CN112426531B - Application of pharmaceutical composition in preparation of medicine for treating kidney diseases - Google Patents
Application of pharmaceutical composition in preparation of medicine for treating kidney diseases Download PDFInfo
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Abstract
The invention provides an application of a pharmaceutical composition in preparing a medicine for preventing or treating kidney diseases, wherein the pharmaceutical composition comprises at least one mitochondrial uncoupler and at least one artemisinin compound, and the pharmaceutical composition can effectively reduce the contents of total urine protein, albumin and urine H2O2, reduce the levels of serum creatinine and serum urea nitrogen, reduce the excretion of NAG, NGAL and Kim-1 in urine, effectively improve renal function, glomerular injury and renal tubular injury, effectively improve renal injury and lipid metabolism abnormality caused by diabetic nephropathy, play a role in protecting kidneys, delay the progression of renal diseases and effectively prevent or treat the renal diseases.
Description
Technical Field
The invention relates to the technical field of biological medicines, and particularly relates to application of a pharmaceutical composition in preparation of a medicine for preventing or treating kidney diseases.
Background
The kidney is an important organ of the human body, and the essential function of the kidney is to maintain the homeostasis of the body by forming urine, such as 1) to remove metabolic wastes in the body, such as creatinine, urea nitrogen and the like; 2) Regulating water, electrolyte and acid-base balance of organism. In addition, the kidney also secretes renin, erythropoietin, active vitamin D3, prostaglandin, kinins and the like, and is a site for degradation of endocrine hormones in the body and a target organ of extrarenal hormones. These functions of the kidney ensure the stability of the internal environment of the body and ensure the normal metabolism of the body.
The kidney diseases are diseases which are primary to the kidney or secondary to other organ diseases and affect the kidney, and the clinical manifestations mainly comprise partial excretion indexes in urine and abnormal symptoms of local parts of the kidney. Kidney disease can be caused by a variety of causes, such as Acute Kidney Injury (AKI) which is often a more sudden and reversible condition due to blood loss, dehydration, or drug use, etc.; chronic Renal Failure (CRF) is an irreversible disorder with progressive loss of renal function, one of the main causes of CRF is diabetes mellitus, which causes diabetic nephropathy, and clinical treatments for chronic renal failure mainly include symptomatic treatment and alternative treatments such as peritoneal dialysis, hemodialysis, and kidney transplantation, but the effect is limited.
While Chronic Kidney Disease (CKD) is a series of clinical manifestations and metabolic disorder syndromes characterized by progressive deterioration or irreversible damage of kidney structure and function caused by various diseases, according to statistics, the prevalence rate of CKD in adults in China is 13.2%, the prevalence rate is high, but the early awareness rate and the effective treatment rate are low, and the incidence rate of CKD is further increased along with the increase of prevalence rate of diabetes and hypertension in China. Because the prevalence rate is increasing worldwide, CKD has become one of the chronic diseases that endanger human health following cardiovascular and cerebrovascular diseases, diabetes, and malignant tumors. The prevalence of acute kidney injury to chronic kidney disease is also very high, and Diabetic Kidney Disease (DKD), one of microvascular complications of diabetes, progresses slowly, and finally progresses to End-stage renal disease (ESRD), one of the main causes of death of Diabetic patients. About 20% -40% of diabetic patients in China have combined DKD, the pathogenesis of DKD is not completely clear up to now, and other common kidney diseases also comprise hypertension, glomerulonephritis, kidney injury caused by infection and the like.
The currently known methods for treating renal diseases mainly adopt different treatment methods capable of maintaining renal functions according to the degree of the disease, such as diet therapy, drug therapy, peritoneal dialysis, hemodialysis therapy, or kidney transplantation, and in particular, dialysis therapy such as hemodialysis or peritoneal dialysis or kidney transplantation is required to be relied on once renal insufficiency occurs. Hemodialysis treatment is considered as a final treatment method for kidney diseases, but only metabolic wastes that are retained in the body due to renal dysfunction are removed from blood, and the renal function of a serious disorder cannot be recovered, so that a patient has to rely on dialysis equipment for a long time and dialysis treatment that costs a high amount, and in many cases, the probability of eventually causing complications such as cardiac insufficiency and infection increases. The kidney transplantation is the only method capable of radically treating the renal insufficiency, but the problems of limited sources, rejection reaction and the like exist, so that the development of a medicament capable of effectively treating the renal diseases, particularly capable of preventing and treating the renal diseases at an early stage, is still a technical problem to be solved in the field.
At present, the commonly used medicines are mainly symptomatic support treatment medicines, including medicines for treating diabetes, hypertension, hyperlipidemia, anemia and the like. In addition, steroid anti-inflammatory drugs are mainly used for nephritis, and immunosuppressive agents, antiplatelet agents, hypotensive agents, diuretics, and the like can be used for etiology or disease. In diabetic nephropathy, on the one hand, blood glucose is strictly controlled, and on the other hand, hypotensive agents such as angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, and calcium blockers are used. For example, glucocorticoid can be used to inhibit inflammatory reaction and immune reaction, inhibit aldosterone secretion, and inhibit the combined action of diuretic hormone secretion affecting glomerular basement membrane permeability, thereby exerting the effects of inducing diuresis and reducing urine protein.
