Application of combined medication of orbitazine fumarate and temozolomide in treatment of brain glioma

Abstract

The present invention belongs to the field of medicines, and particularly relates to the clinical application of the combined medication of orbitazine fumarate and temozolomide in the treatment of brain glioma. According to the present invention, the clinical application of the combined medication of orbitazine fumarate and temozolomide in the treatment of brain glioma is provided for the first time. Orbitazine fumarate and temozolomide have an obvious synergistic effect, such that the curative effect is effectively improved, and is more remarkable compared with that of a single component, and the lethality of tumor cells is improved; the dosage is effectively reduced, thus reducing the toxic and side effects. Due to the combined use of the two, the cost can be saved, the economic burden of a patient is relieved, a new way is provided for prevention and treatment of brain glioma, and the application prospect is wide in the field of medicine science.

Description

Application of the combination of orbitazine fumarate and temozolomide in the treatment of brain glioma

Technical field

[0001] The invention belongs to the field of medicine and relates to the application of a combined administration of orbitazine fumarate and temozolomide in treating brain gliomas. [Background Technology]

[0002] Gliomas, which originate from brain glial cells, are the most common primary intracranial tumors. More than half of these tumors are glioblastoma multiforme (GBM), the most malignant type. The World Health Organization (WHO) classification of central nervous system tumors categorizes gliomas into grades I-IV, with grades I and II considered low-grade gliomas and grades III and IV considered high-grade.

[0003] Gliomas account for 32% of all primary central nervous system tumors and 81% of all malignant central nervous system tumors. The incidence of malignant gliomas is 5-8 per 1 million, and the 5-year mortality rate ranks third among systemic tumors, after pancreatic cancer and lung cancer. The World Health Organization (WHO) published a 1998 ranking of tumor mortality rates, ranking malignant gliomas as the second leading cause of death among cancer patients under 34 years of age and the third leading cause of death among those aged 35 to 54. According to the Central Brain Tumor Registry of the United States (CBTRUS), GBM has the highest incidence among primary malignant central nervous system tumors, accounting for 46.1% (approximately 3.20 per 100,000), with a higher incidence in males than in females. The incidence of GBM increases with age, peaking at 75 to 84 years of age, and the median age of newly diagnosed patients is 64 years. The 2012 China Cancer Registry Report shows that the mortality rate for brain and central nervous system malignant tumors in China is 3.87 per 100,000 people, ranking 9th among the top ten most fatal tumors. Central nervous system malignant tumors, particularly malignant gliomas, impose a significant socioeconomic and family burden and remain a hot topic in cancer research.

[0004] The pathogenesis of gliomas remains unclear. Two identified risk factors are exposure to high-dose ionizing radiation and high-penetrance genetic mutations associated with rare syndromes. In recent years, research on the pathogenesis of high-grade gliomas has focused on allelic loss of heterozygosity and genetic variation, DNA mismatch repair, disrupted cell signaling pathways (such as the EGFR and PDGF pathways), mutations in genes involved in the PI3K / AKt / PTEN, Ras, and P53 / RB1 pathways, and cancer stem cell research. Clinical manifestations of gliomas primarily include increased intracranial pressure, neurological and cognitive impairment, and seizures. Treatment of gliomas primarily relies on surgical resection, combined with radiotherapy and chemotherapy. Surgery can alleviate clinical symptoms, prolong survival, and obtain sufficient tumor specimens for pathological diagnosis and molecular genetic testing. Radiotherapy can kill or inhibit tumor cells and prolong patient survival. Conventional fractionated external beam radiotherapy is the standard radiotherapy for gliomas.

