CN117357533A - Application of combination of obutylamine fumarate and temozolomide in treating brain glioma - Google Patents
Application of combination of obutylamine fumarate and temozolomide in treating brain glioma Download PDFInfo
- Publication number
- CN117357533A CN117357533A CN202311459703.6A CN202311459703A CN117357533A CN 117357533 A CN117357533 A CN 117357533A CN 202311459703 A CN202311459703 A CN 202311459703A CN 117357533 A CN117357533 A CN 117357533A
- Authority
- CN
- China
- Prior art keywords
- temozolomide
- fumarate
- group
- brain
- combination
- 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.)
- Pending
Links
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 title claims abstract description 86
- 229960004964 temozolomide Drugs 0.000 title claims abstract description 86
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 title claims abstract description 73
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 73
- 201000007983 brain glioma Diseases 0.000 title claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 27
- 206010018338 Glioma Diseases 0.000 claims abstract description 22
- 208000032612 Glial tumor Diseases 0.000 claims abstract description 15
- 238000011282 treatment Methods 0.000 claims description 30
- 208000005017 glioblastoma Diseases 0.000 claims description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 238000009472 formulation Methods 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 3
- 206010003571 Astrocytoma Diseases 0.000 claims description 2
- 206010002224 anaplastic astrocytoma Diseases 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 208000002409 gliosarcoma Diseases 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 31
- 229940079593 drug Drugs 0.000 abstract description 21
- 210000004881 tumor cell Anatomy 0.000 abstract description 9
- 230000002195 synergetic effect Effects 0.000 abstract description 8
- 231100000331 toxic Toxicity 0.000 abstract description 6
- 230000002588 toxic effect Effects 0.000 abstract description 6
- 230000002147 killing effect Effects 0.000 abstract description 2
- 241000700159 Rattus Species 0.000 description 63
- 241001465754 Metazoa Species 0.000 description 53
- 210000004556 brain Anatomy 0.000 description 49
- 206010028980 Neoplasm Diseases 0.000 description 35
- 230000004083 survival effect Effects 0.000 description 33
- 230000034994 death Effects 0.000 description 15
- 235000019786 weight gain Nutrition 0.000 description 14
- 102000003952 Caspase 3 Human genes 0.000 description 13
- 108090000397 Caspase 3 Proteins 0.000 description 13
- 230000004584 weight gain Effects 0.000 description 12
- 238000000034 method Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 238000001959 radiotherapy Methods 0.000 description 9
- 101100496572 Rattus norvegicus C6 gene Proteins 0.000 description 8
- 230000037396 body weight Effects 0.000 description 8
- 231100000673 dose–response relationship Toxicity 0.000 description 8
- 208000001780 epistaxis Diseases 0.000 description 8
- 208000011309 nasal bleeding Diseases 0.000 description 8
- 238000011065 in-situ storage Methods 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 6
- 208000016261 weight loss Diseases 0.000 description 6
- 230000004580 weight loss Effects 0.000 description 6
- XIQVNETUBQGFHX-UHFFFAOYSA-N Ditropan Chemical compound C=1C=CC=CC=1C(O)(C(=O)OCC#CCN(CC)CC)C1CCCCC1 XIQVNETUBQGFHX-UHFFFAOYSA-N 0.000 description 5
- 208000032843 Hemorrhage Diseases 0.000 description 5
- 230000000740 bleeding effect Effects 0.000 description 5
- 210000005013 brain tissue Anatomy 0.000 description 5
- 238000002512 chemotherapy Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 208000029824 high grade glioma Diseases 0.000 description 5
- 201000011614 malignant glioma Diseases 0.000 description 5
- 229960005434 oxybutynin Drugs 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 238000002054 transplantation Methods 0.000 description 5
- 238000010171 animal model Methods 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 210000001508 eye Anatomy 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 210000000214 mouth Anatomy 0.000 description 4
- 210000003928 nasal cavity Anatomy 0.000 description 4
- 230000000306 recurrent effect Effects 0.000 description 4
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 3
- 206010070863 Toxicity to various agents Diseases 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 229940100198 alkylating agent Drugs 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 230000008499 blood brain barrier function Effects 0.000 description 3
- 210000001218 blood-brain barrier Anatomy 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 201000007455 central nervous system cancer Diseases 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000011272 standard treatment Methods 0.000 description 3
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 238000011226 adjuvant chemotherapy Methods 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 229960000397 bevacizumab Drugs 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 190000008236 carboplatin Chemical compound 0.000 description 2
- 229960005243 carmustine Drugs 0.000 description 2
- 208000025997 central nervous system neoplasm Diseases 0.000 description 2
- 229940000425 combination drug Drugs 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 238000001325 log-rank test Methods 0.000 description 2
- 229960002247 lomustine Drugs 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 231100000272 reduced body weight Toxicity 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000007492 two-way ANOVA Methods 0.000 description 2
- 102000010400 1-phosphatidylinositol-3-kinase activity proteins Human genes 0.000 description 1