However, the conventional remedies for kidney diseases are mainly directed to specific symptoms, and it is difficult to substantially block the progress of renal insufficiency, and thus the clinical needs cannot be sufficiently satisfied. In addition, side effects of long-term use of drugs are also a problem, for example, glucocorticoid causes significant side effects such as bone marrow suppression, liver function impairment, sexual dysfunction, gastrointestinal dysfunction, etc., and clinical recommendation suggests that the dosage or the use thereof be reduced as much as possible, and a safe and effective drug for treating renal diseases is in need of further development.
Disclosure of Invention
The invention aims to provide application of a pharmaceutical composition in preparing a medicament for preventing or treating kidney diseases, wherein the pharmaceutical composition comprises at least one mitochondrial uncoupling agent and at least one artemisinin compound, and the pharmaceutical composition can effectively delay the progression of the kidney diseases.
The inventor carries out a series of animal experimental researches on the combined application of the mitochondria uncoupler and the artemisinin compound, finds that the drug combination can effectively prevent and treat kidney diseases, has obviously better effect than single drug, and can obviously reduce total urine protein, albumin and urine H 2 O 2 The content of the compound can reduce the levels of serum creatinine and serum urea nitrogen, reduce the excretion of urinary albumin, NAG, NGAL and Kim-1, effectively improve renal function and glomerular and renal tubular injuries, effectively improve abnormal lipid metabolism caused by the renal injuries and diabetic nephropathy, play a role in protecting the kidney, delay the progression of renal diseases, and can be used for preparing medicaments for preventing and treating the renal diseases.
The invention provides an application of a pharmaceutical composition in preparing a medicament for preventing or treating kidney diseases, wherein the pharmaceutical composition comprises at least one mitochondria uncoupler and at least one artemisinin compound.
In some embodiments, the mitochondrial uncoupling agent is selected from one or more of benzimidazoles, anthranilates, phenylhydrazones, 2-hydroxy-benzamides, acyldithiocarbamates, salicylates, coumarins, or arylamines having mitochondrial uncoupling activity, or pharmaceutically acceptable salts, solvates, or prodrugs thereof.
Further, in a preferred embodiment of the present invention, the mitochondrial uncoupling agent is a 2-hydroxy-benzamide compound, and further preferably, the mitochondrial uncoupling agent is niclosamide ethanolamine salt.
In some embodiments, the artemisinin compound is selected from artemisinin or an artemisinin derivative, and further, in some embodiments of the invention, the artemisinin derivative is selected from one or more of Dihydroartemisinin (DI) or a derivative thereof, artesunate (Artesunate) or a derivative thereof, artemether (Art) or a derivative thereof, arteether (Arteether) or a derivative thereof, artesunone (Artemisone) or a derivative thereof, artesunone (artenolone) or a derivative thereof.
In some preferred embodiments, the artemisinin compound is artemether.
In some embodiments, the mass ratio of mitochondrial uncoupling agent to artemisinin compound in the pharmaceutical composition is 1-40:0.05-20.
Further preferably, the mass ratio of the mitochondrial uncoupler to the artemisinin compound in the pharmaceutical composition is 2:0.3.
in some embodiments, the kidney disease in the present invention is a kidney disease caused by a nephropathy or an external injury, preferably, the kidney disease is an acute kidney injury disease, a chronic kidney injury disease, or nephritis, more preferably, a glomerular or tubular injury disease.
Preferably, the kidney disease is a chronic kidney disease (or failure), an acute kidney disease (or failure), a primary glomerular disease, a secondary glomerular disease, a tubular disease, interstitial nephritis, diabetic nephropathy, a non-diabetic kidney disease, hypertensive nephropathy, hereditary nephropathy, metabolic nephropathy, an autoimmune-related kidney disease, a tumor-related kidney disease, an infection-related kidney disease, drug-induced kidney damage, a kidney transplant rejection-related kidney disease, a pregnancy-related kidney disease, kidney transplant failure, kidney cancer, or the like.
Preferably, the diabetic nephropathy is kidney damage caused by type 1 diabetes or type 2 diabetes.
In some embodiments, the medicament further comprises a pharmaceutically acceptable carrier or excipient to prepare a pharmaceutical formulation suitable for administration.
In some embodiments, the pharmaceutical formulation may be for oral, sublingual, parenteral, topical, rectal, systemic, sub-buccal or implant use.
Further, the pharmaceutical preparation may be a tablet, oral solution, injection, ophthalmic solution, dermal or transdermal preparation, ointment, gel, cream, lotion, patch, dispersion system, emulsion, osmotic pump, subcutaneous implant, microencapsulated drug system, particle, microsphere, modified release system, targeted release system or pill.