[0005] The treatment of GBM mainly adopts a comprehensive treatment that combines multiple treatment methods such as surgery and radiotherapy and chemotherapy. Postoperative radiotherapy for GBM combined with temozolomide and adjuvant chemotherapy has become the standard treatment for newly diagnosed GBM in adults. Due to the aggressive nature of high-grade gliomas, even after treatment with the standard regimen of temozolomide concurrent radiotherapy and adjuvant chemotherapy, the progression-free survival of glioblastoma patients is 6.9 months, indicating that the vast majority of high-grade glioma patients will relapse after the initial treatment. Glioma recurrence or progression refers to the worsening of clinical symptoms during the treatment process, and the imaging manifestations are obvious tumor enlargement and (or) the appearance of new tumor lesions. Among them, local recurrence of the tumor is the most important initial recurrence mode, and other recurrence modes include cerebrospinal fluid dissemination and distant recurrence.

[0006] Treatment options for recurrent GBM include re-surgery, radiotherapy, and adjuvant systemic therapy, including cytotoxic chemotherapy, angiogenesis inhibitors, and immunotherapy, but there is currently no standard treatment for recurrent GBM. Surgery has a very limited role in patients with recurrent GBM and is only suitable for patients with local recurrence. Clinical data confirm that the effect of chemotherapy drugs in treating recurrent GBM is also limited. Options for GBM recurrence include: ① Bevacizumab; ② Bevacizumab plus chemotherapy (irinotecan, carmustine / lomustine, temozolomide, carboplatin); ③ Temozolomide; ④ Lomustine or carmustine monotherapy; ⑤ PCV combination therapy; ⑥ Cyclophosphamide; ⑦ Chemotherapy regimens based on carboplatin or cisplatin.

[0007] Overall, GBM treatment remains a significant challenge, and patient prognosis is poor. Data show that the 5-year survival rate for GBM patients is less than 10%. Therefore, GBM still requires innovative treatments to improve survival outcomes.

[0008] Temozolomide is a relatively well-tolerated oral alkylating agent, an imidazole tetrazine derivative. After oral administration, it is rapidly absorbed and readily crosses the blood-brain barrier. It is converted into a potent alkylating agent within cells, alkylating guanine, damaging DNA, and leading to tumor cell death. In 2002, Stupp et al. reported the clinical efficacy of temozolomide as a first-line treatment for newly diagnosed glioblastoma, finding a significant improvement in patient survival. In 2005, Stupp et al. further reported the results of a clinical trial combining radiotherapy with concurrent and subsequent adjuvant temozolomide for glioblastoma, demonstrating that this regimen significantly improved median survival and two-year survival rates, extending the median survival from 12.1 months to 14.6 months and the two-year survival rate from 10.4% to 26.5%. Since then, the Stupp regimen has been widely recommended as the standard treatment for newly diagnosed glioblastoma in North America, Europe, and Australia. While temozolomide has demonstrated promising results since its clinical application, its efficacy rate remains below 50%, primarily due to drug resistance. According to past experience, at the half-effective concentration of the drug, the inhibitory effect of multi-drug combination regimens on tumor cells is often higher than that of single-drug chemotherapy regimens. Therefore, two-drug and multi-drug combination regimens containing temozolomide have become new research hotspots.

[0009] Orbitazine fumarate is a Procaspase-3 agonist and a potent pro-apoptotic agent. The apoptotic protein Caspase-3 plays a crucial role in inhibiting tumor progression. It is generally believed that Caspase-3 is the primary terminal enzyme in the apoptotic process and a crucial component of the CTL cell-mediated killing mechanism. In approximately half of human tumors, Caspase-3 expression is low, leading to uncontrolled tumor cell proliferation. However, Procaspase-3 is highly expressed in various tumor tissues, such as neuroblastoma, lymphoma, leukemia, melanoma, and liver cancer. Procaspase-3 expression in colorectal cancer tissue is six times higher than in adjacent normal tissue. High expression of Procaspase-3 has been detected in various tumor cell lines, including lung cancer, renal cancer, and breast cancer. Given the high expression of Procaspase-3 in tumor tissue and the existence of a "safety mechanism" that prevents Procaspase-3 from being effectively converted to Caspase-3, catalyzing the conversion of Procaspase-3 to Caspase-3 contributes to anti-tumor effects.