- SHKSWTUELIHTPG-UHFFFAOYSA-N 1h-imidazole;tetrazine Chemical class C1=CNC=N1.C1=CN=NN=N1 SHKSWTUELIHTPG-UHFFFAOYSA-N 0.000 description 1
- 108700028369 Alleles Proteins 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- 206010022773 Intracranial pressure increased Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 102000014160 PTEN Phosphohydrolase Human genes 0.000 description 1
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- GZOSMCIZMLWJML-VJLLXTKPSA-N abiraterone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CC[C@H](O)CC3=CC2)C)CC[C@@]11C)C=C1C1=CC=CN=C1 GZOSMCIZMLWJML-VJLLXTKPSA-N 0.000 description 1
- 229960000853 abiraterone Drugs 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 238000011281 clinical therapy Methods 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 238000011393 cytotoxic chemotherapy Methods 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 230000007614 genetic variation Effects 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 208000030173 low grade glioma Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000013178 mathematical model Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000033607 mismatch repair Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 230000009251 neurologic dysfunction Effects 0.000 description 1
- 208000015015 neurological dysfunction Diseases 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 238000010827 pathological analysis Methods 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 235000018770 reduced food intake Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000009121 systemic therapy Methods 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention belongs to the field of medicines, and particularly relates to clinical application of a combination of obutyramine fumarate and temozolomide in treating glioma. The invention provides the clinical application of the combination of the obutylamine fumarate and the temozolomide in treating the brain glioma for the first time, the obutylamine fumarate and the temozolomide have obvious synergistic effect, the curative effect is effectively improved, the curative effect is more obvious compared with the single-component curative effect, and the killing property on tumor cells is improved; effectively reduces the dosage, thereby reducing the toxic and side effects. The combination of the two can save the cost, lighten the economic burden of patients, provide a new way for preventing and treating the brain glioma and has wide application prospect in the field of medicine and pharmacy.
Description
Technical Field
The invention belongs to the field of medicines, and relates to application of a combination of obutyramine fumarate and temozolomide in treating brain glioma.
Background
Gliomas refer to tumors originating from brain glial cells, the most common primary intracranial tumor, of which more than half are glioblastomas (Glioblastoma Multiforme, GBM) with the highest malignancy. The World Health Organization (WHO) central nervous system tumor classification classifies gliomas into classes I-IV, low-grade gliomas as class I and class II, and high-grade gliomas as class III and class IV.
Gliomas account for 32% of all primary central nervous system tumors, and 81% of central nervous system malignancies. The incidence rate of malignant glioma is (5-8)/100 ten thousand, and the death rate of 5 years is inferior to pancreatic cancer and lung cancer in systemic tumor, and the rank is 3. WHO 1998 published ranking in terms of tumor mortality, glioblastoma was the 2 nd cause of death in patients under 34 years old and the 3 rd cause of death in patients between 35 and 54 years old [2] . According to U.S. brain tumor registry (Central Brain Tumor Registry of the United States, CBTRUS) statistics, GBM is most frequently seen in primary malignant central nervous system tumors, accounting for 46.1%, approximately 3.20/10 ten thousand, and more men than women; the incidence of GBM increases with age, with the highest occurrence being 75-84 years and the median age of the new diagnosis being 64 years. The chinese tumor registration report in 2012 showed that chinese brain and central nervous system malignant tumors have mortality of 3.87/10 ten thousand, the 9 th of ten-thousand high mortality tumors. Malignant gliomas represent central nervous system malignant tumors, which cause huge social and economic and family burdens, and are always hot spots for the current tumor research.
The pathogenesis of gliomas is unknown, and two risk factors currently identified are: exposure to high doses of ionizing radiation and high-penetrance genetic mutations associated with rare syndromes. In recent years, the hot spots for research on pathogenesis of high-grade glioma include: heterozygous deletion of alleles, genetic variation studies of genes, DNA mismatch repair, cell signaling pathway disorders (e.g., EGFR and PDGF pathways), PI3K/AKt/PTEN, ras and P53/RB1 pathway gene mutations, and tumor stem cell studies, among others. The clinical manifestations of gliomas mainly include three major categories, namely increased intracranial pressure, neurological dysfunction and cognitive dysfunction and seizures. The brain glioma treatment mainly comprises surgical excision and combines comprehensive treatment methods such as radiotherapy, chemotherapy and the like. The operation can relieve clinical symptoms, prolong the life time, and obtain enough tumor specimens for clear pathological diagnosis and molecular genetic detection. The radiotherapy can kill or inhibit tumor cells, prolong the life cycle of patients, and the conventional external irradiation is the standard treatment of brain glioma radiotherapy.