Further, the present invention provides the use of a kit or kit comprising at least one mitochondrial uncoupling agent and at least one artemisinin compound in separate packages for the preparation of a medicament for the prevention or treatment of renal disease.
Optionally, the mitochondrial uncoupling agent and the artemisinin compound can be administered simultaneously or sequentially, and the administration sequence does not influence the prevention or treatment effect.
In some embodiments, the mitochondrial uncoupling agent is selected from one or more of benzimidazoles, anthranilates, phenylhydrazones, 2-hydroxy-benzamides, salicylates, acyldithiocarbamates, coumarins, or arylamines having mitochondrial uncoupling activity, or pharmaceutically acceptable salts, solvates, or prodrugs thereof.
Further, in a preferred embodiment of the present invention, the mitochondrial uncoupling agent is a 2-hydroxy-benzamide compound, and even more preferably, the mitochondrial uncoupling agent is niclosamide ethanolamine salt.
In some embodiments, the artemisinin compound is selected from artemisinin or an artemisinin derivative, and further, in some embodiments of the invention, the artemisinin derivative is selected from one or more of Dihydroartemisinin (DI) or a derivative thereof, artesunate (Artesunate) or a derivative thereof, artemether (Art) or a derivative thereof, arteether (Arteether) or a derivative thereof, artesunone (Artemisone) or a derivative thereof, artesunone (artenolone) or a derivative thereof.
In some preferred embodiments, the artemisinin compound is artemether.
In some embodiments, the mass ratio of mitochondrial uncoupler to artemisinin compound in the kit or kit is 1-40:0.05-20.
Preferably, in some embodiments, the mass ratio of mitochondrial uncoupler to artemisinin compound in the kit or kit is 2:0.3.
in some embodiments, the medicament further comprises a pharmaceutically acceptable carrier or excipient to prepare a pharmaceutical formulation suitable for administration.
In some embodiments, the pharmaceutical formulation may be for oral, sublingual, parenteral, topical, rectal, systemic, sub-buccal or implant use.
Further, the pharmaceutical preparation may be a tablet, oral solution, injection, ophthalmic solution, dermal or transdermal preparation, ointment, gel, cream, lotion, patch, dispersion system, emulsion, osmotic pump, subcutaneous implant, microencapsulated drug system, particle, microsphere, modified release system, targeted release system or pill.
In some embodiments, the kidney disease in the present invention is a kidney disease caused by a nephropathy or an external injury, preferably, the kidney disease is an acute kidney injury disease, a chronic kidney injury disease, or nephritis, more preferably, a glomerular or tubular injury disease. Preferably, the kidney disease is a chronic kidney disease (or failure), an acute kidney disease (or failure), a primary glomerular disease, a secondary glomerular disease, a tubular disease, interstitial nephritis, diabetic nephropathy, a non-diabetic kidney disease, hypertensive nephropathy, hereditary nephropathy, metabolic nephropathy, an autoimmune-related kidney disease, a tumor-related kidney disease, an infection-related kidney disease, drug-induced kidney damage, a kidney transplant rejection-related kidney disease, a pregnancy-related kidney disease, kidney transplant failure, kidney cancer, or the like.
More preferably, the diabetic nephropathy is kidney damage caused by type 1 diabetes or type 2 diabetes.
In some embodiments, the agent for preventing or treating kidney disease is an agent that reduces the rate of excretion of total protein in urine in a mammal.
In some embodiments, the agent for preventing or treating kidney disease is reducing urinary H in a mammal 2 O 2 A drug for an excretion rate.
In some embodiments, the agent for preventing or treating kidney disease is an agent that decreases serum creatinine levels in a mammal.
In some embodiments, the agent for preventing or treating kidney disease is an agent that reduces serum urea nitrogen levels in a mammal.
In some embodiments, the agent for preventing or treating kidney disease is an agent that reduces urinary albumin excretion rate in a mammal.
In some embodiments, the agent for preventing or treating kidney disease is an agent that decreases urinary NAG excretion rate in a mammal.
In some embodiments, the agent for preventing or treating renal disease is an agent that decreases urinary NGAL excretion rate in a mammal.
In some embodiments, the agent for preventing or treating kidney disease is an agent that decreases Kim-1 excretion rate in urine in a mammal.
The mammal is a human.
The invention has the beneficial effects that: the pharmaceutical composition, the kit and the complete set of medicines in the invention achieve unexpected technical effects, and can significantly reduce total urine protein, albumin and urine H 2 O 2 The content of the active ingredients in the composition can reduce serum creatinine and serum urea nitrogen levels, reduce NAG, NGAL and Kim-1 excretion, effectively improve renal function and renal tubule and glomerular injury, effectively improve renal injury and abnormal lipid metabolism caused by diabetic nephropathy, protect the kidney, delay the progression of the renal disease, and effectively prevent or treat acute and chronic renal diseases and diabetic nephropathy related diseases.