[0010] Studies have shown that Orbitazine Fumarate significantly inhibits the growth of various tumor cells and has the potential to be used in combination with temozolomide to treat gliomas and radiotherapy to treat head and neck tumors. Based on previous nonclinical research results and clinical experience with similar drugs, the company plans to apply for the use of Orbitazine Fumarate in the treatment of gliomas, as well as the clinical treatment of gliomas with the combination of Orbitazine Fumarate and temozolomide.

[0011] [Summary of the invention]

[0012] The present invention provides an application of a combined use of orbitazine fumarate and temozolomide in treating brain gliomas, wherein the combined use enhances the anti-tumor efficacy.

[0013] The present invention provides a pharmaceutical composition comprising orbitazine fumarate and temozolomide for use as a combined medication, wherein the composition is used to treat gliomas. The present invention also provides a preparation comprising the pharmaceutical composition and its use in treating gliomas. The present invention also provides the use of orbitazine fumarate in a medicament for treating gliomas.

[0014] In one aspect, the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition comprises therapeutically effective amounts of orbitazine fumarate and temozolomide for use as a combination.

[0015] Furthermore, the dosage ratio of the orbitazine fumarate and temozolomide is, for example, 450-800 mg / d:150-250 mg / m2 or 450-800 mg / d:50-125 mg / m2.

[0016] In another aspect, the present invention provides use of the above-mentioned pharmaceutical composition in a drug for treating brain glioma, wherein the brain glioma includes anaplastic astrocytoma, anaplastic oligoastrocytoma, glioblastoma or gliosarcoma.

[0017] In another aspect, the present invention provides a pharmaceutical preparation, wherein the preparation comprises a therapeutically effective amount of the pharmaceutical composition and a pharmaceutically acceptable excipient.

[0018] The dosage form of the preparation may be, but is not limited to, injection, tablet, granule or capsule.

[0019] Furthermore, the administration of the orbitazine fumarate and temozolomide is such that every 28 days constitutes one treatment cycle.

[0020] Furthermore, the administration of orbitazine fumarate is a single or multiple administration for 28 consecutive days per treatment cycle.

[0021] Furthermore, the temozolomide is administered continuously or discontinuously multiple times in each treatment cycle.

[0022] Furthermore, the temozolomide is administered continuously or discontinuously for 5 to 14 days in each treatment cycle.

[0023] In another aspect, the present invention provides use of the above-mentioned combination of preparations in treating brain gliomas, including anaplastic astrocytoma, anaplastic oligoastrocytoma, glioblastoma or gliosarcoma.

[0024] In another aspect, the present invention provides a method for treating brain glioma using the pharmaceutical composition or pharmaceutical preparation of the present invention, comprising administering a therapeutically effective amount of the pharmaceutical composition or pharmaceutical preparation to a patient.

[0025] In another aspect, the present invention provides use of orbitazine fumarate in a drug for treating brain glioma.

[0026] Furthermore, the brain glioma includes anaplastic astrocytoma, anaplastic oligoastrocytoma, glioblastoma or gliosarcoma.

[0027] Furthermore, the administration of orbitazine fumarate is for 28 consecutive days per treatment cycle.

[0028] Furthermore, the drug comprises a therapeutically effective amount of orbitazine.

[0029] Furthermore, the adult dosage of the orbitazine fumarate is 384 mg / d-1152 mg / d. Preferably, the adult dosage of the orbitazine fumarate is 450 mg / d-800 mg / d.