The GBM treatment method mainly adopts comprehensive treatment combining various treatment modes such as operation, radiotherapy and chemotherapy and the like. GBM postoperative radiation therapy in combination with temozolomide in combination with adjuvant chemotherapy has become the standard treatment regimen for new diagnosis of GBM in adults. Due to the invasive nature of high-grade gliomas, even though temozolomide is treated by standard protocols of synchronous radiotherapy and chemotherapy and adjuvant chemotherapy, glioblastoma patients have a progression-free survival period of 6.9 months, which indicates that most of high-grade glioma patients relapse after primary treatment, glioma relapse or progression refers to clinical symptom deterioration in the treatment process, and imaging shows obvious tumor enlargement and/or appearance of new tumor focus. Wherein, the local recurrence of the tumor is the most main primary recurrence mode, and other recurrence modes include cerebrospinal fluid spreading and distant recurrence.
Treatment options for recurrent GBM include re-surgery, radiation therapy, and adjuvant systemic therapies, including cytotoxic chemotherapy, angiogenesis inhibitors, and immunotherapy, but no standard treatment for recurrent GBM is currently available. Surgery has very limited effect in recurrent GBM patients, and is only applicable to patients with local recurrence. Clinical data confirm that chemotherapeutic agents have limited efficacy in treating recurrent GBM. GBM post-recurrence options: (1) bevacizumab; (2) bevacizumab plus chemotherapy (i Li Tikang, carmustine/lomustine, temozolomide, carboplatin); (3) temozolomide; (4) lomustine or carmustine single drug treatment; (5) PCV combination regimen treatment; (6) cyclophosphamide; (7) carboplatin or cisplatin-based chemotherapy regimen.
Overall, GBM treatment remains a significant challenge, patient prognosis is poor, and data indicate that GBM patients have less than 10% survival rates over 5 years. Therefore, GBM also requires innovative treatments to achieve improved prognosis for survival.
Temozolomide is an orally taken alkylating agent with relatively good tolerance, and imidazole tetrazine derivative is quickly absorbed after oral administration, is easy to pass through a blood brain barrier and is converted into a powerful alkylating agent in cells, so that guanine is alkylated, DNA is damaged, and tumor cells die. Stupp is equal to 2002, reports the clinical effect of temozolomide as a first-line drug for treating the glioblastoma newly diagnosed, and the survival rate of patients is obviously improved. Stupp is equal to 2005, further reports the results of clinical trials of radiotherapy and synchronization and subsequent auxiliary temozolomide treatment on glioblastoma, and the scheme can obviously improve the median survival time and two-year survival rate of patients, the median survival time is prolonged from 12.1 months to 14.6 months, and the 2-year survival rate is improved from 10.4% to 26.5%. Since then, the Stupp regimen was widely recommended by North America, europe, and Australia as the standard therapeutic regimen for the new diagnosis of glioblastoma. Temozolomide has achieved a pleasing therapeutic effect since the clinical application, but its effective rate is less than 50%, and the main reason for this result is its drug resistance. According to the previous experience, under the action of half effective concentration of the drug, the inhibition effect of the multi-drug combination scheme on tumor cells is always higher than that of single-drug chemotherapy scheme, so that the two-drug and multi-drug combination scheme containing temozolomide becomes a new research hot spot [3] 。
Obitazine fumarate is a Procaspase-3 agonist, a potent pro-apoptotic agent. The apoptosis protein Caspase-3 plays an important role in inhibiting tumor development, and it is now generally considered that Caspase-3 is the most main terminal shear enzyme in the apoptosis process and also an important component of CTL cell killing mechanism. In approximately half of human tumors, caspase-3 is under-expressed, resulting in uncontrolled proliferation of tumor cells. And Procaspase-3 is highly expressed in various tumor tissues such as neuroblastoma, lymphoma, leukemia, melanoma and liver cancer, and the expression of Procaspase-3 in intestinal cancer tissues is 6 times that of paracancerous normal tissues. High expression of Procaspase-3 was detected in various tumor cell lines such as lung cancer, kidney cancer, breast cancer. Procaspase-3 is highly expressed based on tumor tissue, and the presence of a "safe" results in an inefficient conversion of Procaspase-3 to Caspase-3. Thus contributing to the antitumor effect of catalyzing the conversion of Procaspase-3 to Caspase-3.
Studies show that the obuzine fumarate has remarkable inhibition effect on the growth of various tumor cells, and has the potential of treating brain glioma by combining with temozolomide and treating head and neck tumors by combining with radiotherapy. Based on the clinical practice of the same kind of medicines as the result of the prior non-clinical study, the application is to carry out a clinical therapy of the combination drug of the obutyramide fumarate and the temozolomide on glioma.