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FIG. 1 results of the effect of each administration group on the total urinary protein excretion rate in mice in example 1, wherein # P <0.05, # P <0.01, compared to the renal disease group; p <0.05 compared to NEN group; p <0.05 compared to the Art group; n =6 per group.
FIG. 2 urine H of mice from each group of administration in example 1 2 O 2 Effect of excretion Rate results, wherein, # P compared with Kidney disease group<0.05，###P<0.001; compared with NEN group, P is<0.05; in comparison with the Art group,. Diamond-P<0.05; n =6 per group.
FIG. 3 results of the effect of each administration group on mouse serum urea nitrogen levels in example 1, wherein # P <0.05, # P <0.01, compared to the renal disease group; n =6 per group.
Figure 4 results of the effect of each dosing group on mouse blood creatinine levels in example 1, wherein # P <0.05 compared to the renal disease group; n =6 per group.
Figure 5 results of the effect of each dosing group on mouse serum Triglyceride (TG) levels in example 1, wherein, # # P <0.01 compared to the renal disease group; in comparison with the NEN group, the present invention, a tangle-solidup-P <0.01; p <0.05 compared to the Art group; n =6 per group.
Figure 6 results of the effect of each dosing group on total serum cholesterol (TC) levels in mice in example 1, where # P <0.05 compared to the renal disease group; p <0.05 compared to NEN group; p <0.05 compared to the Art group; n =6 per group.
Figure 7 results of the effect of each administration group on mouse serum Low Density Lipoprotein (LDL) levels in example 1, wherein # P <0.05 compared to the renal disease group; n =6 per group.
FIG. 8 is a graph showing the results of the effect of # P <0.01 and # P <0.001 on the urinary albumin excretion rate of mice in each administration group in example 2, compared with the diabetic group; compared with the NEN group, a-solidup-P is less than 0.001; in comparison with the set of Art,. Diamond-solid. P <0.001; n =8 per group.
Figure 9 results of effect of each administration group on urinary NAG levels in mice in example 2, wherein, # # P <0.01, # # P <0.001 compared to diabetic groups; compared with the NEN group, a-solidup-P is less than 0.001; in comparison with the set of Art,. Diamond-solid. P <0.001; n =8 per group.
Figure 10 results of the effect of each dosing group on urinary NGAL levels in mice in example 2, wherein, # # P <0.01, # # P <0.001, compared to the diabetic group; compared with the NEN group, a-solidup-P is less than 0.001; in comparison with the set of Art,. Diamond-solid. P <0.001; n =8 per group.
FIG. 11 results of the effect of each group on Kim-1 levels in urine in mice in example 2, wherein # P <0.05, # P <0.01, # P <0.001; p <0.05 compared to NEN group; p <0.05 compared to the Art group; n =8 per group.
Fig. 12 results of effects of each administration group on serum triglycerides of mice in example 2, wherein # P <0.01, # P <0.001 in the administration group of the pharmaceutical composition compared with the diabetic group; compared with the NEN group, a-solidup-P is less than 0.001; n =8 per group.
Figure 13 results of effect of each dosing group on total serum cholesterol in mice in example 2, wherein # P <0.05 compared to diabetic group; compared with the NEN group, a-solidup-P is less than 0.001; diamond-solid P <0.01, compared to the Art group; n =8 per group.
Detailed Description
The present invention is further described below by way of specific examples, and the scope of application of the present invention is not limited to the following examples. Since the present invention has been described in terms of the following preferred embodiments, certain modifications and equivalent variations will be apparent to those of ordinary skill in the art and are intended to be included within the scope of the present invention.
Unless defined otherwise herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by one of ordinary skill in the art. The meaning and scope of a term should be clear, however, in the event of any potential ambiguity, the definition provided herein takes precedence over any dictionary or extrinsic definition. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "including" and other forms is not limiting.
In order that the invention may be more readily understood, selected terms are defined below.
The Artemether (abbreviated as Art) is called methyl reduced artemisinin, is called Artemeth English, has the CAS number of 71963-77-4, and has the chemical structural formula shown as the following figure:
the mitochondrial uncoupling agent in the invention includes, but is not limited to, 2-hydroxy-benzamide compounds, benzimidazole compounds, phenylhydrazone compounds, N-phenyl anthranilate compounds, salicylic acid compounds, acyl dithiocarbamate compounds, coumarins or arylamine compounds with mitochondrial uncoupling activity, or pharmaceutically acceptable salts, solvent compounds or prodrugs thereof.
The Niclosamide Ethanolamine (NEN) is named Niclosamide ethanolamine by English, is named as N- (2-chloro-4-nitrophenyl) -2-hydroxy-5-chlorobenzamide ethanolamine by chemical name, has CAS number of 1420-04-8, and has a chemical structural formula shown as the following figure:
artemisinin compounds, including artemisinin and artemisinin derivatives, include but are not limited to Dihydroartemisinin (DI) or its derivatives, artesunate (Artesunate) or its derivatives, artemether (Art) or its derivatives, arteether (Arteether) or its derivatives, artesunone (Artemisone) or its derivatives, artesunone (artenolone) or its derivatives, and Artesunate (artenolone) or its derivatives.
