to a medicine for preventing or treating acute pyelonephritis and its application. Background Art

[0002] Acute pyelonephritis (APN) is an infectious disease of the urinary system caused by bacterial infection. It has an acute onset and typical symptoms include high fever, bladder irritation symptoms, low back pain, etc., and may also cause loss of appetite, nausea, vomiting, and some patients experience pain in the upper or whole abdomen. Common complications of acute pyelonephritis include renal papillary necrosis, perinephric abscess, toxic shock, etc. The main pathological basis of APN is the ascending of bacteria from vesicoureteral reflux, and its main pathogen is Escherichia coli.

[0003] APN is mainly treated with antibiotics. β-lactam antibacterial drugs include piperacillin sodium, tazobactam sodium, tazobactam sodium, sulbactam sodium, amoxicillin, etc. Among them, piperacillin sodium, piperacillin sodium tazobactam sodium, piperacillin sodium sulbactam sodium are often selected as the first choice drugs for acute pyelonephritis in clinical practice. Potentiators are added to piperacillin sodium tazobactam sodium and piperacillin sodium sulbactam sodium, and the efficacy is further released. They have high activity against many drug-resistant strains. Matrine (Mat) is a tetracyclic quinoline alkaloid found in Sophora flavescens. It has anti-inflammatory, antioxidant and anti-apoptotic effects and has been used in the treatment of diseases such as lung injury, liver injury and kidney injury.

[0004] The present application found that piperacillin sodium and matrine have a synergistic effect in treating acute pyelonephritis, and thus proposed the present invention. Summary of the invention

[0005] The purpose of the present invention is to provide a medicine which can effectively treat acute pyelonephritis.

[0006] In one aspect of the present invention, the present invention provides a pharmaceutical composition comprising piperacillin sodium and matrine or a pharmaceutically acceptable salt thereof, wherein the weight ratio of piperacillin sodium and matrine or a pharmaceutically acceptable salt thereof, calculated on the basis of piperacillin sodium and matrine, is 1-10:1-5.

[0007] Preferably, the weight ratio of piperacillin sodium to matrine or its pharmaceutically acceptable salts is 4-7:1-5 based on piperacillin sodium and matrine.

[0008] More preferably, the weight ratio of piperacillin sodium and matrine or its pharmaceutically acceptable salts, calculated as piperacillin sodium and matrine, is 5:5, 5:4, 5:3, 5:2.5, 5:2, or 5:1.

[0009] More preferably, the weight ratio of piperacillin sodium to matrine or its pharmaceutically acceptable salts is 5:2-4 based on piperacillin sodium and matrine.

[0010] In another aspect of the present invention, the present invention provides a kit comprising piperacillin sodium and matrine or a pharmaceutically acceptable salt thereof, wherein the weight ratio of piperacillin sodium and matrine or a pharmaceutically acceptable salt thereof, calculated on the basis of piperacillin sodium and matrine, is 1-10:1-5.

[0011] Preferably, the weight ratio of piperacillin sodium to matrine or its pharmaceutically acceptable salts is 4-7:1-5 based on piperacillin sodium and matrine.

[0012] More preferably, the weight ratio of piperacillin sodium and matrine or its pharmaceutically acceptable salts, calculated as piperacillin sodium and matrine, is 5:5, 5:4, 5:3, 5:2.5, 5:2, or 5:1.

[0013] More preferably, the weight ratio of piperacillin sodium to matrine or its pharmaceutically acceptable salts is 5:2-4 based on piperacillin sodium and matrine.

[0014] In the present invention, the pharmaceutically acceptable salt of matrine includes a salt formed by matrine and a pharmaceutically acceptable acid.

[0015] In another aspect, the present invention also provides use of the pharmaceutical composition in preparing a drug for treating kidney disease.

[0016] Preferably, the renal disease includes acute pyelonephritis, chronic pyelonephritis, acute glomerulonephritis, chronic glomerulonephritis, latent glomerulonephritis, nephrotic syndrome, IgA nephropathy, renal tubular acidosis, tubular-interstitial disease, systemic lupus erythematosus nephropathy, diabetic nephropathy, hepatic nephropathy, gouty nephropathy, scleroderma nephropathy, renal insufficiency, acute renal failure, chronic renal failure or drug-induced renal damage.