Disclosure of Invention
The invention provides application of the combination drug of the obutylamine fumarate and the temozolomide in treating brain glioma. The combined drug enhances the anti-tumor curative effect.
The invention provides a pharmaceutical composition comprising obuzine fumarate and temozolomide as a combined medicament for the treatment of brain glioma. The invention also provides a preparation containing the pharmaceutical composition and application thereof in treating brain glioma. The invention also provides application of the pharmaceutical composition in preparing the preparation.
In one aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of obutylamine fumarate and temozolomide for use as a combination for the treatment of brain glioma.
Preferably, the brain glioma is an anaplastic astrocytoma, an anaplastic oligodendroastrocytoma, a glioblastoma or a gliosarcoma, etc.
Preferably, the ratio of the oxybutynin fumarate to temozolomide is 450-800mg/d, 150-250mg/m 2 Or 450-800mg/d, 50-125mg/m 2 。
In another aspect, the invention provides a pharmaceutical formulation, wherein the formulation comprises a therapeutically effective amount of the pharmaceutical composition and a pharmaceutically acceptable adjuvant, for use in the treatment of glioma.
The formulation may be, but is not limited to, an injection, a tablet, a granule, or a capsule.
Preferably, the use of obutylamine fumarate and temozolomide is 1 treatment cycle every 28 days.
Preferably, the obutyzine fumarate is administered in a single or multiple doses for 28 consecutive days per treatment cycle.
Preferably, the temozolomide is administered as a plurality of doses, either continuously or discontinuously, per treatment cycle.
Preferably, the temozolomide is administered continuously or discontinuously for 5 to 14 days per treatment cycle.
In another aspect, the invention provides a use for the preparation of a pharmaceutical formulation comprising a therapeutically effective amount of a pharmaceutical composition according to the invention for the treatment of glioma.
In another aspect, the invention provides a method of treating glioma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition or pharmaceutical formulation.
The invention discloses the synergistic effect of the obutyramine fumarate and temozolomide in treating the glioma for the first time, and the obutyramine fumarate and temozolomide respectively have obvious treatment effect on a rat C6 glioma model; under the current combination scheme, the two medicines are combined to have synergistic effect, and simultaneously have a relieving effect on the toxic effect of temozolomide, wherein the synergistic effect is shown by that the low-dose combination is added effect, and the medium-dose combination and the next-highest-dose combination are synergistic effect; the toxicity is relieved by adding the combined dose groups, the anti-tumor effect is obviously improved, the consumption of temozolomide is reduced by combined administration, and thus, the toxic and side effects are reduced, and the method has obvious significance for the application of the combination of the obutylamine fumarate and the temozolomide in resisting glioma.
Drawings
Fig. 1: the effect of the combination of obutyramine fumarate and temozolomide on the survival of tumor-bearing rats (Log-rank test, statistically significant differences between each drug-treated group compared to model control group, P < 0.01).
Fig. 2: brain weight distribution map of each group of tumor-bearing rats (surviving rats).
Fig. 3: brain weight/body mass index profile (surviving rats) for each group of tumor-bearing rats.
Fig. 4: brain weight profile of each group of tumor-bearing rats (all rats).
Fig. 5: brain weight/body mass index profile for each group of tumor-bearing rats (all rats).
Fig. 6: a general photograph of the tumor-bearing brain of the subject rat.
Fig. 7: brain tissue sections of partially tumor-bearing rats (HE staining). Wherein: tumor tissue is visible, a hemorrhagic focus appears partially, a: model control 1 (surviving at the end of the trial); b: model control 2 (surviving at the end of the trial); c: model control 3 (death during trial); d: model control 4 (death during trial); e: low dose combination 1 (survival at the end of trial); f: low dose combination 2 (surviving at the end of the trial).
Fig. 8: the effect of the combination of the test substance obutylamine fumarate and temozolomide on the body weight of tumor-bearing rats (compared to the control group) P <0.05, P <0.01, P <0.001 (Two-way ANOVA and Bonferroni test of pairwise comparison).
Fig. 9: the effect of the combination of the test obutyramine fumarate and temozolomide on the relative body weight of tumor-bearing rats (compared to the control group) vs control < P <0.05, < P <0.01, < P <0.001 (Two-way ANOVA and Bonferroni test of pairwise comparison).
Fig. 10: the obutyramine fumarate and temozolomide are used singly in the dose-response curve for influencing the survival rate of the rat C6 brain glioma brain in-situ transplantation tumor model animal.
Fig. 11: the effect of the Obitazine fumarate on the survival of animals in the rat C6 brain glioma brain in situ transplantation tumor model in combination with temozolomide (comparison of the expected additive dose-response curve with the actual dose-response curve).
Fig. 12: graph of body weight gain values for the obuzin fumarate alone group.
Fig. 13: graph of body weight gain values for temozolomide alone group.
