CN115634228A - Application of purine synthesis inhibitor in preparation of medicine for treating ischemia and ischemia reperfusion injury - Google Patents
Application of purine synthesis inhibitor in preparation of medicine for treating ischemia and ischemia reperfusion injury Download PDFInfo
- Publication number
- CN115634228A CN115634228A CN202110820479.3A CN202110820479A CN115634228A CN 115634228 A CN115634228 A CN 115634228A CN 202110820479 A CN202110820479 A CN 202110820479A CN 115634228 A CN115634228 A CN 115634228A
- Authority
- CN
- China
- Prior art keywords
- ischemia
- injury
- reperfusion injury
- renal
- synthesis inhibitor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 206010063837 Reperfusion injury Diseases 0.000 title claims abstract description 53
- 208000028867 ischemia Diseases 0.000 title claims abstract description 53
- 208000012947 ischemia reperfusion injury Diseases 0.000 title claims abstract description 43
- 230000006825 purine synthesis Effects 0.000 title claims abstract description 31
- 239000003814 drug Substances 0.000 title claims abstract description 30
- 239000003112 inhibitor Substances 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 206010063897 Renal ischaemia Diseases 0.000 claims abstract description 33
- 230000006378 damage Effects 0.000 claims abstract description 22
- 208000027418 Wounds and injury Diseases 0.000 claims abstract description 10
- 208000014674 injury Diseases 0.000 claims abstract description 10
- 230000003907 kidney function Effects 0.000 claims abstract description 6
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims description 70
- 229960001428 mercaptopurine Drugs 0.000 claims description 34
- 230000010410 reperfusion Effects 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 12
- 241000699670 Mus sp. Species 0.000 claims description 11
- 230000006907 apoptotic process Effects 0.000 claims description 10
- 210000004027 cell Anatomy 0.000 claims description 8
- 208000037906 ischaemic injury Diseases 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 7
- DQNQNLWKAGZNIT-UHFFFAOYSA-N methyl 2,6-dichloropyrimidine-4-carboxylate Chemical compound COC(=O)C1=CC(Cl)=NC(Cl)=N1 DQNQNLWKAGZNIT-UHFFFAOYSA-N 0.000 claims description 6
- 230000004083 survival effect Effects 0.000 claims description 6
- 210000000056 organ Anatomy 0.000 claims description 5
- 230000010024 tubular injury Effects 0.000 claims description 5
- 208000037978 tubular injury Diseases 0.000 claims description 5
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 4
- 208000006011 Stroke Diseases 0.000 claims description 4
- 230000002490 cerebral effect Effects 0.000 claims description 4
- 208000031225 myocardial ischemia Diseases 0.000 claims description 4
- 238000002054 transplantation Methods 0.000 claims description 4
- 210000003292 kidney cell Anatomy 0.000 claims description 3
- 210000004185 liver Anatomy 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 230000001640 apoptogenic effect Effects 0.000 claims 1
- 210000003734 kidney Anatomy 0.000 abstract description 23
- 229940079593 drug Drugs 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 2
- 229940126585 therapeutic drug Drugs 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 33
- 241000699666 Mus <mouse, genus> Species 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 210000005239 tubule Anatomy 0.000 description 7
- QXOPTIPQEVJERB-JQWIXIFHSA-N (2s)-2-[[5-[2-[(6s)-2-amino-4-oxo-5,6,7,8-tetrahydro-1h-pyrido[2,3-d]pyrimidin-6-yl]ethyl]-4-methylthiophene-2-carbonyl]amino]pentanedioic acid Chemical compound C1=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)SC(CC[C@H]2CC=3C(=O)N=C(N)NC=3NC2)=C1C QXOPTIPQEVJERB-JQWIXIFHSA-N 0.000 description 6
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 6
- 229950003819 pelitrexol Drugs 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000000302 ischemic effect Effects 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000013042 tunel staining Methods 0.000 description 5
- 238000000692 Student's t-test Methods 0.000 description 4
- 210000002254 renal artery Anatomy 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000012353 t test Methods 0.000 description 4
- KWYLVDGOCQSPDM-UHFFFAOYSA-N 3,7-dihydropurine-6-thione Chemical compound SC1=NC=NC2=C1NC=N2.S=C1N=CNC2=C1NC=N2 KWYLVDGOCQSPDM-UHFFFAOYSA-N 0.000 description 3
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 210000001367 artery Anatomy 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000036770 blood supply Effects 0.000 description 3
- 229940109239 creatinine Drugs 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 210000002919 epithelial cell Anatomy 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 229960002725 isoflurane Drugs 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- -1 oxygen radicals Chemical class 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 150000003212 purines Chemical class 0.000 description 2