[0017] Preferably, the kidney disease includes acute pyelonephritis and acute glomerulonephritis.

[0018] Preferably, the pharmaceutical composition, medicine or kit of the present invention further comprises a pharmaceutically acceptable adjuvant.

[0019] Preferably, piperacillin sodium and matrine or a pharmaceutically acceptable salt thereof in the pharmaceutical composition, medicine or kit of the present invention can be administered in the same or different pharmaceutical preparations. The pharmaceutical dosage forms of piperacillin sodium and matrine or a pharmaceutically acceptable salt thereof can be the same or different, for example, piperacillin sodium can be an injection dosage form, and matrine can be an oral dosage form. Piperacillin sodium and matrine or a pharmaceutically acceptable salt thereof can be administered simultaneously or sequentially.

[0020] In the medical use described above, the administration time, number of administrations and frequency of administration of piperacillin sodium and matrine or their pharmaceutically acceptable salts, etc., need to be determined according to the specific diagnosis results of the disease, which is within the technical scope of those skilled in the art. The treatment regimen for mice or rats is applied to humans, and the effective doses of all drugs for humans can be converted by the effective doses of the drugs for mice or rats, which is also easy to achieve for those of ordinary skill in the art.

[0021] As pharmaceutically acceptable adjuvants, any adjuvant known to be suitable for preparing a specific drug or pharmaceutical composition can be used. Examples include, but are not limited to, solvents, excipients, dispersants, emulsifiers, solubilizers, gel formers, ointment bases, antioxidants, preservatives, stabilizers, carriers, fillers, bonding agents, thickeners, complexing agents, disintegrants, buffers, penetration enhancers, polymerizers, lubricants, coating agents, propellants, tonicity regulators, surfactants, colorants, flavoring agents, sweeteners and dyes. Particularly adjuvants suitable for the type of desired formulation and desired mode of administration are used.

[0022] For adult patients, the compound of the present invention can be administered orally or parenterally in a dose of 0.001 to 500 mg once a day or several times a day. It should be noted that the dose can be appropriately increased or decreased depending on the type of disease to be treated, the patient's age, weight, symptoms, etc.

[0023] Beneficial effects:

[0024] The present invention provides a drug for treating acute pyelonephritis and its application, wherein the drug comprises piperacillin sodium and matrine as active pharmaceutical ingredients, piperacillin sodium itself has a good therapeutic effect on acute pyelonephritis, matrine has anti-inflammatory, antioxidant, anti-apoptotic and other effects, and when used in combination with piperacillin sodium, it can greatly enhance the therapeutic activity of piperacillin sodium for acute pyelonephritis, release its efficacy, and play a synergistic role. This is very helpful for developing more drug combination forms of piperacillin sodium. DETAILED DESCRIPTION

[0025] The present invention is described in more detail hereinafter to facilitate understanding of the present invention.

[0026] The experimental methods in the following examples are all conventional methods unless otherwise specified. If no specific techniques or conditions are specified in the examples, they are carried out according to the techniques or conditions described in the literature in the art or according to the product instructions.

[0027] Example 1: The therapeutic effect of the pharmaceutical composition of the present invention on APN

[0028] Main reagents: Piperacillin sodium for injection was purchased from Wuhan Kemik Biotechnology; matrine was purchased from Beijing Solebao Technology; secretory immunoglobulin A (SIgA), serum creatinine, urine creatinine, procalcitonin (PCT), high-sensitivity C-reactive protein (hs-CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-10 (IL-10) enzyme-linked adsorbent reaction (ELISA) kits were purchased from Wuhan Yipu Biotechnology.