Fig. 14: the effect of the weight gain of animals model for in situ transplantation of rat C6 brain glioma brain with obutyramine fumarate (comparison of expected additive dose-response curve with actual dose-response curve).
Detailed Description
The invention is further illustrated in the following drawings and specific examples, which are not intended to limit the invention in any way. Unless otherwise indicated, reagents, methods and apparatus employed in the present invention are those conventional in the art, and unless otherwise indicated, the materials of the kits used in the following examples are all commercially available.
Examples: in-vivo animal efficacy experiment for researching inhibition effect of combination of obuzine fumarate and temozolomide on growth of brain glioma
1. Experimental materials
(1) Medicament: oxybutyzine fumarate, temozolomide;
(2) Test cells: rat central nervous cytoma C6 cells.
(3) Experimental animals: wistar rats, clean grade, 120-150g, female, supplied by experimental animal technologies, ltd, beijing, villous, license number for experimental animals: SCXK- (jing) 2012-0001. Experimental animal pass number: no.110011210104738227. The animals tested were housed in sterile, independently blown IVC cages from experimental animal center of the medium-research-creation (beijing) biotechnology limited, animal facility license number: SCXK- (jing) 2017-0006. The rats were fed with a sterilized diet, free drinking water, specially formulated for rats. The temperature in the animal laboratory is kept at about 25 ℃ and the relative humidity is kept at 40-70%.
2. Experimental grouping
The grouping result is as follows:
1) Model control group
2) Obitzine fumarate 40mg/kg group (Low dose group)
3) Abirazine fumarate 80mg/kg group (Medium dose group)
4) Obitzine fumarate 160mg/kg group (high dose group)
5) Temozolomide 6.25mg/kg group (low dose group)
6) Temozolomide 12.5mg/kg group (medium dose group)
7) Temozolomide 25mg/kg group (high dose group)
8) Obitus-zine fumarate 40mg/kg + temozolomide 6.25mg/kg group (Low dose combination)
9) Obitus-zine fumarate 80mg/kg + temozolomide 12.5mg/kg group (Medium dose combination group)
10 Abiraterone fumarate 120mg/kg + temozolomide 18.75mg/kg group (next highest dose combination group)
3. Experimental method
The test substance, obutyzine fumarate, was dissolved in 40% hydroxypropyl-beta-cyclodextrin and administered by gavage once daily. Temozolomide drug is administered by gastric lavage once a day after being dissolved by 0.5% sodium carboxymethyl cellulose. And simultaneously observing the conditions, activity conditions and survival conditions of animals in each group, such as abnormal activity, death of animals and the like, and recording in time.
And ending the experiment when the model control group of rats die half way. Killing the living rats after anesthesia, counting the death time and the survival rate of the animals, taking the tumor-bearing whole brain tissue of the rats, weighing, calculating the brain weight/body mass index, and selecting a part of normal tissue sections of the brain tissue of the animals; the indexes such as animal survival condition, brain weight/body mass index and the like are used as indexes for evaluating the in-situ tumor growth inhibition effect of the brain of the rat glioma C6 rat by using the obutylamine fumarate, temozolomide and the two medicines together.
(1) Example 1 model control group
The model control group had early weight loss, bleeding in the nasal cavity, eyes and oral cavity of animals (6 d), low status, reduced food intake, death of animals started on day 7, 2 animals died on day 8, 1 animal died on day 9, 2 animals died on day 10, and more than half of animals died in the whole group of 10 rats by day 11, so the experiment was forcedly ended according to the experimental scheme, and the survival rate at the end of the experiment was 40%. The surviving rats in this group had 1 dying, and 3 had a decrease in body weight. Rats were sacrificed, brain tissues were taken and weighed, and the average brain weight of the surviving rats of this group was 2.142.+ -. 0.179g, and the brain weight/body mass index was calculated to be 1.471.+ -. 0.205%. When the animals die, brain tissues are taken and weighed, the brain weight of all rats in the group is 1.924 +/-0.242 g, and the calculated brain weight/body mass index is 1.365+/-0.172%.
(2) EXAMPLE 2 Obtusifizine fumarate administration group
The obuzine fumarate was administered 1 time per day by intragastric administration for a total of 10 times. The animals in each group have weight loss, the bleeding phenomenon of the nasal cavity, eyes and oral cavity of the animals is later than that of the model control group, and the death number of the animals is obviously reduced.
The oxybutynin fumarate 40mg/kg dosing group developed nasal bleeding on day 7. On day 81 animals died, on day 92 animals died, on day 101 animals died, 4 rats co-died at the end of the trial with a survival rate of 60%. Among the surviving rats, 1 rat had significantly reduced body weight. The average brain weight of the surviving rats in this group was 2.066 + -0.092 g, and the brain weight/body mass index was 1.313+ -0.154%; the total brain weight of the rats in this group was 2.048.+ -. 0.157g, and the calculated brain weight/body mass index was 1.344.+ -. 0.149%.