- 210000005084 renal tissue Anatomy 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- AUHDWARTFSKSAC-HEIFUQTGSA-N (2S,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-2-(6-oxo-1H-purin-9-yl)oxolane-2-carboxylic acid Chemical compound [C@]1([C@H](O)[C@H](O)[C@@H](CO)O1)(N1C=NC=2C(O)=NC=NC12)C(=O)O AUHDWARTFSKSAC-HEIFUQTGSA-N 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- SKCBPEVYGOQGJN-SOOFDHNKSA-N 5-phospho-D-ribosylamine Chemical compound NC1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O SKCBPEVYGOQGJN-SOOFDHNKSA-N 0.000 description 1
- 230000002407 ATP formation Effects 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 238000000116 DAPI staining Methods 0.000 description 1
- 108010067770 Endopeptidase K Proteins 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 229940123457 Free radical scavenger Drugs 0.000 description 1
- 206010056328 Hepatic ischaemia Diseases 0.000 description 1
- 102000006933 Hydroxymethyl and Formyl Transferases Human genes 0.000 description 1
- 108010072462 Hydroxymethyl and Formyl Transferases Proteins 0.000 description 1
- 102000018251 Hypoxanthine Phosphoribosyltransferase Human genes 0.000 description 1
- 108010091358 Hypoxanthine Phosphoribosyltransferase Proteins 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- GRSZFWQUAKGDAV-UHFFFAOYSA-N Inosinic acid Natural products OC1C(O)C(COP(O)(O)=O)OC1N1C(NC=NC2=O)=C2N=C1 GRSZFWQUAKGDAV-UHFFFAOYSA-N 0.000 description 1
- 206010025598 Malignant hydatidiform mole Diseases 0.000 description 1
- 208000007201 Myocardial reperfusion injury Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000027721 electron transport chain Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000008393 encapsulating agent Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical class NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical class O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 229940028843 inosinic acid Drugs 0.000 description 1
- 235000013902 inosinic acid Nutrition 0.000 description 1
- 239000004245 inosinic acid Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 108010045959 phosphoribosyl pyrophosphate aminotransferase Proteins 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 239000002213 purine nucleotide Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses application of a purine synthesis inhibitor in preparation of a medicine for preventing and/or treating ischemia and ischemia-reperfusion injury, in particular application in medicines for preventing and/or treating renal ischemia injury and ischemia-reperfusion injury. The invention proves the great potential of the purine synthesis inhibitor as a medicine for preventing and treating renal ischemia and ischemia-reperfusion injury, and discovers that the purine synthesis inhibitor has good treatment effect on the ischemia and ischemia-reperfusion injury. The purine synthesis inhibitor can inhibit the damage of kidney functions caused by the ischemia of the kidney and the ischemia-reperfusion injury, provides a new potential therapeutic drug for the ischemia and the ischemia-reperfusion injury, expands the indications of the purine synthesis inhibitor, and has great 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 of rapidly proliferating tumor cells. 6-Mercaptopurine (6-Mercaptopurine) is a purine analog synthesized in 1951, and blocks the salvage pathway of purine nucleotides by competitively inhibiting hypoxanthine-guanine phosphoribosyl transferase; inhibiting the de novo purine synthesis pathway by inhibiting phosphoribosyl pyrophosphate aminotransferase from interfering with the formation of phosphoribosyl amine; 6-MP nucleotide is produced by phosphoribosylation, and conversion of inosinic acid to adenine and guanine nucleotide is inhibited. This allows 6-mercaptopurine to effectively inhibit the synthesis of DNA and RNA, thereby inhibiting the growth of tumor cells. Methyl 2, 6-dichloropyrimidine-4-carboxylate (Pellitrexol) has an antiproliferative effect by inhibiting the synthesis of purine by inhibiting glycine amide nucleotide formyltransferase. Currently, 6-mercaptopurine has been used in the treatment of cancer and autoimmune diseases, including acute leukemia, chorioepithelial carcinoma, malignant hydatidiform mole, psoriatic arthritis, and inflammatory bowel disease. Pelitresol is currently in relevant clinical research as a new candidate anticancer drug. According to literature information, the effects of purine synthesis inhibitors on ischemia and ischemia reperfusion injury have not been reported.
