CN115634228B - Application of purine synthesis inhibitor in preparation of medicines for treating ischemia and ischemia reperfusion injury - Google Patents
Application of purine synthesis inhibitor in preparation of medicines for treating ischemia and ischemia reperfusion injury Download PDFInfo
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Abstract
The invention discloses application of a purine synthesis inhibitor in preparing a medicament for preventing and/or treating ischemia and ischemia reperfusion injury, in particular to application in preparing a medicament for treating renal ischemia injury and ischemia reperfusion injury. The invention proves the great potential of the purine synthesis inhibitor as a medicament for preventing and treating kidney ischemia and ischemia reperfusion injury, and discovers that the purine synthesis inhibitor has good treatment effect on ischemia and ischemia reperfusion injury. The purine synthesis inhibitor can inhibit the damage of kidney functions caused by ischemia and ischemia reperfusion injury, provides a new potential therapeutic drug for ischemia and ischemia reperfusion injury, expands the indication of the purine synthesis inhibitor, and has larger market potential and application value.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of a purine synthesis inhibitor in preparation of a medicine for treating ischemia and ischemia reperfusion injury.
Background
Nucleotide antitumor drugs are a class of chemotherapeutic drugs that act by inhibiting nucleotide synthesis by rapidly proliferating tumor cells. 6-Mercaptopurine (6-Mercaptopurine) is a purine analog synthesized in 1951, blocking the salvage pathway of purine nucleotides by competitively inhibiting hypoxanthine-guanine phosphoribosyl transferase; inhibiting the de novo synthesis pathway of purine by inhibiting phosphoribosyl pyrophosphate aminotransferase from interfering with phosphoribosyl amine formation; the conversion of inosine nucleotide to adenine and guanine nucleotide is inhibited by phosphoribosyl formation of 6-MP nucleotide. This enables 6-mercaptopurine to effectively inhibit the synthesis of DNA and RNA, thereby inhibiting the growth of tumor cells. Methyl 2, 6-dichloropyrimidine-4-carboxylate (split) has an antiproliferative effect by inhibiting glycyl amine nucleotide formyl transferase and thus purine synthesis. Currently, 6-mercaptopurine has been used in the treatment of cancer and autoimmune diseases, including acute leukemia, chorioapithelia cancer, malignant grape embryo, psoriatic arthritis, inflammatory enteritis, and the like. The use of split-xol as a candidate anticancer drug is under clinical research. According to literature information, the effects of purine synthesis inhibitors on ischemia and ischemia reperfusion injury have not been reported.
The lack of blood supply can cause ischemia and hypoxia of tissues to cause damage, while ischemia reperfusion is a damage condition occurring after blood supply is restored in ischemic tissues, mainly caused by the increase of active oxygen after blood supply is restored. In case of tissue ischemia, the electron transfer chain function is impaired, electrons cannot be transferred effectively, resulting in electron accumulation and reduced ATP generation. During reperfusion, the ischemic tissue acquires a large amount of oxygen and generates a large amount of oxygen radicals. In addition, ischemia causes a decrease in the synthesis ability of antioxidant enzymes, and oxygen radicals cannot be effectively scavenged, resulting in an increase in active oxygen. The types of ischemia and ischemia reperfusion injury include various types such as kidney ischemia and ischemia reperfusion injury, myocardial ischemia and ischemia reperfusion injury, liver ischemia and ischemia reperfusion injury, cerebral apoplexy, organ transplantation and the like. The damage caused by the damage of kidney functions caused by the ischemia and ischemia reperfusion injury of the kidney is very great, and can cause high mortality rate clinically. Reperfusion is an essential means of rescuing ischemic organs, but the damage caused by reperfusion remains a significant clinical challenge, and currently there is still a lack of very effective intervention. The use of free radical scavengers to ameliorate the damage caused by ischemia reperfusion would be an effective way of intervention. There remains a great clinical need to develop more effective interventions to address the needs of patients.