The oxybutynin fumarate 80mg/kg dosing group showed ocular bleeding on day 8. At day 9 and 10, 1 animal died and at the end of the trial 2 rats died altogether, with a survival rate of 80%. In the surviving rats, there were 2 rats with a significant decrease in body weight. The average brain weight of the surviving rats in this group was 2.157.+ -. 0.146g, and the brain weight/body mass index was 1.392.+ -. 0.140%; the total brain weight of the rats in this group was 2.090.+ -. 0.257g, and the calculated brain weight/body mass index was 1.389.+ -. 0.162.
The Obitzine fumarate 160mg/kg dosing group was observed to have oral-nasal bleeding in animals and weight loss in animals on day 8. On day 9 1 animal died and at the end of the trial 1 rat died altogether with a survival rate of 90%. Among the surviving rats, 2 rats had significantly reduced body weight. The average brain weight of the surviving rats in this group was 2.188+ -0.226 g, and the brain weight/body mass index was 1.285+ -0.126%; the total brain weight of the rats in this group was 2.137.+ -. 0.266g, and the calculated brain weight/body mass index was 1.289.+ -. 0.120g.
(3) EXAMPLE 3 temozolomide administration group
Temozolomide is administered 1 time per day by intragastric administration and 10 times in total. The animal activity ability of each group is better than that of the model control group, the weight loss occurs, the bleeding phenomenon of the nasal cavity, eyes and oral cavity of the animal is less, and the death number of the animal is obviously reduced.
Oral and nasal bleeding was observed in the temozolomide 6.25mg/kg dosing group on day 7. 1 animal died on day 10, and 2 rats died altogether at the end of the trial with a survival rate of 80%. The average brain weight of the surviving rats in this group was 2.083.+ -. 0.240g, and the brain weight/body mass index was 1.262.+ -. 0.153%; the total brain weight of the rats in this group was 2.000.+ -. 0.283g, and the calculated brain weight/body mass index was 1.238.+ -. 0.174g.
Temozolomide 12.5mg/kg dosing group was observed to have oral and nasal bleeding on day 7, and individual animals began to lose weight. At the end of the test, 1 rat died altogether, with a survival rate of 90% at 10 days 1 animal died. The average brain weight of the surviving rats in this group was 2.077+ -0.135 g, and the brain weight/body mass index was 1.350+ -0.110%; the total brain weight of the rats in this group was 1.971.+ -. 0.359g, and the calculated brain weight/body mass index was 1.284.+ -. 0.234%.
Temozolomide 25mg/kg dosing group was observed to have oral and nasal bleeding on day 9 and individual animals began to lose weight. At the end of the test, no death of the animals occurred and the survival rate was 100%. The average brain weight of the rats was
1.971.+ -. 0.111g, brain weight/body mass index 1.366.+ -. 0.098%.
(4) Obitazine fumarate and temozolomide combined administration group
The oxybutynin fumarate and temozolomide are combined for administration, so that animal weight, activity and bleeding of the nasal cavity, eyes and oral cavity of the animal are reduced, and the death number of the animal is also reduced.
The Obitzine fumarate 40mg/kg + temozolomide 6.25mg/kg group was observed on day 7 to have oral and nasal bleeding and weight loss in the animals. On day 9 1 animal died and at the end of the trial 1 rat died altogether with a survival rate of 90%. The average brain weight of the surviving rats in this group was 2.077.+ -. 0.059g, and the brain weight/body mass index was 1.241.+ -. 0.045%; the total brain weight of the rats in this group was 2.025.+ -. 0.172g, and the calculated brain weight/body mass index was 1.246.+ -. 0.045%.
The Obitzine fumarate 80mg/kg + temozolomide 12.5mg/kg group was observed to have 1 animal with oral-nasal bleeding and 3 animals with weight loss on day 8. At the end of the test, no death of the animals occurred and the survival rate was 100%. The average brain weight of the rats in this group was 2.104.+ -. 0.188g, and the brain weight/body mass index was 1.311.+ -. 0.185%.
No oral and nasal bleeding was observed in animals during the administration period of 120mg/kg of obutyramine fumarate and 18.75mg/kg of temozolomide, the weight of 5 animals was reduced, no death of the animals occurred, and the survival rate was 100%. The average brain weight of the rats in this group was 2.097.+ -. 0.145g, and the brain weight/body mass index was 1.345.+ -. 0.134%.
Table 1 shows: the single-use group of the obutyramine fumarate, the single-use group of the temozolomide fumarate, the combination of the obutyramine fumarate and the temozolomide can improve the survival rate of animals with rat C6 brain glioma brain in-situ tumor models, and the obvious dose-effect relationship is presented.