"serum creatinine" (Cr) is a product of human muscle metabolism, is a small molecule substance that can be filtered through the glomerulus, is rarely absorbed in the renal tubules, and creatinine produced in the body every day is almost completely excreted with urine, and is generally not affected by urine volume. Clinical detection of serum creatinine is one of the main methods for understanding renal function, and is an important index of renal function.
"Total urine protein" means the total protein content in 24 hours urine, which is an important index for measuring kidney function, and normally, human urine contains no protein or only trace amount of protein, but when the kidney is diseased, the protein flowing along with blood circulation flows through the kidney, and the protein leaks into urine due to the damage of kidney filtration function and is discharged from urethra to form proteinuria.
"urinary albumin" is also an index reflecting abnormal leakage protein of kidney, albumin is a normal protein in blood, but albumin is only present in a very small amount in urine under normal physiological conditions, but when a patient suffers from diabetes or other kidney injury diseases, renal angiogenesis is changed, the function of kidney filtration protein (especially albumin) is changed, and albuminuria is one of the common signs of kidney diseases, particularly glomerular diseases.
"serum urea nitrogen" is a nitrogen-containing compound in plasma other than proteins that is removed from the body by filtration through the glomeruli. Blood levels will rise during renal dysfunction. Therefore, it is clinically used as an index for judging the glomerular filtration function.
The NAG is particularly rich in the content of proximal tubular epithelial tissues and is one of the most sensitive indexes of the tubular functions, and the urinary NAG activity has very important significance on the positioning diagnosis of tubular diseases, nephrotic syndromes, urinary tract infection, the monitoring of renal transplant rejection and the early diagnosis of diabetic nephropathy caused by heavy metals or medicaments.
"NGAL" (neutrophil gelatinase lipocalin) has a molecular weight of 25kD, is a small molecule secretory protein produced by epithelial cells and neutrophils of various tissues, is separated from human neutrophils, appears in damaged renal tubules in large amount when renal tubular epithelial cells are stimulated, and can be used as an early diagnosis sensitive marker.
"Kim-1" (renal injury molecule-1) is a specific marker that can be expressed in large amounts in the urine and serum of patients with acute renal injury, appears in injured renal tissues, and is dissolved during repair of renal tubular epithelial cell injury, and the dissolved fragment can be detected in the urine.
The inventor of the application further proves that the pharmaceutical composition regulates the function and the biosynthesis of mitochondria from different aspects, regulates the redox state of kidney, and can play a role in improving kidney diseases through kidney pathology and molecular experiments, so that the technical effects of physiology, kidney injury, pathological changes, inflammation and other pathologies and improvement effects of kidney diseases are obviously superior to those of a single medicine in the pharmaceutical composition, and the results show that the pharmaceutical composition can be used as a candidate medicine for effectively treating other diseases such as injury diseases, metabolic diseases, inflammatory diseases, tumors and the like.
The following are.
Embodiments of the present invention will be described in detail with reference to examples. In the examples, reagents or instruments used by manufacturers, which are not indicated, are commercially available products, and specific conditions are not indicated, and the reagents or instruments are operated according to the conventional operation in the field or the instruction for using the reagents/instruments. .
Example 1 Adriamycin Kidney disease model mouse treatment results
1. Preparation of animal models
Male BALB/C mice (body weight 20-25 g) were controlled to have a constant room temperature of 20-23 ℃,12 hours of light and 12 hours of dark cycles, and were allowed to simultaneously and freely eat and drink water, and an Adriamycin nephropathy mouse model was prepared by administering a single tail vein injection of 10.4 mg/kg Adriamycin (Adriamycin, dissolved in physiological saline), and a normal group was administered a single tail vein injection of an equal amount of physiological saline, and the results of the tests demonstrated successful renal injury modeling. Adriamycin was purchased from Sigma, USA, BALB/c mice were purchased from southern medical university animal center, and animal experiments were conducted strictly according to animal ethical guidelines and regulations of Chinese medicine university, guangzhou.
2. Results of drug administration test
2.1 Experiment grouping
After 2 weeks, BALB/c experimental mice were randomly assigned to the following groups: doxorubicin nephropathy model group (i.e., adriamycin nephropathiy, nephropathic group), doxorubicin nephropathy model + NEN treatment group (i.e., NEN group), doxorubicin nephropathy model + Art treatment group (i.e., art group), doxorubicin nephropathy model + NEN + Art treatment group (i.e., pharmaceutical composition group). After grouping, the nephrotic group was given standard feed feeding, the NEN group was given NEN-supplemented feed feeding (NEN and feed mixed at a ratio of 2g. Wherein NEN is purchased from Cheng Tianheng Chu Biotech, inc. of Hubei and Art is purchased from Chengdu Kangbang Biotech, inc.