Disclosure of Invention
In order to solve the problems, the invention aims to provide a novel medicament for treating ischemia and ischemia reperfusion injury, in particular to a medicament for treating kidney ischemia and ischemia reperfusion injury, which can effectively protect kidney functions and provides a novel alternative medicament for preventing and treating ischemia and reperfusion injury.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
use of a purine synthesis inhibitor for the preparation of a medicament for the treatment of ischemic injury and/or ischemia reperfusion injury.
The use of a purine synthesis inhibitor for the manufacture of a medicament for the prevention of ischemic injury and/or ischemia reperfusion injury.
Wherein the ischemia and ischemia reperfusion injury includes myocardial ischemia and ischemia-reperfusion injury, liver ischemia and ischemia reperfusion injury, cerebral apoplexy, organ transplantation, and the like, in addition to kidney ischemia and ischemia reperfusion injury.
Taking kidney ischemia and ischemia reperfusion injury as examples, preventing and/or treating kidney ischemia injury is specifically embodied in reducing apoptosis proportion of kidney cells; the prevention and/or treatment of renal ischemia reperfusion injury is embodied in the following aspects: 1) Reducing the apoptosis proportion of kidney cells; 2) Effectively relieving the damage of the renal tubule caused by the ischemia reperfusion of the kidney; 3) Reducing damage to renal function from renal ischemia reperfusion; 4) Effectively improves the survival rate of the mice with kidney ischemia reperfusion injury.
Wherein the purine synthesis inhibitor comprises 6-Mercaptopurine (6-Mercap) or pharmaceutically acceptable salt thereof, and 2, 6-dichloropyrimidine-4-methyl formate (split) or pharmaceutically acceptable salt thereof.
Further, the medicament comprises 6-mercaptopurine or a pharmaceutically acceptable salt thereof.
In the above-described use of the present invention, the medicament contains an effective dose of 6-mercaptopurine or a pharmaceutically acceptable salt thereof. An effective dose is a unit dosage form (e.g., the amount in a tablet of drug) for administration of a unit dose or a unit dose (e.g., a unit body weight dose) for a treated patient. In the present invention, the subject to be treated with the drug is a mammal, including human, mouse, etc. According to the equivalent dose conversion relation between the human and the experimental animal, the unit weight dose of the human can be estimated by using the dose of the animal. Equivalent dose of the experimental mice was 12 times that of the human in terms of unit body weight dose.
In the invention, the effective dose of 6-mercaptopurine for treating kidney ischemia and ischemia reperfusion injury in 6-week-old C57BN/6J mice is 50-100 mg/kg.
According to the conversion relation of the effective dose of the adult and the mouse, the standard weight of the adult is set to be 60kg, and the effective dose of the adult is 250-500 mg per day.
The 6-mercaptopurine can be formulated as desired into oral dosage forms, such as tablets.
Further, the medicament comprises split rexol or a pharmaceutically acceptable salt thereof.
In the above-described use of the invention, the medicament contains an effective dose of the split rexol or a pharmaceutically acceptable salt thereof. An effective dose is a unit dosage form (e.g., the amount in a tablet of drug) for administration of a unit dose or a unit dose (e.g., a unit body weight dose) for a treated patient. In the present invention, the subject to be treated with the drug is a mammal, including human, mouse, etc. According to the equivalent dose conversion relation between the human and the experimental animal, the unit weight dose of the human can be estimated by using the dose of the animal. Equivalent dose of the experimental mice was 12 times that of the human in terms of unit body weight dose.
In the invention, the effective dose of the split rexol for treating kidney ischemia and ischemia reperfusion injury in 6-week-old C57BN/6J mice is 5-10 mg/kg.
According to the conversion relation between the effective dose of the adult and the effective dose of the mice, the standard weight of the adult is set to be 60kg, and the effective dose of the adult is 25-50 mg per day.
The invention also provides a medicament for preventing and/or treating ischemia injury and a medicament for preventing and/or treating ischemia reperfusion injury.