[0030] The present invention discloses for the first time the synergistic effect of combining opioid fumarate with temozolomide in improving the treatment of brain gliomas. Opioid fumarate and temozolomide, when used alone, have significant therapeutic effects on a rat C6 brain glioma model. Under the current combination regimen, the two drugs have a synergistic effect when used together, and at the same time, have a mitigating effect on the toxic effects of temozolomide. The synergistic effect is manifested as an additive effect in the low-dose combination group, and a synergistic effect in the medium-dose and second-highest-dose combination groups. The mitigating toxicity is manifested as an additive effect in the various combination dose groups, achieving a significant improvement in the anti-tumor effect. The combined use of the drugs reduces the dosage of temozolomide, thereby reducing toxic side effects. This has significant significance for the combined use of opioid fumarate and temozolomide in treating brain gliomas.

Brief Description of the Drawings

[0031] Figure 1: Effect of the combination of orbitazine fumarate and temozolomide on the survival of tumor-bearing rats (Log-rank test, there were significant statistical differences between each drug treatment group and the model control group, P < 0.01).

[0032] Figure 2: Brain redistribution of tumor-bearing rats in each group (surviving rats).

[0033] Figure 3: Distribution of brain weight / body weight index of tumor-bearing rats in each group (surviving rats).

[0034] Figure 4: Brain redistribution of tumor-bearing rats in each group (all rats).

[0035] Figure 5: Distribution of brain weight / body weight index of tumor-bearing rats in each group (all rats).

[0036] Figure 6: Gross photograph of the tumor-bearing brain of the test rats.

[0037] Figure 7: Sections of brain tissue from tumor-bearing rats (HE staining). Tumor tissue is visible, with some hemorrhages. A: Model control 1 (still alive at the end of the experiment); B: Model control 2 (still alive at the end of the experiment); C: Model control 3 (died during the experiment); D: Model control 4 (died during the experiment); E: Low-dose combination 1 (still alive at the end of the experiment); F: Low-dose combination 2 (still alive at the end of the experiment).

[0038] Figure 8: Effects of the combined use of orbitazine fumarate and temozolomide on the body weight of tumor-bearing rats (compared with the control group) *P<0.05, **P<0.01, ***P<0.001 (Two-way ANOVA and Bonferroni test for pairwise comparisons).

[0039] Figure 9: Effects of the combined use of orbitazine fumarate and temozolomide on the relative body weight of tumor-bearing rats (compared with the control group) vs control*P<0.05, **P<0.01, ***P<0.001 (Two-way ANOVA and Bonferroni test for pairwise comparisons).

[0040] Figure 10: Dose-effect curves of the effects of orbitazine fumarate and temozolomide alone on the survival rate of rat C6 glioma orthotopic transplanted tumor model animals.

[0041] Figure 11: Effect of the combination of orbitazine fumarate and temozolomide on the survival rate of rats in the orthotopic transplantation model of C6 glioma (comparison of the expected additive dose-effect curve and the actual dose-effect curve).

[0042] Figure 12: Body weight gain curve of the orbitazine fumarate monotherapy group.

[0043] Figure 13: Body weight gain curve of the temozolomide monotherapy group.

[0044] Figure 14: Effect of the combination of orbitazine fumarate and temozolomide on body weight gain in rats with orthotopic C6 glioma transplanted tumor model (comparison of expected additive dose-effect curve and actual dose-effect curve). [Specific implementation method]

[0045] The present invention is further described below with reference to the accompanying drawings and specific examples, but the examples do not limit the present invention in any way. Unless otherwise specified, the reagents, methods, and equipment used in the present invention are conventional reagents, methods, and equipment in the art. Unless otherwise specified, the kit materials used in the following examples are all commercially available.

[0046] Example: In vivo animal efficacy study on the inhibitory effect of the combination of orbitazine fumarate and temozolomide on brain glioma tumor growth

[0047] 1. Experimental Materials

[0048] (1) Drugs: Orbitazine fumarate, temozolomide;

[0049] (2) Test cells: rat central neuroblastoma C6 cells.