Insufficient blood supply can lead to ischemia and hypoxia of tissues and further damage, while ischemia reperfusion is the damage condition after blood supply is restored in ischemic tissues, mainly due to the damage of tissues caused by the increase of active oxygen after blood supply is restored. In tissue ischemia, the electron transport chain is functionally impaired, failing to efficiently transport electrons, resulting in accumulation of electrons and reduced ATP production. During reperfusion, the ischemic tissue receives a large amount of oxygen and produces a large amount of oxygen radicals. In addition, ischemia causes a decrease in the synthesis ability of antioxidant enzymes, and fails to effectively scavenge oxygen radicals, resulting in an increase in active oxygen. The types of ischemia and ischemia-reperfusion injury include various ones such as renal ischemia and ischemia-reperfusion injury, myocardial ischemia and ischemia-reperfusion injury, hepatic ischemia and ischemia-reperfusion injury, cerebral apoplexy, organ transplantation, etc. The damage caused by the damage of the kidney function caused by the kidney ischemia and the ischemia reperfusion injury is very large, and the death rate can be high clinically. Reperfusion is an essential means for saving ischemic organs, but the damage caused by reperfusion is still a great clinical challenge, and at present, very effective intervention means are still lacked. The use of free radical scavengers to ameliorate damage from ischemia reperfusion would likely be an effective way to intervene. There is still a great clinical need to develop more effective intervention and treatment to meet the needs of patients.
Disclosure of Invention
In order to solve the problems, the invention aims to provide a novel medicine for treating ischemia and ischemia-reperfusion injury, in particular to a medicine for treating renal ischemia and ischemia-reperfusion injury, which can effectively protect renal functions and provide a novel alternative medicine for preventing and treating ischemia and reperfusion injury.
In order to achieve the purpose, the invention adopts the following technical scheme:
application of purine synthesis inhibitor in preparing medicine for treating ischemia injury and/or ischemia reperfusion injury.
Use of a purine synthesis inhibitor for the preparation of a medicament for the prevention of ischemic injury and/or ischemia reperfusion injury.
The ischemia and ischemia-reperfusion injury can be caused by renal ischemia and ischemia-reperfusion injury, myocardial ischemia and reperfusion injury after ischemia, liver ischemia and ischemia-reperfusion injury, cerebral apoplexy, organ transplantation, etc.
Taking kidney ischemia and ischemia reperfusion injury as examples, the prevention and/or treatment of the kidney ischemia injury is embodied in reducing the apoptosis ratio of kidney cells; the prevention and/or treatment of renal ischemia reperfusion injury is embodied in the following aspects: 1) Reducing the apoptosis rate of kidney cells; 2) Effectively relieving the injury of renal tubules caused by renal ischemia reperfusion; 3) Reducing the damage of renal ischemia reperfusion to renal function; 4) Effectively improve the survival rate of the mice with renal ischemia-reperfusion injury.
Wherein the purine synthesis inhibitor comprises 6-Mercaptopurine (6-Mercaptopurine) or a pharmaceutically acceptable salt thereof, and methyl 2, 6-dichloropyrimidine-4-carboxylate (Pellitrexol) or a pharmaceutically acceptable salt thereof.