The active ingredient of the medicine is a purine synthesis inhibitor.
Wherein the purine synthesis inhibitor comprises 6-Mercaptopurine (6-Mercaptopurine) or a pharmaceutically acceptable salt thereof, and methyl 2, 6-dichloropyrimidine-4-carboxylate (split) or a pharmaceutically acceptable salt thereof.
In the medicine, the purine synthesis inhibitor can be used as one of the active ingredients, and can also be used as the only active ingredient.
Carrier materials may also be added in the preparation of the medicament.
Such carriers include, but are not limited to: diluents, suspending agents, buffers, granules, emulsions, excipients, encapsulating agents, sprays, binders, fillers, disintegrants, wetting agents, transdermal absorbents, absorption enhancers, surfactants, flavoring agents, colorants, or adsorption carriers.
The above-mentioned medicines can be made into tablet, capsule, solution or injection etc. according to conventional method known to those skilled in the art.
The invention has the following beneficial effects:
1. the inhibitor 6-mercaptopurine and the split-nol can inhibit kidney ischemia and ischemia reperfusion injury.
2. Provides a new potential therapeutic drug for ischemia and ischemia reperfusion injury, expands the indication of purine synthesis inhibitor, and has larger market potential and application value.
Drawings
FIG. 1 shows the experimental results of the purine synthesis inhibitor 6-mercaptopurine and the split extract for rescuing apoptosis caused by ischemic injury of kidney.
FIG. 2 shows the experimental results of the purine synthesis inhibitor 6-mercaptopurine and the split drug for rescuing apoptosis caused by ischemia reperfusion injury of kidney.
FIG. 3 shows the experimental results of the purine synthesis inhibitor 6-mercaptopurine and the split drug for rescuing the damage of the renal tubule caused by ischemia reperfusion injury of the kidney.
FIG. 4 shows the results of experiments on the purine synthesis inhibitor 6-mercaptopurine and the split pexol to rescue elevated levels of serum creatinine and urea nitrogen caused by kidney ischemia reperfusion injury.
FIG. 5 shows the results of experiments in which the purine synthesis inhibitor 6-mercaptopurine and split rexol increased survival in renal ischemia reperfusion injury mice.
Detailed Description
The invention is further described below. The following examples are only for more clearly illustrating the technical aspects of the present invention, and thus are merely examples, and are not intended to limit the scope of the present invention.
The application of purine synthesis inhibitor in preparing medicine for treating ischemia and ischemia reperfusion injury.
The application of purine synthesis inhibitor in preparing medicine for preventing ischemia and ischemia reperfusion injury.
Wherein the ischemia and ischemia reperfusion injury includes myocardial ischemia and ischemia-reperfusion injury, liver ischemia and ischemia reperfusion injury, cerebral apoplexy, organ transplantation, and the like, in addition to kidney ischemia and ischemia reperfusion injury.
Among them, purine synthesis inhibitors include 6-Mercaptopurine (6-MP) and methyl 2, 6-dichloropyrimidine-4-carboxylate (split rexol).
Example 1:
and constructing a kidney ischemia injury mouse model.
A total of 15 kidney ischemia injury experiments were performed using 6 week old C57BN/6J mice, 5 DMSO control groups, 5 6-mercaptopurine treated groups, 5 split rexol treated groups, and the specific procedures were as follows:
injecting DMSO, 6-mercaptopurine (100 mg/kg) or split rexol (10 mg/kg) by tail vein injection for 1h in advance, then inhaling anesthetized mice by isoflurane, dehairing the backs of the mice, shearing off skin and muscle, exposing kidneys, separating renal arteries on two sides, clamping right renal arteries by arterial clamp, carrying out ischemia treatment for 1h, not carrying out ischemia treatment on left kidneys, carrying out other operation identically, taking kidney tissues as pathological specimens, and carrying out TUNEL staining.