[0050] (3) Experimental Animals: Wistar rats, clean grade, 120–150 g, female, provided by Beijing Weitonglihua Laboratory Animal Technology Co., Ltd., Laboratory Animal License No.: SCXK-(Beijing)2012-0001. Laboratory Animal Qualification Certificate No.: 110011210104738227. The animals were housed in sterile, independently ventilated IVC cages at the Laboratory Animal Center of Zhongyanzi Chuang (Beijing) Biotechnology Co., Ltd., Animal Facility License No.: SCXK-(Beijing)2017-0006. The rats were fed a sterilized diet specially formulated for rats and had free access to drinking water. The temperature in the animal laboratory was maintained at approximately 25°C, and the relative humidity was maintained at 40–70%.

[0051] 2. Experimental Grouping

[0052] The grouping results are as follows:

[0053] 1) Model control group

[0054] 2) Orbitazine fumarate 40 mg / kg group (low-dose group)

[0055] 3) Orbitazine fumarate 80 mg / kg group (medium dose group)

[0056] 4) Orbitazine fumarate 160 mg / kg group (high dose group)

[0057] 5) Temozolomide 6.25 mg / kg group (low-dose group)

[0058] 6) Temozolomide 12.5 mg / kg group (medium dose group)

[0059] 7) Temozolomide 25 mg / kg group (high-dose group)

[0060] 8) Orbitazine fumarate 40 mg / kg + temozolomide 6.25 mg / kg group (low-dose combination group)

[0061] 9) Orbitazine fumarate 80 mg / kg + temozolomide 12.5 mg / kg group (medium-dose combination group)

[0062] 10) Orbitazine fumarate 120 mg / kg + temozolomide 18.75 mg / kg group (the second highest dose combination group)

[0063] 3. Experimental methods

[0064] The test substance, orbitazine fumarate, was dissolved in 40% hydroxypropyl-β-cyclodextrin and administered by gavage once daily. Temozolomide was dissolved in 0.5% sodium carboxymethylcellulose and administered by gavage once daily. The condition, activity, and survival of the animals in each group were observed simultaneously. Any abnormal activity or death was recorded promptly.

[0065] The experiment was terminated when more than half of the rats in the model control group had died. The surviving rats were anesthetized and sacrificed, and the time of death and survival rate were recorded. The whole brain tissue of the tumor-bearing rats was obtained and weighed, and the brain weight / body weight index was calculated. Routine tissue sections of the brain tissue of some animals were selected. Indicators such as animal survival, brain weight, and brain weight / body weight index were used to evaluate the inhibitory effects of orbitazine fumarate, temozolomide, and the combination of the two drugs on the growth of orthotopic brain tumors bearing C6 rat gliomas.

[0066] (1) Example 1 Model Control Group

[0067] The model control group experienced early weight loss, with bleeding in the nasal cavity, eyes, and mouth (6 days). The animals became depressed and their food intake decreased. Deaths began on the 7th day, with two animals dying on the 8th day, one on the 9th day, and two on the 10th day. By the 11th day, six of the 10 rats had died, representing more than half of the total group. The experiment was terminated as planned, resulting in a survival rate of 40%. Of the surviving rats in this group, one was near death, and three had lost weight. The rats were sacrificed, and brain tissue was obtained and weighed. The average brain weight of the surviving rats in this group was 2.142±0.179g, resulting in a calculated brain weight / body weight index of 1.471±0.205%. Brain tissue was obtained and weighed at the time of death, resulting in a brain weight of 1.924±0.242g for all rats in this group, resulting in a calculated brain weight / body weight index of 1.365±0.172%.

[0068] (2) Example 2 Orbitazine Fumarate Administration Group

[0069] Orbitazine fumarate was administered orally once daily for a total of 10 doses. The animals in each group experienced weight loss, bleeding in the nasal cavity, eyes, and mouth later than in the model control group, and the number of animal deaths was significantly reduced.