Further, the drug comprises 6-mercaptopurine or a pharmaceutically acceptable salt thereof.
In the above-mentioned use of the present invention, the medicament contains an effective amount of 6-mercaptopurine or a pharmaceutically acceptable salt thereof. An effective dose is a unit dosage form (e.g., amount in a single tablet) or unit dose (e.g., unit weight dose) of the patient being treated. In the present invention, the subject of drug treatment is a mammalian species, including human, mouse, and the like. According to the equivalent dose conversion relationship between the human and the experimental animal, the unit weight dose of the human can be estimated by using the dose of the animal. The equivalent dose of the experimental mice is 12 times that of the human body according to the conversion of the unit weight dose.
In the present invention, the effective dose of 6-mercaptopurine for the treatment of renal ischemia and ischemia-reperfusion injury in 6-week-old C57BN/6J mice is 50-100 mg/kg.
The standard body of the adult is reset to 60kg according to the conversion relation of the effective dose of the adult and the effective dose of the mouse, and the effective dose of the adult is 250-500 mg every day.
The 6-mercaptopurine can be prepared into oral dosage forms according to needs, and the dosage forms are specifically tablets.
Further, the medicament comprises Pelitrexol or a pharmaceutically acceptable salt thereof.
In the above-mentioned use of the present invention, the medicament contains an effective amount of pellitrexol or a pharmaceutically acceptable salt thereof. An effective dose is a unit dosage form (e.g., amount in a single tablet) or unit dose (e.g., unit weight dose) of the patient being treated. In the present invention, the subject of drug treatment is a mammalian species, including human, mouse, and the like. According to the equivalent dose conversion relationship between the human and the experimental animal, the unit weight dose of the human can be estimated by using the dose of the animal. The equivalent dose of the experimental mice is 12 times that of the human body according to the conversion of the unit weight dose.
In the invention, the effective dose of Pellitrexol for treating renal ischemia and ischemia-reperfusion injury in 6-week-old C57BN/6J mice is 5-10 mg/kg.
The standard body of the adult is reset to 60kg according to the conversion relation of the effective dose of the adult and the effective dose of the mouse, and the effective dose of the adult is 25-50 mg every day.
The invention also provides a medicament for preventing and/or treating the ischemic injury and a medicament for preventing and/or treating the 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 (pellitrexol) or a pharmaceutically acceptable salt thereof.
In the medicine, the purine synthesis inhibitor can be used as one of the effective components, and can also be used as the only effective component.
When the medicine is prepared, a carrier material can be added.
Such vectors include, but are not limited to: diluents, suspensions, buffers, granules, emulsions, excipients, encapsulating agents, sprays, adhesives, fillers, disintegrants, humectants, transdermal absorbents, absorption enhancers, surfactants, flavoring agents, colorants, or adsorbent carriers.
The above drugs can be prepared into tablets, capsules, solutions, injections, etc. according to conventional methods known to those skilled in the art.
The invention has the following beneficial effects:
1. renal ischemia and ischemia reperfusion injury can be inhibited by purine synthesis inhibitors 6-mercaptopurine and Pellitrexol.
2. Provides a new potential therapeutic drug for ischemia and ischemia reperfusion injury, expands the indications of purine synthesis inhibitors, and has larger market potential and application value.
Drawings
FIG. 1 shows the results of experiments on the rescue of apoptosis induced by renal ischemic injury by purine synthesis inhibitors 6-mercaptopurine and Pelitrexol.
FIG. 2 shows the experimental results of the purine synthesis inhibitor 6-mercaptopurine and Pellitrexol for rescuing the apoptosis caused by renal ischemia reperfusion injury.
FIG. 3 shows the results of experiments on rescue of renal tubular injury caused by renal ischemia reperfusion injury by purine synthesis inhibitor 6-mercaptopurine and Pellitrexol.
FIG. 4 shows the experimental results of the purine synthesis inhibitor 6-mercaptopurine and Pellitrexol for rescuing the increase of blood creatinine and urea nitrogen caused by renal ischemia reperfusion injury.