TUNEL staining was performed as follows:
paraffin sections were dewaxed with xylene twice for 5 minutes each. Absolute ethanol for 5min, 90% ethanol for 2 min, 70% ethanol for 2 min, distilled water for 2 min, 20. Mu.g/ml DNase-free proteinase K were added dropwise and incubated for 15 min at 37 ℃. TUNEL staining was performed after 3 washes with PBS. 50 μl TUNEL detection solution (5 μl TdT enzyme, 45 μl fluorescent labeling solution) was added dropwise to the sample, incubated at 37deg.C in the dark for 60 min, washed 3 times with PBS, DAPI stained with 100 μg/ml DAPI aqueous solution, incubated at room temperature for 5min, washed 3 times with PBS, and photographed under a fluorescent microscope after sealing with anti-fluorescence quenching sealing solution.
As shown in fig. 1 a, the number of TUNEL-staining positive cells in kidney sections increased after renal ischemia treatment, indicating a significant increase in apoptosis in the kidneys of mice, whereas the proportion of apoptosis was significantly reduced after advanced treatment with 6-mercaptopurine or split rexol.
As shown in fig. 1B, the number of TUNEL positive cells in kidney sections was counted, and with t-test, there was a significant difference between the 6-mercaptopurine-treated and DMSO-treated ischemic groups, and between the split-xol-treated and DMSO-treated ischemic groups. * P <0.001.
The results of FIG. 1 show that the kidney ischemia model is successfully constructed, and the treatment of 6-mercaptopurine or split rexol can effectively protect the kidney and greatly reduce the damage of kidney ischemia to the kidney.
Example 2:
and constructing a kidney ischemia reperfusion injury mouse model.
A total of 36 kidney ischemia reperfusion injury experiments were performed using 6 week old C57BN/6J mice, 12 DMSO control groups (6 sham groups, 6 ischemia reperfusion experiments), 12 6-mercaptopurine treated groups (6 sham groups, 6 ischemia reperfusion experiments), 12 split red ol treated groups (6 sham groups, 6 ischemia reperfusion experiments), and the specific procedures were as follows:
injecting DMSO, 6-mercaptopurine (100 mg/kg) or split rexol (10 mg/kg) by tail vein injection for 1h in advance, then inhaling anesthetized mice by isoflurane, dehairing the backs of the mice, shearing off skin and muscle, exposing kidneys, separating renal arteries on two sides, clamping the renal arteries by arterial clamps, loosening arterial clamps after 45min of ischemia, observing blood flow recovery condition, closing abdominal cavity by layering suture after the kidneys recover bright red, performing the same operation of the control group without ischemia treatment, performing operation for 48h after operation, taking blood from eyeballs for detecting serum biochemical indexes (creatinine and urea nitrogen), and taking kidney tissues as pathological samples.
As shown in fig. 2 a, the number of TUNEL staining positive cells in kidney sections increased after renal ischemia reperfusion treatment, indicating a significant increase in apoptosis in the mouse kidney, whereas the proportion of apoptosis was significantly reduced after advanced treatment with 6-mercaptopurine or split rexol.
As shown in fig. 2B, the number of TUNEL positive cells in kidney sections was counted, and with t-test, there was a significant difference between the 6-mercaptopurine-treated and DMSO-treated ischemia-reperfusion groups, and the split-xol-treated and DMSO-treated ischemia-reperfusion groups. * P <0.001.
From the results of FIG. 2, it was demonstrated that 6-mercaptopurine or split rexol treatment was effective in alleviating apoptosis caused by renal ischemia reperfusion.
As shown in fig. 3 a, morphological observation of tubular with H & E staining significantly increased tubular injury after renal ischemia reperfusion treatment, whereas tubular injury was significantly reduced after advanced treatment with 6-mercaptopurine or split rexol.
As shown in fig. 3B, kidney sections were subjected to a peller score, with a t-test, there was a significant difference in the peller scores of the 6-mercaptopurine-treated and DMSO-treated ischemia-reperfusion groups, and the peller scores of the split-xol-treated and DMSO-treated ischemia-reperfusion groups. * P <0.001.