[0070] The group receiving 40 mg / kg of orbitazine fumarate developed nasal bleeding on day 7. One animal died on day 8, two on day 9, and one on day 10, for a total of four deaths at the end of the study, resulting in a survival rate of 60%. Among the surviving rats, one exhibited significant weight loss. The mean brain weight of the surviving rats was 2.066±0.092 g, with a brain-to-body weight index of 1.313±0.154%. The total brain weight of all rats in this group was 2.048±0.157 g, resulting in a calculated brain-to-body weight index of 1.344±0.149%.

[0071] The group receiving orbitazine fumarate at 80 mg / kg experienced eye hemorrhage on day 8. One animal died on day 9 and one on day 10, bringing the total death rate to 80% at the end of the study. Two of the surviving rats showed significant weight loss. The average brain weight of the surviving rats was 2.157±0.146 g, with a brain-to-body weight index of 1.392±0.140%. The total brain weight of all rats in this group was 2.090±0.257 g, resulting in a calculated brain-to-body weight index of 1.389±0.162.

[0072] In the group receiving orbitazine fumarate at 160 mg / kg, oral and nasal bleeding and weight loss were observed on day 8. One animal died on day 9, and by the end of the study, one rat had died, resulting in a 90% survival rate. Two of the surviving rats showed significant weight loss. The average brain weight of the surviving rats was 2.188±0.226g, with a brain-to-body weight index of 1.285±0.126%. The total brain weight of all rats in this group was 2.137±0.266g, resulting in a calculated brain-to-body weight index of 1.289±0.120g.

[0073] (3) Example 3 Temozolomide administration group

[0074] Temozolomide was administered orally once daily for a total of 10 doses. Animals in each group showed improved activity and coat color compared to the model control group, experienced less weight loss, and showed less bleeding in the nasal cavity, eyes, and mouth. The number of animal deaths was significantly reduced.

[0075] In the 6.25 mg / kg temozolomide group, oral and nasal bleeding was observed on day 7. One animal died on days 9 and 10, and one on day 10. By the end of the study, two rats had died, resulting in an 80% survival rate. The mean brain weight of the surviving rats was 2.083 ± 0.240 g, and the brain-to-body weight index was 1.262 ± 0.153%. The total brain weight of all rats in this group was 2.000 ± 0.283 g, resulting in a calculated brain-to-body weight index of 1.238 ± 0.174 g.

[0076] In the 12.5 mg / kg temozolomide group, oral and nasal bleeding was observed on day 7, and some animals began to lose weight. One animal died on day 10, and by the end of the study, one rat had died, resulting in a survival rate of 90%. The average brain weight of surviving rats in this group was 2.077±0.135g, with a brain-to-body weight index of 1.350±0.110%. The total brain weight of all rats in this group was 1.971±0.359g, resulting in a calculated brain-to-body weight index of 1.284±0.234%.

[0077] On day 9, some animals in the 25 mg / kg temozolomide group experienced oral and nasal bleeding, and some began to lose weight. By the end of the trial, no animals had died, resulting in a 100% survival rate. The mean brain weight of the rats was 1.971 ± 0.111 g, and the brain-to-body weight index was 1.366 ± 0.098%.

[0078] (4) Orbitazine fumarate and temozolomide combined administration group

[0079] The combined administration of orbitazine fumarate and temozolomide reduced the weight, activity, nasal, eye and oral bleeding of animals, and the number of animal deaths.

[0080] In the group receiving orbitazine fumarate 40 mg / kg + temozolomide 6.25 mg / kg, oral and nasal bleeding and weight loss were observed on day 7. One animal died on day 9, and by the end of the study, one rat had died, resulting in a 90% survival rate. The mean brain weight of the surviving rats in this group was 2.077±0.059 g, with a brain-to-body weight index of 1.241±0.045%. The brain weight of all rats in this group was 2.025±0.172 g, resulting in a calculated brain-to-body weight index of 1.246±0.045%.