[0029] Establishment of APN model:

[0030] 55 SPF SD rats, male, weight (190±20) g, were raised in the following environment: temperature 20-23°C, relative humidity 60-70%, light for 12 h, alternating light and dark. Among them, 45 rats in the modeling group were fed adaptively for 1 week, and then the APN rat model was prepared according to the literature method (Preparation of acute retrograde pyelonephritis model in rats, Hou Fangyu et al., Chinese Journal of Comparative Medicine, 1998, 10(1): 31-34): the rats were deprived of water for 18 h, anesthetized with 2% sodium pentobarbital intraperitoneally, fixed in supine position, the abdomen was depilated and disinfected, a 2 cm midline incision was made in the lower abdomen, the abdominal wall was cut layer by layer, the left ureter was found, and the No. 4 line was passed from both sides of the left ureter, the penis was clamped with an artery clamp, 0.5 mL of Escherichia coli liquid was injected into the bladder, the abdominal wall was sutured layer by layer, and drinking water and diet were resumed. 24 h after the operation, the ureteral ligature was removed to open the ureter. Ten rats in the sham operation group were injected with 0.5 mL of saline instead of E. coli liquid, and the rest of the operations were the same as those in the modeling group. The modeling time was 3 days. The successful criteria for establishing the APN model were: the number of leukocytes in urine per cubic millimeter was ≥100. Four rats in the modeling group did not meet the APN criteria, and two died.

[0031] Thirty-nine APN rats were randomly divided into model group, piperacillin sodium group, matrine group, piperacillin sodium + matrine group, 10 rats in each group (9 rats in model group). Subsequently, the piperacillin sodium group was given piperacillin sodium 50 mg / kg·d (intraperitoneal injection dissolved in 5% glucose injection) and intragastric administration with 2 ml of normal saline, the matrine group was given matrine 30 mg / kg·d (intragastric administration with 2 ml of normal saline) and simultaneously injected with 5% glucose injection equal to that of the piperacillin sodium group, the piperacillin sodium + matrine group was given piperacillin sodium 50 mg / kg·d (intraperitoneal injection dissolved in 5% glucose injection) and matrine 30 mg / kg·d (intragastric administration with 2 ml of normal saline), and the sham operation group and model group were injected with 5% glucose injection equal to that of the piperacillin sodium group and intragastric administration with 2 ml of normal saline.

[0032] 1. Biochemical index detection. Blood was collected from the abdominal aorta, centrifuged at 3000min for 15min, and the supernatant was taken. Serum creatinine and urine creatinine were detected by sarcosine oxidase method, and SIgA, PCT, hs-CRP, IL-6, L-10, IL-1β, and chemokine-2 (CXCL-2) were detected by ELISA. Rat urine was collected, urine creatinine was detected by sarcosine oxidase method, and urine SIgA was detected by ELISA; WBC was detected by fully automatic blood cell analyzer; urine routine was detected by test strip method.

[0033] 2. Bacteriological examination. Aseptically obtain urine from the bladder and inoculate it on the culture medium. Prepare a homogenate from the kidney and inoculate it on the culture medium. Use the semi-quantitative method, and a bacterial count >10,000 is considered positive, and a bacterial count <500 is considered negative.

[0034] 3. Organ index of rats. After intraperitoneal anesthesia, kidney and bladder tissues were removed and weighed in wet weight. The left-right kidney ratio = left kidney mass / right kidney mass × 100%; kidney index (mg / g) = kidney mass (mg) / body mass (g) × 100%; bladder index (mg / g) = bladder mass (mg) / body mass (g) × 100%.

[0035] 4. SPSS 26.0 statistical software was used for statistical processing. The synergy coefficient was determined by Jin Zhengjun's Q value method, and the Q value was calculated by the following formula: Q = E a+b / (E a +E b -E a ×E b ). a+b is the action rate of the drug composition, E a and E b It is the effect ratio of drug treatment when administered alone. Q<0.85 indicates antagonism, 0.85≤Q<1.15 indicates additive effect, and Q≥1.15 indicates synergistic effect.