The paler scoring criteria were: the kidney tubules are obviously expanded and the cells are flat, and the score is 1; the formation of the tubular inner tube of the kidney tubule is recorded as 2 minutes; the lumen of the kidney tubule has necrotic cells which fall off, but has no tubular and cell debris, and the score is 1; epithelial cell granulosis, scored 1 minute; the vacuolation sample degeneration of the epithelial cells is recorded for 1 minute; epithelial nuclei shrink and score 1. 10 views were selected for each tissue, 10 diseased tubules were randomly selected for each high power (200 times) view, the scores were summed up for 100 tubules, and the total score divided by 100 was the patient's beller score.
From the results of FIG. 3, it was demonstrated that 6-mercaptopurine or split rexol treatment was effective in alleviating the damage to the tubules caused by ischemia reperfusion of the kidneys.
As shown in FIG. 4A, serum creatinine and urea nitrogen increased after renal ischemia reperfusion treatment, but serum creatinine and urea nitrogen were no longer increased after prior treatment with 6-mercaptopurine or Portorexol.
As shown in fig. 4B, with t-test, there was a significant difference between the 6-mercaptopurine-treated and DMSO-treated ischemia reperfusion groups, and the split rexol-treated and DMSO-treated ischemia reperfusion groups, P <0.01.
The results of FIG. 4 demonstrate that treatment with 6-mercaptopurine or split rexol is effective in protecting the kidney and greatly reducing damage to kidney function from ischemia reperfusion of the kidney.
As shown in FIG. 5, the overall survival rate of mice after 10 days of renal ischemia reperfusion treatment was 20%, whereas the survival rate after advanced treatment with 6-mercaptopurine or split rexol was 100% or 80%.
The results of FIG. 5 demonstrate that treatment with 6-mercaptopurine or split rexol is effective in protecting the kidneys and greatly improving survival of mice following renal ischemia reperfusion.
In summary, 6-mercaptopurine or split-sol treatment is effective in preventing and treating renal ischemia and ischemia reperfusion injury.
The above examples are intended to be illustrative of the technical solution of the present invention and not limiting, and although the present invention has been described in detail with reference to specific embodiments, it will be apparent to those skilled in the art that modifications and improvements can be made to the technical solution of the present invention. Accordingly, all such modifications and improvements as do not depart from the scope of the invention are intended to be within the scope of the invention.
Claims (3)
1. The application of purine synthesis inhibitor in preparing medicine for treating ischemia injury and/or ischemia reperfusion injury; the purine synthesis inhibitor is selected from 2, 6-dichloropyrimidine-4-methyl formate or pharmaceutically acceptable salt thereof;
the ischemia injury and/or ischemia reperfusion injury is kidney ischemia injury and/or ischemia reperfusion injury.
2. Application of purine synthesis inhibitor in preparing medicine for preventing ischemia injury and/or ischemia reperfusion injury;
the purine synthesis inhibitor is selected from 2, 6-dichloropyrimidine-4-methyl formate or pharmaceutically acceptable salt thereof;
the ischemia injury and/or ischemia reperfusion injury is kidney ischemia injury and/or ischemia reperfusion injury.
3. Use according to claim 1 or 2, characterized in that:
preventing and/or treating the kidney ischemic injury is embodied in reducing the proportion of apoptosis of kidney cells;
preventing and/or treating the renal ischemia reperfusion injury is embodied in the following aspects:
1) Reducing the apoptosis proportion of kidney cells;
2) Effectively relieving the damage of the renal tubule caused by the ischemia reperfusion of the kidney;
3) Reducing damage to renal function from renal ischemia reperfusion;
4) Effectively improves the survival rate of the mice with kidney ischemia reperfusion injury.
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| US8188067B2 (en) * | 2004-04-01 | 2012-05-29 | Teva Pharmaceutical Industries Ltd. | Formulations of 6-mercaptopurine |
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