[0081] In the group receiving orbitazine fumarate 80 mg / kg + temozolomide 12.5 mg / kg, one animal experienced oral and nasal bleeding, and three animals experienced weight loss on day 8. At the end of the trial, no animals died, resulting in a 100% survival rate. The mean brain weight of the rats in this group was 2.104 ± 0.188 g, and the brain weight / body weight index was 1.311 ± 0.185%.

[0082] In the group receiving orbitazine fumarate 120 mg / kg + temozolomide 18.75 mg / kg, no oral or nasal bleeding was observed, 5 animals experienced weight loss, and no mortality occurred, resulting in a 100% survival rate. The mean brain weight of rats in this group was 2.097 ± 0.145 g, and the brain weight / body weight index was 1.345 ± 0.134%.

[0083] Table 1 shows that the orbitazine fumarate monotherapy group, the temozolomide monotherapy group, and the combination of orbitazine fumarate and temozolomide can improve the survival rate of rat C6 glioma in situ tumor model animals, showing an obvious dose-effect relationship.

[0084] Table 2 shows that compared with the control group, the orbitazine fumarate and temozolomide single-drug groups, the orbitazine fumarate and temozolomide combination group improved the survival rate of the model rats.

[0085] Table 3 shows that compared with the survival rate of 40% of the rats in the control group, the survival rates of the rats in the different dose groups of orbitazine fumarate alone were increased to 60%, 80%, and 90%, the survival rates of the rats in the different dose groups of temozolomide alone were increased to 80%, 90%, and 100%, and the survival rates of the rats in the different dose groups of orbitazine fumarate and temozolomide combined were increased to 90%, 100%, and 100%.

[0086] Table 2 Specific death time of rats in each group

[0087] Table 3 Effect of orbitazine fumarate combined with temozolomide on the survival rate of rat brain glioma cell C6 orthotopic transplanted tumor model

[0088] Compared with the control group (Control), *P<0.05, **P<0.01, ***P<0.001 (Kaplan-Meier curve and Log-rank test).

[0089] This study utilizes a one-band-one-line mathematical model based on the mathematical laws of additive multidrug effects discovered in our laboratory. By simulating the dose-response curves of the effects of opioid fumarate and temozolomide on survival and weight gain in a rat C6 glioma model, we calculated the expected dose-response band (line) for additive effects. The dose-response curves observed for the combined use of the two drugs were then compared with the dose-response band (line). For details on the data statistics and calculations for this section, please see the appendix: Quantitative Calculation of Synergy, Additivity, and Antagonism in Drug Effects and Toxicity-Related Indicators of Combined Drug Therapy.

[0090] The data showed that, using weight gain as an evaluation indicator at the end of the trial (actually, the weight change of the test animals at this time reflects the combined effects of the disease severity and drug toxicity, and quantitative analysis of this indicator also has a strong correlation with drug toxicity), the weight gain of the group treated with orbitazine fumarate alone increased with increasing doses, suggesting that orbitazine fumarate has better efficacy and lower toxicity; the weight gain of the group treated with temozolomide alone decreased with increasing doses, suggesting that temozolomide has a stronger therapeutic effect but also has stronger toxic effects; the weight gain of the low and medium dose combination groups of the two drugs was higher than that of the respective single dose groups, and the weight gain of the second highest dose combination group was higher than that of the high dose temozolomide alone group.

[0091] Table 4 shows that, when administered with orbitazine fumarate, the weight gain of the animals increased, while with temozolomide, the weight of the animals decreased with increasing doses. The combined administration of orbitazine fumarate and temozolomide resulted in higher weight gain than that of temozolomide alone. Orbitazine fumarate has good safety.

[0092] Table 5 shows that the weight gain values ​​of the low- and medium-dose combination groups of orbitazine fumarate and temozolomide were higher than those of the respective single-dose groups, and the weight gain value of the second-highest-dose combination group was higher than that of the high-dose temozolomide single-dose group.