Table 2 shows: compared with the control group, the single-drug group of the obutylamine fumarate and the single-drug group of the temozolomide, the combined group of the obutylamine fumarate and the temozolomide improves the survival rate of the model rats.
Table 3 shows: compared with the survival rate of the rats in the control group by 40 percent, the survival rate of the rats in the groups with different doses of the obutyramine fumarate single drug is improved to 60 percent, 80 percent and 90 percent, the survival rate of the rats in the groups with different doses of the temozolomide single drug is improved to 80 percent,
The survival rate of the rats of the groups with different doses of the obutyramine fumarate and the temozolomide is improved to 90%, 100% and 100%.
TABLE 2 specific death time of rats in each group
TABLE 3 Effect of Obetazine fumarate and temozolomide in combination on survival of rat brain glioma cell C6 rat brain in situ transplantation tumor model
P <0.05, < P <0.01, < P <0.001 compared to Control (Control) (Kaplan-Meier curve and Log-rank test).
The invention adopts a mathematical rule based on the addition of the multi-drug combined drug effect discovered in the laboratory and a first-line mathematical model method, and calculates a dose-effect curve (line) of expected addition effect by simulating the dose-effect curve of the effect of the obutylamine fumarate and temozolomide on the survival rate and the weight increase value of the rat C6 glioma model; then, the dose-response curve actually observed for the combination of the two drugs is calculated by comparing the dose-response curve with the dose-response curve (curve). The data statistics and computation process of this section is described in detail in the annex: and (3) quantitatively calculating the synergy, addition and antagonism of the drug effect and the drug toxicity related index of the combined drug.
The data demonstrate that the weight gain value at the end of the test is used as an evaluation calculation index (in practice, the weight change of the tested animal is the manifestation of the combined effect of the disease degree and the drug toxicity, and the quantitative analysis of the index has a strong correlation with the drug toxicity). The weight gain value of the single-use group of the obutyzine fumarate increases along with the increase of the dosage, which indicates that the obutyzine fumarate has better curative effect and smaller toxicity; the weight gain value of the temozolomide single administration group is reduced along with the increase of the dosage, which indicates that the temozolomide has stronger treatment effect and stronger toxic effect; the weight gain value of the two low and medium dose combination groups is higher than that of the single dose group, and the weight gain value of the second high dose combination group is higher than that of the temozolomide high dose single dose group.
Table 4 shows: the method comprises the steps of administering the obutylamine fumarate, administering temozolomide with an increased weight gain value, and administering the temozolomide with a reduced weight of the animal with an increased dosage, wherein the obutylamine fumarate and the temozolomide are combined, and the weight value of the animal is higher than that of the temozolomide administered alone. The oxybutynin fumarate has good safety.
Table 5 shows: the weight gain values of the low and medium dose combination groups of the obutyramine fumarate and the temozolomide are higher than that of the single dose group, and the weight gain value of the next-high dose combination group is higher than that of the high-dose single dose group of the temozolomide.
Table 6 shows: the weight gain values of the low and medium dose combination groups of the obutyramine fumarate and the temozolomide are higher than that of the single dose group, and the weight gain value of the next-high dose combination group is higher than that of the high-dose single dose group of the temozolomide. It is suggested that obutyzine fumarate is capable of antagonizing or alleviating the toxic effects of temozolomide.
TABLE 4 influence of the combination of Obitazine fumarate and temozolomide on the body weight of tumor-bearing rats
TABLE 5 influence of the combination of Obitazine fumarate and temozolomide on the relative body weight of tumor-bearing rats
TABLE 6 Effect of Obetazine fumarate and temozolomide on weight gain of rat C6 brain glioma brain in situ transplantation tumor model animal
Temozolomide belongs to an alkylating agent, can rapidly pass through the blood brain barrier after being orally taken, is the first-choice medicament for treating glioma at present, and has stronger toxicity as a cytotoxic chemotherapeutic medicament. The obutyzine fumarate is a novel antitumor drug capable of penetrating the blood brain barrier, and the mechanism of the obutyzine fumarate is mainly used for promoting the conversion of precapsase-3 in tumor cells into caspase-3 and inducing apoptosis of the tumor cells. The combination of two anticancer drugs with different mechanisms can enhance the therapeutic effect on brain glioma and can also relieve the toxicity.
The invention proves that the obutyramine fumarate and temozolomide fumarate have obvious treatment effect on a rat C6 brain glioma model by single use; under the current combination scheme, the two medicines are combined to have synergistic effect, and simultaneously have a relieving effect on the toxic effect of temozolomide, wherein the synergistic effect is shown by that the low-dose combination is added effect, and the medium-dose combination and the next-highest-dose combination are synergistic effect; toxicity relief was presented as additive effect for each combination dose group.
Claims (10)
1. A pharmaceutical composition comprising obuzine fumarate and temozolomide as a combination for use in the treatment of glioma.