[0036] 5. Results

[0037] 5.1 The effects of drugs on the organ indexes of rats in each group are shown in Table 1. Compared with the sham operation group, the left-right kidney ratio, kidney index, and bladder index of rats in the model group were significantly increased. Compared with the model group, the left-right kidney ratio, kidney index, and bladder index of rats in the piperacillin sodium group and piperacillin sodium + matrine group were significantly decreased, and the left-right kidney ratio, kidney index, and bladder index of rats in the matrine group were decreased. Compared with the piperacillin sodium group and matrine group, the left-right kidney ratio, kidney index, and bladder index of rats in the piperacillin sodium + matrine group showed a more obvious downward trend, and had a synergistic effect.

[0039] Table 1: Comparison of renal indexes in each group of rats

[0040]

[0041]

[0042] Note: Compared with the sham operation group, # P<0.05; compared with the model group, a P<0.05; compared with piperacillin sodium, b P<0.05; compared with the matrine group, c P<0.05

[0043] 4.2 The effects of drugs on the positive rates of urine and kidney bacterial culture in rats of each group are shown in Table 2. The positive rates of urine and kidney bacterial culture in rats of the sham operation group were 0, and the positive rates of urine and kidney bacterial culture in rats of the model group were 100%; compared with the model group, the positive rates of urine and kidney bacterial culture in rats of the piperacillin sodium group and piperacillin sodium + matrine group were significantly decreased, and the positive rates of urine and kidney bacterial culture in rats of the matrine group decreased to a certain extent; among them, the positive rates of urine and kidney bacterial culture in rats of the piperacillin sodium + matrine group were both reduced to 0.

[0044] Table 2: Comparison of bacterial culture results of rats in each group

[0045]

[0046] 4.3 The effects of drugs on urine leukocyte count, urine SIgA, serum creatinine, and urine creatinine level of rats in each group are shown in Table 3. Compared with the sham operation group, the urine leukocyte count, urine creatinine, and serum creatinine levels of rats in the model group were significantly increased, and the urine SIgA level was significantly decreased; compared with the model group, the urine leukocyte count, urine creatinine, and serum creatinine levels of rats in the piperacillin sodium group and the piperacillin sodium + matrine group were significantly decreased, and the urine SIgA level was significantly increased; the urine leukocyte count, urine creatinine, and serum creatinine levels of rats in the matrine group were decreased, and the urine SIgA level was increased. Compared with the piperacillin sodium group and the matrine group, the improvement of urine leukocyte count, urine creatinine level, serum creatinine, and urine SIgA in the piperacillin sodium + matrine group was more obvious, and had a synergistic effect.

[0048] Table 3: Comparison of urine leukocyte count, urine SIgA, serum creatinine and urine creatinine levels in rats of each group

[0049]

[0050] Note: Compared with the sham operation group, # P<0.05; compared with the model group, a P<0.05; compared with piperacillin sodium group, b P<0.05; compared with the matrine group, c P<0.05

[0051] 5.4 The effects of drugs on serum WBC, PCT, and hs-CRP levels of rats in each group are shown in Table 4. Compared with the sham operation group, the WBC, PCT, and hs-CRP levels of rats in the model group were significantly increased; compared with the model group, the WBC, PCT, and hs-CRP levels of rats in the piperacillin sodium group and the piperacillin sodium + matrine group were significantly decreased, and the WBC, PCT, and hs-CRP levels of rats in the matrine group decreased. Compared with the piperacillin sodium group and the matrine group, the improvement of WBC, PCT, and hs-CRP in the piperacillin sodium + matrine group was more obvious, and there was a synergistic effect on WBC and PCT.

[0052] Table 4: Comparison of serum WBC, PCT, and hs-CRP levels in rats of each group

[0053] Group n <![CDATA[WBC(×10 9 / L)]]> PCT (ng / mL) hs-CRP (mg / L) Sham operation group 10 7.86±0.41 0.02±0.00 1.20±0.09 Model Group 9 19.42±2.56* 1.95±0.18* 60.35±7.12 Piperacillin sodium group 10 <![CDATA[10.25±1.67 a ]]> <![CDATA[0.34±0.06 a ]]> 10.21±0.97 Matrine group 10 <![CDATA[18.26±2.03 a ]]> <![CDATA[1.85±0.14 a ]]> 57.32±7.26 Piperacillin sodium + matrine group 10 <![CDATA[8.45±0.58 abc ]]> <![CDATA[0.06±0.02 abc ]]> 3.67±0.26 Q - 1.17 1.16 1.12