[0093] Table 6 shows that the weight gain values ​​of the low- and medium-dose combination groups of orbitazine fumarate and temozolomide were higher than those of the respective single-dose groups, and the weight gain value of the second-highest-dose combination group was higher than that of the high-dose temozolomide single-dose group. This suggests that orbitazine fumarate can counteract or alleviate the toxic effects of temozolomide.

[0094] Table 4 Effects of the combined use of orbitazine fumarate and temozolomide on the body weight of tumor-bearing rats

[0095] Table 5 Effects of the combined use of orbitazine fumarate and temozolomide on the relative body weight of tumor-bearing rats

[0096] Table 6 Effects of orbitazine fumarate combined with temozolomide on body weight gain in rats with orthotopic transplanted C6 glioma model

[0097] Temozolomide is an alkylating agent that rapidly crosses the blood-brain barrier after oral administration. It is currently the preferred treatment for gliomas. However, as a cytotoxic chemotherapy agent, it has significant toxicity. The investigational drug, orbitazine fumarate, is a novel anti-tumor agent that can cross the blood-brain barrier. Its mechanism of action is primarily to promote the conversion of precaspase-3 to caspase-3 in tumor cells, inducing apoptosis. Combining these two anticancer drugs with different mechanisms of action may enhance their therapeutic efficacy against gliomas and potentially mitigate their toxicity.

[0098] The present invention demonstrates that orbitazine fumarate and temozolomide, when used alone, have significant therapeutic effects on a rat C6 glioma model. Under the current combined use regimen, the two drugs exhibit a synergistic effect and alleviate the toxic effects of temozolomide. The synergistic effect is manifested as an additive effect in the low-dose combination group and a synergistic effect in the medium-dose and second-highest-dose combination groups. The toxicity alleviation effect is manifested as an additive effect in each combined dose group.

Claims

1. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises orbitazine fumarate and temozolomide for combined use.

2. The pharmaceutical composition according to claim 1, wherein the dosage ratio of orbitazine fumarate and temozolomide is 450-800 mg / d:150-250 mg / m 2 .

3. Use of a pharmaceutical composition in a drug for treating brain glioma, wherein the pharmaceutical composition comprises the pharmaceutical composition according to any one of claims 1 to 2, and the brain glioma comprises anaplastic astrocytoma, anaplastic oligoastrocytoma, glioblastoma or gliosarcoma.

4. A preparation, wherein the preparation comprises the pharmaceutical composition according to any one of claims 1 to 2 and a pharmaceutically acceptable excipient.

5. The preparation according to claim 4, wherein the dosage form of the preparation comprises injection, tablet, granule or capsule.

6. The preparation according to claim 4, wherein the administration of orbitazine fumarate and temozolomide is one treatment cycle every 28 days.

7. The preparation according to claim 4, wherein the administration of orbitazine fumarate is a single or multiple administration for 28 consecutive days per treatment cycle.

8. The preparation according to claim 4, wherein the temozolomide is administered in multiple doses, continuous or discontinuous, per treatment cycle.

9. The preparation according to claim 4, wherein the temozolomide is administered continuously or discontinuously for 5-14 days in each treatment cycle.

10. Use of a preparation in treating brain glioma, the preparation comprising the preparation according to any one of claims 4 to 9, wherein the brain glioma comprises anaplastic astrocytoma, anaplastic oligoastrocytoma, glioblastoma or gliosarcoma.

11. Application of orbitazine fumarate in the treatment of brain glioma. 12 . The use according to claim 11 , wherein the brain glioma comprises anaplastic astrocytoma, anaplastic oligoastrocytoma, glioblastoma or gliosarcoma.

13. The use according to claim 11, wherein the administration of orbitazine fumarate is for 28 consecutive days per treatment cycle.

14. The use according to claim 11, characterized in that: The medicament comprises a therapeutically effective amount of orbitazine.

15. The use according to claim 14, wherein the dosage of orbitazine fumarate for adults is 384 mg / d-1152 mg / d, and preferably, the dosage of orbitazine fumarate for adults is 450 mg / d-800 mg / d.

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