2. The pharmaceutical composition of claim 1, wherein the brain glioma is an anaplastic astrocytoma, an anaplastic oligodendroastrocytoma, a glioblastoma, or a gliosarcoma.
3. The pharmaceutical composition according to claim 1, wherein the ratio of the amounts of the obutylamine fumarate and temozolomide is 450-800mg/d, 150-250mg/m 2 。
4. A formulation comprising the pharmaceutical composition of any one of claims 1-3 and a pharmaceutically acceptable adjuvant, for use in the treatment of glioma.
5. The formulation of claim 4, wherein the formulation is in the form of an injection, a tablet, a granule, or a capsule.
6. The formulation of claim 4, wherein the obutylamine fumarate and temozolomide are used for 1 treatment cycle every 28 days.
7. The formulation of claim 4, wherein the use of the obuzine fumarate is a single or multiple administration for 28 consecutive days per treatment cycle.
8. The formulation of claim 4, wherein the temozolomide is administered as multiple doses, either continuously or discontinuously, per treatment cycle.
9. The formulation of claim 4, wherein the temozolomide is administered continuously or discontinuously for 5-14 days per treatment cycle.
10. Use of a formulation comprising the pharmaceutical composition of any one of claims 1-3 for the preparation of a medicament for the treatment of glioma.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311459703.6A CN117357533A (en) | 2023-11-03 | 2023-11-03 | Application of combination of obutylamine fumarate and temozolomide in treating brain glioma |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311459703.6A CN117357533A (en) | 2023-11-03 | 2023-11-03 | Application of combination of obutylamine fumarate and temozolomide in treating brain glioma |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117357533A true CN117357533A (en) | 2024-01-09 |
Family
ID=89396502
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202311459703.6A Pending CN117357533A (en) | 2023-11-03 | 2023-11-03 | Application of combination of obutylamine fumarate and temozolomide in treating brain glioma |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117357533A (en) |
-
2023
- 2023-11-03 CN CN202311459703.6A patent/CN117357533A/en active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3066101B1 (en) | Combination therapy for cancer using bromodomain and extra-terminal (bet) protein inhibitors | |
Heist et al. | Phase I/II study of AT-101 with topotecan in relapsed and refractory small cell lung cancer | |
CN105705148B (en) | Cancer therapy using a combination of plinabulin and a taxane | |
JP6365993B2 (en) | Method and application of soft tissue sarcoma with quinoline derivative, and medicinal composition for treating soft tissue sarcoma | |
KR100953483B1 (en) | Formulation of amino acids and riboflavin useful to reduce toxic effects of cytotoxic chemotherapy | |
JP2006508974A (en) | Combination chemotherapy comprising MEK inhibitor and capecitabine (CAPECITABINE) for treating cancer | |
EP3429614B1 (en) | Method of treating triple negative breast cancer | |
AU2016279096B2 (en) | Composition containing carboplatin and use | |
TW201300107A (en) | Combination therapy | |
TW202214242A (en) | Use of chiauranib or derivatives thereof in manufacture of medicament for prevention and/or treatment of non-hodgkin's lymphoma | |
CN105476996B (en) | The purposes of curcumin and Afatinib therapeutic alliance non-small cell lung cancer | |
US11000518B2 (en) | Use of combination of VEGFR inhibitor and PARP inhibitor in preparation of medicament for treating gastric cancer | |
WO2020192506A1 (en) | Chiauranib for treatment of small cell lung cancer | |
CN110314222B (en) | Application of bortezomib and panobinostat or vorinostat composition in preparation of drug-resistant MLL leukemia treatment drugs | |
KR101741281B1 (en) | Pharmaceutical composition comprising a3 adenosine receptor agonist (ib-meca/cf-101) for treatment of psoriasis | |
CN113329749A (en) | Combination therapy for the treatment of uveal melanoma | |
CN112638378A (en) | Composition for eradicating helicobacter pylori | |
CN117357533A (en) | Application of combination of obutylamine fumarate and temozolomide in treating brain glioma | |
EP3949970A1 (en) | Combined use of a-nor-5? androstane compound drug and anticancer drug | |
TW202029961A (en) | Use of ar antagonist combined with parp inhibitor in preparation of medicament for treating prostate cancer | |
TW201934123A (en) | Pharmaceutical composition for preventing or treating cancer comprising PI3 kinase inhibitor and cytotoxicity anticancer agents | |
EP4110326B1 (en) | Combination comprising alpelisib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid | |
CN115364231B (en) | Pharmaceutical composition for enhancing anti-tumor effect of EZH2 inhibitor and application thereof | |
RU2784869C1 (en) | Chiauranib for treating small cell lung cancer | |
WO2024046332A1 (en) | Pharmaceutical composition and use thereof |
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 |