[0054] Note: Compared with the sham operation group, # P<0.05; compared with the model group, a P<0.05; compared with piperacillin sodium group, b P<0.05; compared with the matrine group, c P<0.05

[0055] 5.5 The effects of drugs on the serum IL-6, IL-10, IL-1β, CXCL-2, and SIgA levels of rats in each group are shown in Table 5. Compared with the sham operation group, the IL-6, IL-1β, and CXCL-2 levels of rats in the model group were significantly increased, and the IL-10 and SIgA levels were significantly decreased; compared with the model group, the IL-6, IL-1β, and CXCL-2 levels of rats in the piperacillin sodium group and the piperacillin sodium + matrine group were significantly decreased, and the IL-10 and SIgA levels were significantly increased. The IL-6, IL-1β, and CXCL-2 levels of rats in the matrine group were decreased, and the IL-10 and SIgA levels were decreased. Compared with the piperacillin sodium group and the matrine group, the improvement of IL-6, IL-10, IL-1β, CXCL-2, and SIgA in rats in the piperacillin sodium + matrine group was more obvious, and had a synergistic effect.

[0056] Table 5: Comparison of serum IL-6, IL-10, IL-1β, CXCL-2, and SIgA levels in rats of each group (pg / mL, )

[0057]

[0058] Note: Compared with the sham operation group, # P<0.05; compared with the model group, a P<0.05; compared with piperacillin sodium group, b P<0.05; compared with the matrine group, c P<0.05

[0059] In summary, the experimental results show that the combination of piperacillin sodium + matrine has a very significant effect on improving the left and right kidney mass ratio, renal index, bladder index, urine white blood cell count, urine SIgA, serum creatinine, urine creatinine and serum WBC, PCT, hs-CRP, IL-6, IL-10, IL-1β, CXCL-2, SIgA, and eliminating inflammation in APN rats, and achieved a synergistic therapeutic effect compared with piperacillin sodium and matrine.

[0060] The above is only a preferred embodiment of the present invention. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present invention. These improvements and supplements should also be regarded as the scope of protection of the present invention.

Claims

1. A pharmaceutical composition comprising piperacillin sodium and matrine or a pharmaceutically acceptable salt thereof, wherein the weight ratio of piperacillin sodium to matrine or a pharmaceutically acceptable salt thereof is 1-10:1-5, calculated on the basis of piperacillin sodium and matrine.

2. The pharmaceutical composition according to claim 1, characterized in that The weight ratio of piperacillin sodium to matrine or its pharmaceutically acceptable salt is 4-7:1-5 based on piperacillin sodium and matrine.

3. The pharmaceutical composition according to claim 1, characterized in that The weight ratio of piperacillin sodium to matrine or its pharmaceutically acceptable salt is 5:2-4 based on piperacillin sodium and matrine.

4. A kit comprising piperacillin sodium and matrine or a pharmaceutically acceptable salt thereof, wherein the weight ratio of piperacillin sodium to matrine or a pharmaceutically acceptable salt thereof is 1-10:1-5, calculated on the basis of piperacillin sodium and matrine.

5. Use of the pharmaceutical composition according to any one of claims 1 to 3 in the preparation of a drug for treating kidney disease.

6. The use according to claim 5, characterized in that: The kidney diseases include acute pyelonephritis, chronic pyelonephritis, acute glomerulonephritis, chronic glomerulonephritis, latent glomerulonephritis, nephrotic syndrome, IgA nephropathy, renal tubular acidosis, tubular-interstitial lesions, systemic lupus erythematosus nephropathy, diabetic nephropathy, hepatic nephropathy, gouty nephropathy, scleroderma nephropathy, renal insufficiency, acute renal failure, chronic renal failure or drug-induced renal damage.

7. The use according to claim 6, characterized in that: The kidney diseases include acute pyelonephritis and acute glomerulonephritis.

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