2.2 Parameter and index measuring method
2 weeks after dosing, urine was collected using a mouse metabolism cage (Tenebis, italy), and total urine protein and urine H were measured for 24H 2 O 2 The rate of excretion. And blood samples and kidney tissue samples were collected for determination of serum creatinine and serum urea nitrogen. Collecting blood samples of mice, and measuring lipid metabolism related indexes including serum Triglyceride (TG), total Cholesterol (TC) and serum low-density lipoprotein (LDL). Total urine protein was determined using the Bio-Rad Total protein assay kit, urine H 2 O 2 The assay was performed using Amplex UltraRed (Invitrogen, usa) reagents and the biochemical indices were measured using a fully automated biochemical analyzer (Roche, switzerland).
2.3 Statistical analysis method
The metrology data is expressed as mean ± standard deviation. The statistical differences between the two groups of samples were analyzed using independent sample t-test, the comparison between the groups of samples was performed using one-way anova, the statistical analysis was processed using SPSS 16.0 statistical software, and differences of significance were considered statistically when P < 0.05.
2.4 Results of the experiment
The pharmaceutical composition can obviously reduce the total urine protein and urine H of doxorubicin nephropathy mice 2 O 2 Excretion rate, and serum urea nitrogen, serum creatinine levels.
Fig. 1 shows the effect of the pharmaceutical composition on the total urinary protein excretion rate of mice, and it can be seen from the graph that the total urinary protein excretion rate of NEN group, art group and the pharmaceutical composition group is significantly decreased compared to the renal disease group, wherein the total urinary protein excretion rate of NEN group is decreased by 47.3% compared to the renal disease group, the total urinary protein excretion rate of Art group is decreased by 42.7% compared to the renal disease group, and the total urinary protein excretion rate of the pharmaceutical composition group is decreased by 67.8% compared to the renal disease group. It can be seen that the improvement effect of the drug combination group on the excretion rate of total protein in urine is far better than that of the single drug groups (namely NEN group and Art group), and the statistical difference is significant compared with the two groups of single drug groups.
FIG. 2 shows the drug combination for mouse urine H 2 O 2 Effect of Excretion Rate As can be seen from the graph, urine H was observed in the NEN group, the Art group and the pharmaceutical composition group, compared with the nephropathy group 2 O 2 The excretion rates were all significantly decreased, with the NEN group comparing to the nephropathy group urine H 2 O 2 The excretion rate is reduced by 47.9 percent, and the urine H is compared with the nephropathy group in the Art group 2 O 2 The excretion rate is reduced by 45.1%, and the urine H of the medicine composition group is compared with that of the kidney disease group 2 O 2 The excretion rate was reduced by 80.5%. As can be seen, the pharmaceutical composition group was for urine H 2 O 2 The excretion rate improving effect of the traditional Chinese medicine is far lower than that of single medicine groups (namely NEN group and Art group), and the traditional Chinese medicine has obvious statistical difference compared with the two single medicine groups.
FIG. 3 is a graph showing the effect of the pharmaceutical composition on the serum urea nitrogen level of mice, and it can be seen from the graph that the serum urea nitrogen levels of the NEN group, the Art group and the pharmaceutical composition group are all significantly reduced compared with the nephropathy group, wherein the serum urea nitrogen level of the NEN group is reduced by 15.2% compared with the nephropathy group, the serum urea nitrogen level of the Art group is reduced by 23.3% compared with the nephropathy group, and the serum urea nitrogen level of the pharmaceutical composition group is reduced by 28.1% compared with the nephropathy group. It can be seen that the pharmaceutical composition group had an improved effect on serum urea nitrogen levels over the single drug group (i.e., NEN group and Art group).
FIG. 4 is a graph showing the effect of the pharmaceutical composition on serum creatinine level in mice, in which the mean serum creatinine levels in the NEN group, the Art group and the pharmaceutical composition group are significantly decreased compared to the nephropathy group, wherein the serum creatinine level in the NEN group is decreased by 32.4% compared to the nephropathy group, the serum creatinine level in the Art group is decreased by 46.1% compared to the nephropathy group, and the serum creatinine level in the pharmaceutical composition group is decreased by 40.2% compared to the nephropathy group. It can be seen that the group of pharmaceutical compositions is effective in reducing serum creatinine levels.
Fig. 5 shows the effect of each administration group on the serum Triglyceride (TG) level of mice, and it can be seen from the data in the figure that the serum TG content of the drug composition group has obvious statistical difference compared with the NEN and Art groups, wherein, compared with the kidney disease group, the drug composition has # P <0.01, compared with the NEN group, a-solidup P <0.01, and compared with the Art group, P <0.05, which indicates that the drug composition can effectively reduce the serum triglyceride content of mice.
FIG. 6 shows the effect of each group on Total Cholesterol (TC) in serum of mice, and the data in the figure shows that the TC content in serum of the drug combination group is statistically different from that of the NEN and Art treatment groups, wherein # P of the drug combination is less than 0.05 compared with the kidney group; p <0.05 compared to NEN group; compared with the Art group, P is less than 0.05, which shows that the compound can effectively reduce the content of total cholesterol in serum of the kidney injury mice.