FIG. 5 shows the results of experiments on the purine synthesis inhibitors 6-mercaptopurine and Pellitrexol to increase the survival rate of mice with renal ischemia reperfusion injury.
Detailed Description
The present invention is further explained below. The following examples are only for illustrating the technical solutions of the present invention more clearly, and therefore are only used as examples, and the protection scope of the present invention is not limited thereby.
Application of purine synthesis inhibitor in preparing medicine for treating ischemia and ischemia reperfusion injury is provided.
Application of purine synthesis inhibitor in preparing medicine for preventing ischemia and ischemia reperfusion injury.
The ischemia and ischemia-reperfusion injury is not only aiming at renal ischemia and ischemia-reperfusion injury, but also comprises myocardial ischemia and post-ischemia reperfusion injury, liver ischemia and ischemia-reperfusion injury, cerebral apoplexy, organ transplantation and the like.
Among them, purine synthesis inhibitors include 6-Mercaptopurine (6-Mercaptopurine, 6-MP) and methyl 2, 6-dichloropyrimidine-4-carboxylate (penitrexol).
Example 1:
constructing a kidney ischemia injury mouse model.
A total of 15 mice, 6 weeks old C57BN/6J, were used for the renal ischemic injury test, 5 DMSO control groups, 5 6-mercaptopurine treated groups, and 5 Pellitrexol treated groups, and the specific procedures were as follows:
injecting DMSO, 6-mercaptopurine (100 mg/kg) or Pellitrexol (10 mg/kg) in advance by a tail vein injection mode for 1h, then adopting isoflurane to inhale and anaesthetize a mouse, unhairing the back of the mouse, cutting skin and muscle, exposing kidney, separating renal arteries on two sides, clamping the renal artery on the right side by using an artery clamp, performing ischemic treatment for 1h, not performing ischemic treatment on the kidney on the left side, performing the same other operation, taking kidney tissues as pathological samples, and performing TUNEL staining.
TUNEL staining was performed as follows:
paraffin sections were dewaxed with xylene twice for 5 minutes each. Absolute ethanol for 5 minutes, 90% ethanol for 2 minutes, 70% ethanol for 2 minutes, distilled water for 2 minutes, 20. Mu.g/ml DNase-free proteinase K was added dropwise and incubated at 37 ℃ for 15 minutes. TUNEL staining was performed after 3 PBS washes. 50 μ l of TUNEL detection solution (5 μ l of TdT enzyme, 45 μ l of fluorescent labeling solution) was dropped on the sample, and after incubation for 60 minutes at 37 ℃ in the dark, PBS was washed 3 times, DAPI staining was performed with 100 μ g/ml DAPI aqueous solution, after incubation for 5 minutes at room temperature, PBS was washed 3 times, and after mounting with anti-fluorescent quenching mounting solution, photographing was performed under a fluorescent microscope.
As shown in fig. 1, a cell number in the kidney section that was positive for TUNEL staining increased after the renal ischemia treatment, indicating that apoptosis in the mouse kidney significantly increased, whereas the proportion of apoptosis was significantly reduced after prior treatment with 6-mercaptopurine or pellitrexol.
As shown in fig. 1B, the number of TUNEL positive cells in the kidney sections was counted, and the 6-mercaptopurine-treated ischemia group was significantly different from the DMSO-treated ischemia group, and the pellitrexol-treated ischemia group was significantly different from the DMSO-treated ischemia group by using the t-test. * P <0.001.
The results in figure 1 show that the kidney ischemia model is successfully constructed, and the 6-mercaptopurine or Pelitrexol treatment can effectively protect the kidney and greatly reduce the damage of the kidney ischemia to the kidney.
Example 2:
constructing a kidney ischemia reperfusion injury mouse model.
