Medicine for treating acute pyelonephritis and application thereof

Abstract

The present invention relates to a drug for treating acute pyelonephritis and its use. The drug comprises piperacillin sodium and matrine as active ingredients. Matrine enhances the therapeutic efficacy of piperacillin sodium for kidney disease, particularly acute pyelonephritis, by releasing its efficacy and achieving a synergistic effect. This is highly helpful for developing more drug combinations of piperacillin sodium.

Description

Technical Field

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

[0002] Acute pyelonephritis (APN) is a urinary tract infection caused by bacteria. It presents with an acute onset, with typical symptoms including high fever, bladder irritation, and lower back pain. Symptoms may include loss of appetite, nausea, and vomiting, and some patients may experience upper or general abdominal pain. Common complications of acute pyelonephritis include renal papillary necrosis, perinephric abscesses, and toxic shock. The primary pathological basis of APN is bacterial ascent via vesicoureteral reflux, with Escherichia coli being the primary pathogen.

[0003] APN is primarily treated with antibiotics. β-lactam antibiotics include piperacillin sodium, tazobactam sodium, tazobactam sodium, sulbactam sodium, and amoxicillin. Piperacillin sodium, piperacillin sodium tazobactam sodium, and piperacillin sodium sulbactam sodium are often clinically chosen as the first-line treatments for acute pyelonephritis. Potentiators are added to piperacillin sodium tazobactam sodium and piperacillin sodium sulbactam sodium to further enhance their efficacy, demonstrating high activity against many drug-resistant strains. Matrine (Mat), a tetracyclic quinoline alkaloid found in Sophora flavescens, exhibits anti-inflammatory, antioxidant, and anti-apoptotic effects and has been used to treat conditions such as lung, liver, and kidney damage.

[0004] The present application discovered 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 that 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 pharmaceutically acceptable salts thereof 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 pharmaceutically acceptable salts thereof 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 renal 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, the piperacillin sodium and matrine or its pharmaceutically acceptable salts in the pharmaceutical composition, medicament, or kit of the present invention can be administered in the same or different pharmaceutical formulations. The pharmaceutical dosage forms of piperacillin sodium and matrine or its pharmaceutically acceptable salts can be the same or different. For example, piperacillin sodium can be in an injectable dosage form, and matrine can be in an oral dosage form. Piperacillin sodium and matrine or its pharmaceutically acceptable salts can be administered simultaneously or sequentially.

[0020] In the medical uses described above, the administration time, number of administrations, and frequency of administration of piperacillin sodium and matrine, or pharmaceutically acceptable salts thereof, etc., need to be determined based on the specific diagnosis of the disease, and this is within the skill of those skilled in the art. When a treatment regimen for mice or rats is applied to humans, the effective doses of all drugs for humans can be converted from the effective doses of the drugs for mice or rats, which is also easily achievable by those skilled in the art.

[0021] As pharmaceutically acceptable adjuvants, any adjuvant known to be suitable for preparing a particular medicament 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, binding agents, thickeners, complexing agents, disintegrants, buffers, penetration enhancers, polymerizing agents, lubricants, coating agents, propellants, tonicity regulators, surfactants, colorants, flavorings, sweeteners, and dyes. In particular, adjuvants of a type suitable for the desired formulation and desired route of administration are used.

[0022] For adult patients, the compounds of the present invention can be administered orally or parenterally in a single dose of 0.001 to 500 mg once a day or divided into several doses. This dosage can be appropriately increased or decreased depending on the type of disease being treated, the patient's age, weight, and symptoms.

[0023] Beneficial effects:

[0024] The present invention provides a drug for treating acute pyelonephritis and its use. The drug contains piperacillin sodium and matrine as active ingredients. Piperacillin sodium itself has a good therapeutic effect on acute pyelonephritis, and matrine has anti-inflammatory, antioxidant, and anti-apoptotic effects. When used in combination with piperacillin sodium, piperacillin sodium can greatly enhance the therapeutic activity of piperacillin sodium for acute pyelonephritis, unleash its efficacy, and achieve a synergistic effect. This is very helpful for developing more drug combinations of piperacillin sodium. DETAILED DESCRIPTION

[0025] The present invention is described in more detail below 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 were carried out according to the techniques or conditions described in the literature in the field 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 Solaibao 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] Fifty-five male SPF SD rats weighing (190±20) g were housed in a controlled environment with a temperature of 20-23°C, a relative humidity of 60-70%, and a 12-hour light cycle with alternating light and dark conditions. Forty-five rats in the modeling group were fed adaptively for one week and then developed into an APN rat model according to the literature (Establishment of an 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 hours and anesthetized with 2% sodium pentobarbital intraperitoneally. The rats were fixed in a supine position, the abdomen was hairless and disinfected, and a 2 cm midline incision was made in the lower abdomen. The abdominal wall was opened layer by layer. After the left ureter was located, a No. 4 suture was passed through 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 and eating were resumed. 24 hours after the operation, the ureteral ligature was removed to open the ureter. Ten rats in the sham-operated group were injected with 0.5 mL of saline instead of E. coli liquid. All other procedures were the same as those in the model group. The model was established for three days. The successful APN model was established with a urine white blood cell count of ≥100 per cubic millimeter. Four rats in the model group did not meet the APN criteria, and two died.

[0031] Thirty-nine rats with APN were randomly divided into a model group, a piperacillin sodium group, a matrine group, and a piperacillin sodium + matrine group, with 10 rats in each group (nine rats in the model group). Subsequently, the piperacillin sodium group was given 50 mg / kg·d of piperacillin sodium (intraperitoneally injected in 5% glucose injection) and gavaged with 2 ml of normal saline. The matrine group was given 30 mg / kg·d of matrine (intraperitoneally injected with 2 ml of normal saline) and simultaneously injected with the same amount of 5% glucose injection as the piperacillin sodium group. The piperacillin sodium + matrine group was given 50 mg / kg·d of piperacillin sodium (intraperitoneally injected in 5% glucose injection) and 30 mg / kg·d of matrine (intraperitoneally injected with 2 ml of normal saline). The sham-operated and model groups were injected with the same amount of 5% glucose injection as the piperacillin sodium group and gavaged with 2 ml of normal saline.

[0032] 1. Biochemical marker testing. Blood was collected from the abdominal aorta and centrifuged at 3000 nm for 15 min. The supernatant was collected and assayed for serum and urine creatinine using the sarcosine oxidase method. SIgA, PCT, hs-CRP, IL-6, L-10, IL-1β, and chemokine-2 (CXCL-2) were assayed using ELISA. Urine was collected and assayed for creatinine using the sarcosine oxidase method and SIgA using ELISA. White blood cell counts were measured using an automated hematology analyzer. Urinalysis was performed using a test strip.

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

[0034] 3. Rat Organ Index. After intraperitoneal anesthesia, kidney and bladder tissues were removed and weighed wet. 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. Statistical analysis was performed using SPSS 26.0 statistical software. The synergy coefficient was determined by the Jin Zhengjun Q value method, and the Q value was calculated using the following formula: Q = E a+b / (E a +E b -E a ×E b ). E a+b is the action rate of the drug composition, E a and E b Q is the ratio of the drug's effect when administered alone. Q < 0.85 indicates antagonism, 0.85 ≤ Q < 1.15 indicates additive effect, and Q ≥ 1.15 indicates synergism.

[0036] 5. Results

[0037] 5.1 The effects of the drugs on the organ indices of rats in each group are shown in Table 1. Compared with the sham-operated 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 the piperacillin sodium + matrine group were significantly decreased. The left-right kidney ratio, kidney index, and bladder index of rats in the matrine group were decreased to a certain extent. Compared with the piperacillin sodium group and the 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, indicating a synergistic effect.

[0038] Table 1: Comparison of renal indexes in rats of various groups

[0039]

[0040]

[0041] 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

[0042] 4.2 The effects of the drugs on the positive rates of bacterial culture in urine and kidney of rats in each group are shown in Table 2. The positive rates of bacterial culture in urine and kidney of rats in the sham-operated group were both 0, and the positive rates of bacterial culture in urine and kidney of rats in the model group were both 100%. Compared with the model group, the positive rates of bacterial culture in urine and kidney of rats in the piperacillin sodium group and the piperacillin sodium + matrine group were significantly decreased, and the positive rates of bacterial culture in urine and kidney of rats in the matrine group decreased to a certain extent. Among them, the positive rates of bacterial culture in urine and kidney of rats in the piperacillin sodium + matrine group were both reduced to 0.

[0043] Table 2: Comparison of bacterial culture results in rats of each group

[0044]

[0045] 4.3 The effects of the drugs on urine white blood cell count, urine SIgA, serum creatinine, and urine creatinine levels in rats in each group are shown in Table 3. Compared with the sham-operated group, the urine white blood cell 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 white blood cell 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 white blood cell count, urine creatinine, and serum creatinine levels of rats in the matrine group decreased slightly, and the urine SIgA level increased slightly. Compared with the piperacillin sodium group and the matrine group, the improvement in urine white blood cell count, urine creatinine level, serum creatinine, and urine SIgA in rats in the piperacillin sodium + matrine group was more significant, and a synergistic effect was observed.

[0046] Table 3: Comparison of urine leukocyte count, urine SIgA, serum creatinine, and urine creatinine levels in rats of each group

[0047]

[0048] Note: Compared with the sham operation group, # P<0.05; compared with the model group, a P<0.05; compared with the piperacillin sodium group, b P<0.05; compared with the matrine group, c P<0.05

[0049] 5.4 The effects of the drugs on serum WBC, PCT, and hs-CRP levels in rats in each group are shown in Table 4. Compared with the sham-operated 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 to a certain extent. Compared with the piperacillin sodium group and the matrine group, the improvement in WBC, PCT, and hs-CRP in the piperacillin sodium + matrine group was more significant, and a synergistic effect was observed on WBC and PCT.

[0050] Table 4: Comparison of serum WBC, PCT, and hs-CRP levels in rats of each group

[0051] 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

[0052] Note: Compared with the sham operation group, # P<0.05; compared with the model group, a P<0.05; compared with the piperacillin sodium group, b P<0.05; compared with the matrine group, c P<0.05

[0053] 5.5 The effects of the drugs on serum IL-6, IL-10, IL-1β, CXCL-2, and SIgA levels in rats of each group are shown in Table 5. Compared with the sham-operated group, the IL-6, IL-1β, and CXCL-2 levels of rats in the model group were significantly increased, while 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, while 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, while 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 levels in rats in the piperacillin sodium + matrine group was more significant, and a synergistic effect was observed.

[0054] Table 5: Comparison of serum IL-6, IL-10, IL-1β, CXCL-2, and SIgA levels in rats of each group (pg / mL, )

[0055]

[0056] Note: Compared with the sham operation group, # P<0.05; compared with the model group, a P<0.05; compared with the piperacillin sodium group, b P<0.05; compared with the matrine group, c P<0.05

[0057] In summary, the experimental results showed that the combination of piperacillin sodium + matrine had 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.

[0058] 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 for treating acute pyelonephritis, 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 based on the weight of piperacillin sodium to 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. Use of the pharmaceutical composition according to any one of claims 1 to 3 in the preparation of a medicament for treating acute pyelonephritis.

Images