FIG. 7 shows the effect of each administration group on Low Density Lipoprotein (LDL) in the serum of mice, and the data in the figure show that the serum low density lipoprotein content of the pharmaceutical composition group is obviously reduced compared with the NEN group and the Art group, which indicates that the pharmaceutical composition can effectively reduce the LDL content in the serum of mice with diabetic nephropathy. Therefore, the pharmaceutical composition of the invention also has a better effect on the improvement of lipid metabolism disorder and related indexes caused by the lipid metabolism disorder.
The experiment results show that the pharmaceutical composition can effectively reduce total protein in urine and urine H 2 O 2 The excretion rate, the serum creatinine and the serum urea nitrogen level can effectively improve the abnormal lipid metabolism caused by the kidney diseases, and the effect of the pharmaceutical composition is obviously superior to the improvement effect of a single medicine on the indexes.
Example 2 diabetic model mouse treatment results
1. Preparation of animal models
Male C57BL/6 mice were controlled to a constant room temperature of 20-23 ℃,12 hours light and 12 hours dark cycle conditions, while free to eat and drink. The type 1 diabetes mouse model is induced by intraperitoneal injection of 55mg/kg Streptozotocin (STZ) dissolved in citric acid buffer solution for 5 continuous days, fasting blood glucose is measured 9 days after the last STZ injection, and the detection result proves that the diabetes molding is successful.
In the preparation process of the animal model: male C57BL/6 mice (body weight 22-26 g) were purchased from Guangdong provincial medical laboratory animal center. Animal experiments are strictly carried out according to related ethical guidelines and regulations of animals of Guangzhou Chinese medicine university; STZ was purchased from Sigma, usa.
2. Test and results of group administration
2.1 Experiment grouping
The mice successfully modeled were randomly assigned to the following groups: a diabetes model group (i.e., diabetes group), a diabetes model + NEN treatment group (i.e., NEN group), a diabetes model + Art treatment group (i.e., art group), a diabetes model + NEN + Art treatment group (i.e., pharmaceutical composition group). After grouping, the diabetes group was fed with standard diet, the diabetes + NEN group was fed with NEN-supplemented diet (NEN and diet mixed at a ratio of 10g/1 kg), the diabetes + Art group was fed with Art-supplemented diet (Art and diet mixed at a ratio of 0.67g/1 kg), and the diabetes + pharmaceutical composition group was fed with NEN-supplemented and Art-supplemented diet (NEN/Art/diet mixed at a ratio of 10g/0.67g/1 kg), and the total period was observed for 8 weeks. Wherein NEN is purchased from Cheng Tianheng Chu Biotech, inc. of Hubei and Art is purchased from Chengdu Kangbang Biotech, inc.
2.2 Measurement of parameters and indices
Urine NAG, serum Triglyceride (TG), total Cholesterol (TC) contents were measured with a biochemical analyzer (roche), mouse body weights were weighed with the drug for 8 weeks, and urine was collected using a mouse metabolism cage (tenibous, italy). Fasting blood glucose was measured for each group of mice using a glucometer (roche, switzerland), after the mice were sacrificed, the kidneys of each group of mice were removed and kidney tissue samples were collected.
After 8 weeks of administration, the levels of urinary albumin, NGAL and Kim-1 of each group of mice were measured by ELISA assay, wherein the albumin assay kit was purchased from Bethyyl, USA; NGAL and Kim-1 assay kits were purchased from R & D systems, USA, and the procedures were followed.
2.3 Statistical analysis method
The metrology data is expressed as mean ± standard deviation. Statistical differences between the two groups of samples were analyzed using independent sample t-test, comparisons between the groups of samples were analyzed using one-way anova, statistical analysis was processed using SPSS 16.0 statistical software. P <0.05 was considered statistically significant.
2.4 Results of the experiment
The pharmaceutical composition can obviously reduce the excretion rates of urinary albumin, urinary NAG, NGAL and Kim-1 of mice.
Fig. 8 shows the effect of each administration group on the urinary albumin level of mice, and it can be seen from the figure that the urinary albumin excretion rates at 24 hours were significantly decreased in the NEN group, the Art group, and the pharmaceutical composition group compared with the diabetic group, but it can be seen from the data that the urinary albumin excretion rates of the pharmaceutical composition group were decreased by 63% in the NEN group, 37% in the Art group and 30% in the NEN group compared with the diabetic group. Therefore, the 24-hour urinary albumin content of the pharmaceutical composition group is far lower than that of the single medicine group, and the pharmaceutical composition group has very significant statistical difference compared with the two single medicine groups.
Fig. 9 is a detection result of NAG level in urine of mice by each administration group, and it can be seen that the NAG level of mice after dry prognosis of the pharmaceutical composition group has very significant statistical difference compared with the single drug treatment effect of NEN group and Art group, and can significantly reduce the excretion level of NAG in urine of mice.