A total of 36 mice, 6 weeks old C57BN/6J, were used for the renal ischemia-reperfusion injury test, 12 DMSO control groups (6 sham operation groups, 6 ischemia-reperfusion test groups), 12 6-mercaptopurine treatment groups (6 sham operation groups, 6 ischemia-reperfusion test groups), 12 Pellitrexol treatment groups (6 sham operation groups, 6 ischemia-reperfusion test groups), and the following specific operations were carried out:
injecting DMSO, 6-mercaptopurine (100 mg/kg) or Pellitrexol (10 mg/kg) in advance by a tail vein injection mode 1h, then adopting isoflurane to inhale an anesthetized mouse, unhairing the back of the mouse, cutting skin and muscle, exposing a kidney, separating renal arteries on two sides, closing the renal arteries by using an artery clamp, loosening the artery clamp after 45min of ischemia, observing the blood flow recovery condition, closing an abdominal cavity by layered suture after the kidney recovers bright red, performing no ischemia treatment on a control group, performing the same other operation operations, performing 48h after operation, performing eyeball blood sampling 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 mouse kidneys, while the fraction of apoptosis was significantly reduced after prior treatment with 6-mercaptopurine or Pelitrexol.
As shown in fig. 2B, the number of TUNEL positive cells in the kidney section was counted, and the 6-mercaptopurine-treated ischemia-reperfusion group was significantly different from the DMSO-treated ischemia-reperfusion group, and the Pelitrexol-treated ischemia-reperfusion group was significantly different from the DMSO-treated ischemia-reperfusion group, using the t-test. * P <0.001.
From the results in FIG. 2, it is shown that 6-mercaptopurine or Pellitrexol treatment was effective in alleviating apoptosis caused by renal ischemia-reperfusion.
As shown in fig. 3, morphological observation of the tubules with H & E staining showed a significant increase in tubular injury after renal ischemia reperfusion treatment, while the tubular injury was significantly reduced after prior treatment with 6-mercaptopurine or pelitrenol.
As shown in fig. 3B, the Paller scores of the kidney sections were significantly different from those of the DMSO-treated ischemia-reperfusion groups and pellitrexol-treated ischemia-reperfusion groups using the t-test. * P <0.001.
The Paller score criteria were: the renal tubules are obviously expanded and the cells are flat, and the score is 1; the mark 2 is formed by the tubular shape in the renal tubule; the renal tubule lumen has desquamated necrotic cells, but has no cast and cell debris, and is marked with 1 point; epithelial cell granule-like degeneration, score 1; epithelial cell vacuole-like degeneration, score 1; epithelial cell nuclei are pycnotactic and scored 1. 10 fields per tissue were selected, 10 diseased tubules per high power (200 x) of the field were randomly selected, summed over 100 tubule scores, and the total score divided by 100 to give the Paller score for the tissue.
From the results in FIG. 3, it is shown that 6-mercaptopurine or Pellitrexol treatment was effective in relieving renal tubular injury caused by renal ischemia-reperfusion.
As shown in FIG. 4A, serum creatinine and urea nitrogen were elevated after renal ischemia reperfusion treatment, but no more after prior treatment with 6-mercaptopurine or Pellitrexol.
As shown in fig. 4B, using the t-test, there was a significant difference between the 6-mercaptopurine-treated ischemia-reperfusion group and the DMSO-treated ischemia-reperfusion group, and a significant difference between the Pelitrexol-treated ischemia-reperfusion group and the DMSO-treated ischemia-reperfusion group,. P <0.01.
The results in FIG. 4 show that treatment with 6-mercaptopurine or Pelitrenol is effective in protecting the kidney and greatly reducing the damage of renal ischemia-reperfusion on renal function.
As shown in FIG. 5, the overall survival of the mice was 20% 10 days after renal ischemia-reperfusion treatment, whereas the survival was 100% or 80% after prior treatment with 6-mercaptopurine or Pellitrexol.
From the results in FIG. 5, it is demonstrated that treatment with 6-mercaptopurine or Pellitrexol is effective in protecting the kidney and greatly increasing the survival rate of mice after renal ischemia reperfusion.
In summary, 6-mercaptopurine or pellitrexol treatment was shown to be effective in the prevention and treatment of renal ischemia and ischemia reperfusion injury.
The above examples are intended to illustrate the technical solution of the present invention and not to limit the same, and although the present invention has been described in detail with reference to the specific embodiments, it will be apparent to those skilled in the art that modifications or improvements can be made to the technical solution of the present invention. Therefore, it is within the scope of the present invention to make modifications or improvements without departing from the scope of the present invention.
Claims (7)
1. Application of purine synthesis inhibitor in preparing medicine for treating ischemia injury and/or ischemia reperfusion injury.
2. Use of a purine synthesis inhibitor for the preparation of a medicament for the prevention of ischemic injury and/or ischemia reperfusion injury.
3. Use according to claim 1 or 2, characterized in that: the purine synthesis inhibitor is selected from at least one of the following: 6-mercaptopurine or a pharmaceutically acceptable salt thereof, and 2, 6-dichloropyrimidine-4-carboxylic acid methyl ester or a pharmaceutically acceptable salt thereof.
4. Use according to any one of claims 1-3, characterized in that: the ischemic injury and/or ischemia-reperfusion injury comprises: renal ischemia injury and/or ischemia reperfusion injury, myocardial ischemia injury and/or post-ischemia reperfusion injury, liver ischemia injury and/or ischemia reperfusion injury, cerebral apoplexy, and organ transplantation.
5. Use according to claim 4, characterized in that:
the prevention and/or treatment of said renal ischemic injury is embodied in reducing the apoptotic rate of renal cells;
the prevention and/or treatment of said renal ischemia reperfusion injury is embodied in the following aspects:
1) Reducing the apoptosis rate of kidney cells;
2) Effectively relieving the renal tubular injury caused by renal ischemia reperfusion;
3) Reducing the damage of renal ischemia reperfusion to renal function;
4) Effectively improve the survival rate of the mice with renal ischemia-reperfusion injury.
6. A medicine for preventing and/or treating ischemia injury and/or ischemia reperfusion injury comprises purine synthesis inhibitor as active ingredient.
7. The medicament of claim 6, wherein: the purine synthesis inhibitor is selected from at least one of the following: 6-mercaptopurine or a pharmaceutically acceptable salt thereof, and 2, 6-dichloropyrimidine-4-carboxylic acid methyl ester or a pharmaceutically acceptable salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110820479.3A CN115634228B (en) | 2021-07-20 | 2021-07-20 | Application of purine synthesis inhibitor in preparation of medicines for treating ischemia and ischemia reperfusion injury |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110820479.3A CN115634228B (en) | 2021-07-20 | 2021-07-20 | Application of purine synthesis inhibitor in preparation of medicines for treating ischemia and ischemia reperfusion injury |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115634228A true CN115634228A (en) | 2023-01-24 |
| CN115634228B CN115634228B (en) | 2024-03-19 |
Family
ID=84940052
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110820479.3A Active CN115634228B (en) | 2021-07-20 | 2021-07-20 | Application of purine synthesis inhibitor in preparation of medicines for treating ischemia and ischemia reperfusion injury |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115634228B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001064183A (en) * | 1999-08-31 | 2001-03-13 | Toa Eiyo Ltd | Ischemia and reperfusion damage inhibitor |
| CN1394857A (en) * | 1994-07-28 | 2003-02-05 | 阿格罗尼制药公司 | Compound used as antiproliferative agent and glycinamide ribonucleotide transformylase inhibitor |
| US20060009473A1 (en) * | 2004-04-01 | 2006-01-12 | Lerner E I | Formulations of 6-mercaptopurine |
| WO2009109356A1 (en) * | 2008-03-03 | 2009-09-11 | Medizinische Hochschule Hannover | Cytostatic compositions |