FIG. 10 shows the measurement results of the NGAL level in urine of mice by each administration group, and it can be seen that the average of NGAL level in urine of mice after dry-treatment of the pharmaceutical composition is about half of that of single-drug treatment of NEN group and Art group, and has obvious statistical difference compared with the single-drug treatment effect, wherein compared with the diabetes group, the # P of the pharmaceutical composition group is less than 0.001; compared with the NEN group, a-solidup-P is less than 0.001; in contrast to the set of Art,. Diamond-solid. P <0.001.
FIG. 11 shows the results of testing the Kim-1 level in the urine of mice by each administration group, and it can be seen that the Kim-1 level in the urine of mice in the pharmaceutical composition group is lower than that of the single drug, wherein the Kim-1 level in the urine of mice in the NEN group and the Art group is respectively reduced by 32% and 36% compared with the diabetic group, while the Kim-1 level in the pharmaceutical composition group is reduced by 53% compared with the diabetic group, and the pharmaceutical composition group has statistical difference compared with the single drug treatment effect of the NEN group and the Art group.
Fig. 12 is a test result of Triglyceride (TG) level in serum of mice by each administration group, and it can be seen that, compared with the NEN treatment group, the TG content level in serum of the pharmaceutical composition group has a relatively obvious statistical difference, and can effectively reduce the content of triglyceride in serum of diabetic mice, which is beneficial to lipid metabolism.
Fig. 13 is a test result of Total Cholesterol (TC) level in serum of mice by each administration group, and it can be seen from the result that when NEN and Art are administered alone, TC level of mice is not significantly different from that of diabetic group, and is slightly increased from specific data, but the pharmaceutical composition of the present invention significantly reduces total cholesterol level in serum of mice after administration, which shows that it can improve other indexes of kidney disease and also effectively improve lipid metabolism of mice.
The experimental results show that the pharmaceutical composition disclosed by the invention not only can effectively reduce the excretion rates of urinary albumin, NAG, NGAL and Kim-1, but also can effectively improve lipid metabolism disorder caused by kidney diseases, and the effect of the pharmaceutical composition is very obvious in statistical difference compared with that of a single medicine.
It can be seen from the combination of the experimental data and results of examples 1-2 that the pharmaceutical composition provided by the present invention can effectively reduce total urine protein and H urine protein 2 O 2 The excretion rate, the serum creatinine and the serum urea nitrogen level are reduced, and the excretion of urine albumin, NAG, NGAL and Kim-1 is reduced, namely the pharmaceutical composition has obvious effects on multiple relevant indexes of kidney diseases, can perform kidney protection in multiple dimensions, not only effectively improve the kidney function and the damage of glomeruli and renal tubules, but also effectively improve the kidney damage and lipid metabolism abnormality caused by diabetic nephropathy, further protect the kidney, and can effectively prevent or treat the kidney damage and the diseases related to the diabetic nephropathy.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (5)
1. The application of a pharmaceutical composition in preparing a medicine for treating kidney diseases is characterized in that the pharmaceutical composition comprises niclosamide ethanolamine salt and artemether, and the mass ratio of the niclosamide ethanolamine salt to the artemether in the pharmaceutical composition is 10:0.67, the kidney disease is diabetic nephropathy.
2. The application of a pharmaceutical composition in preparing a medicine for treating kidney diseases is characterized in that the pharmaceutical composition comprises niclosamide ethanolamine salt and artemether, and the mass ratio of the niclosamide ethanolamine salt to the artemether in the pharmaceutical composition is 2:0.3, the kidney disease is acute kidney disease, and the pharmaceutical composition can effectively reduce the excretion rate of total urine protein, the excretion rate of urine albumin, the excretion rate of H2O2 in urine, the excretion rate of serum creatinine, the excretion rate of urea nitrogen in serum, the excretion rate of NAG in urine, the excretion rate of NGAL in urine and the excretion rate of Kim-1 in urine to realize the treatment of the kidney disease.
3. Use according to any of claims 1 or 2, wherein the medicament further comprises pharmaceutically acceptable excipients to prepare a suitable pharmaceutical formulation.
4. The use according to claim 3, wherein the pharmaceutical formulation is for oral, sublingual, systemic, rectal, buccal or implant administration.
5. The use according to claim 4, wherein the pharmaceutical formulation is a tablet, an oral solution, an injection, an ophthalmic solution, an ointment, a gel, a cream, a lotion, a patch, an emulsion, an osmotic pump, a subcutaneous implant, a microencapsulated drug system, microspheres, a targeted release system or a pill.
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| Pengxun Han等.Niclosamide ethanolamine improves diabetes and diabetic kidney disease in mice.《Am J Transl Res》.2018,第10卷(第10期),第1071-1084页. * |
| Yao Wang等.Artemether improves type 1 diabetic kidney disease by regulating mitochondrial function.《 Am J Transl Res》.2019,第11卷(第11期),第3879-3889页. * |
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