-
2021
- 2021-07-20 CN CN202110820479.3A patent/CN115634228B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1394857A (en) * | 1994-07-28 | 2003-02-05 | 阿格罗尼制药公司 | Compound used as antiproliferative agent and glycinamide ribonucleotide transformylase inhibitor |
| JP2001064183A (en) * | 1999-08-31 | 2001-03-13 | Toa Eiyo Ltd | Ischemia and reperfusion damage inhibitor |
| US20060009473A1 (en) * | 2004-04-01 | 2006-01-12 | Lerner E I | Formulations of 6-mercaptopurine |
| WO2009109356A1 (en) * | 2008-03-03 | 2009-09-11 | Medizinische Hochschule Hannover | Cytostatic compositions |
Non-Patent Citations (5)
| Title |
|---|
| CHIH-ZEN CHANG等: "6-Mercaptopurine attenuates adhesive molecules in experimental vasospasm", ACTA NEUROCHIR, vol. 152, pages 861 - 867, XP019805093 * |
| EMMANUEL等: "Purine Nucleotide Availability Regulates mTORC1 Activity through the Rheb GTPase", CELL REPORTS, vol. 9 * |
| HUA SU等: "Interleukin-6 Signaling Pathway and Its Role in Kidney Disease: An Update", FRONTIERS IN IMMUNOLOGY, vol. 8, pages 2 - 3 * |
| 杨龙灿: "雷帕霉素在肝脏缺血再灌注损伤中对细胞自噬作用机制的研究", 中国优秀硕士学位论文全文数据库 医药卫生科技辑, no. 8, pages 21 - 24 * |
| 许位: "新型AMPA受体拮抗剂对大鼠脑梗死再灌注损伤的脑保护作用的实验研究", 中国优秀硕士学位论文全文数据库 医药卫生科技辑, no. 2, pages 33 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115634228B (en) | 2024-03-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Polak et al. | Mode of action of the 2-nitroimidazole derivative benznidazole | |
| KR100516827B1 (en) | Nitric Oxide Production Inhibitor | |
| AU2015242363C1 (en) | Glycolipids and pharmaceutical compositions thereof for use in therapy | |
| AU606038B2 (en) | Tissue growth regulation | |
| US5512573A (en) | Use of phthaloylhydrazide derivatives as anti-hypoxic and defensive agents | |
| WO2000043023A1 (en) | Pharmaceutical composition with adhesion molecule expression regulating activity | |
| CN115634228B (en) | Application of purine synthesis inhibitor in preparation of medicines for treating ischemia and ischemia reperfusion injury | |
| CN113925867A (en) | Application of dronedarone hydrochloride and 5-fluorouracil in preparation of antitumor drugs | |
| CN111450089A (en) | Application of Bepridil or KB-R7943 in preparation of medicine for treating melanoma | |
| CA2226340A1 (en) | Drug for ameliorating brain diseases | |
| EP1372695A2 (en) | Cell damage inhibitor | |
| CN113855688A (en) | Application of Vina-ginsenoside R18 in preparation of anti-dengue virus pharmaceutical preparation | |
| AU2004296129A2 (en) | CHP-gemcitabin combined agent and use thereof as anti-tumoural active substances | |
| CN104844606B (en) | Parasiticide pyrazine isoquinoline derivative | |
| CN113827587A (en) | Application of salvianolic acid A in preparing medicine for preventing thrombotic cerebral ischemia | |
| CN117731654B (en) | New application of JJH201601 in treatment of primary glioma and recurrent glioma | |
| RU2294200C2 (en) | Method for prophylaxis and treatment of dirofilariasis in dogs | |
| JPH11209282A (en) | Hepatic function-improving agent containing bergenin and its derivative as active ingredient | |
| CN115645385B (en) | Application of licochalcone B in preparation of medicines for treating and/or preventing type I interferon diseases | |
| CN100560088C (en) | The purposes of Herba Sophorae alopecuroidis total alkali in the banded antiherpetic thing of preparation treatment | |
| CN114853715B (en) | Organic nitrite donor ketal type prodrug, preparation method and medical application thereof | |
| CN115607606B (en) | Application of capsicum-derived nano vesicles in preparation of drugs for preventing and treating atherosclerosis diseases | |
| CN111632046B (en) | Application of naphthoquinone dimer in preparation of anti-tumor metastasis drugs | |
| WO2022183493A1 (en) | Application of polyphenol compound | |
| CN110384694B (en) | Application of xenicane diterpenoid compound in preparation of antioxidant neuroprotective drug |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |