Use of combination of olanzapine with quercetin in treating and / or ameliorating schizophrenia

Abstract

The present application relates to the field of pharmaceutical technology, and particularly, to use of a combination of olanzapine with quercetin in preparing a medicament for treating and / or ameliorating schizophrenia. According to the present application, the combination of olanzapine with quercetin can ameliorate hyperactivity, cognitive impairment, and perceptual disturbance caused by schizophrenia. The effect of the combination is significantly superior to that of olanzapine monotherapy. Also, according to the present application, quercetin can mitigate adverse effects induced by olanzapine during the treatment of schizophrenia, such as weight gain, increased food intake, and elevated blood glucose.

Description

Application of olanzapine combined with quercetin in the treatment and / or improvement of schizophrenia

[0001] This application claims priority to the Chinese patent application filed with the China Patent Office on October 24, 2023, with application number 202311381361.0 and invention name “Application of Olanzapine Combined with Quercetin in the Treatment and / or Improvement of Schizophrenia”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present application belongs to the field of pharmaceutical technology, and specifically relates to the use of olanzapine combined with quercetin in treating and / or improving schizophrenia. Background Art

[0003] Numerous studies have found that various flavonoid extracts exhibit multiple biological activities, including antioxidant, anti-inflammatory, hypoglycemic, hypolipidemic, and hypotensive properties, in both animal and human intervention studies. Quercetin, also known as quercetin or quercetin, is a typical natural flavonoid compound found widely in fruits and vegetables. Studies have shown that quercetin can increase the expression of glucokinase in diabetic rats, promoting glycogen synthesis and lowering blood sugar through the GSK-AKT pathway. Quercetin can also alter the hyperglycemic state of rats by promoting the expression of glucose transporters. Therefore, quercetin may have therapeutic effects on metabolic dysfunction caused by antipsychotic drugs.

[0004] Schizophrenia is a common mental illness with high prevalence, disability, and poverty rates, resulting in an average loss of 14.5 years of life expectancy. Schizophrenia has complex etiologies and is more common in young adults, most commonly between the ages of 16 and 40, severely impacting patients' daily lives. Currently, antipsychotics are the most effective treatment for schizophrenia. Compared to traditional antipsychotics, second-generation antipsychotics (SGAs) maintain efficacy while reducing the incidence of extrapyramidal and other adverse reactions, leading to their widespread use. These drugs primarily include clozapine, olanzapine, risperidone, quetiapine, and aripiprazole. They are effective for both positive and negative symptoms and rarely cause elevated prolactin and extrapyramidal side effects. However, they can be associated with adverse effects such as weight gain and metabolic syndrome. A meta-analysis showed that olanzapine is more likely to cause increased weight and BMI, as well as abnormal FPG, triglycerides, and HDL-C levels. Medication compliance is the key to treating schizophrenia, and adverse drug reactions can seriously affect medication compliance, so it is imperative to find ways to reduce the side effects of antipsychotic drugs.

[0005] Summary of the Invention

[0006] The present application provides the use of olanzapine combined with quercetin in the preparation of a drug for treating and / or improving schizophrenia. The combination of olanzapine and quercetin can treat and / or improve schizophrenia. At the same time, quercetin can also improve the metabolic dysfunction caused by olanzapine in the treatment of schizophrenia.

[0007] To solve the above technical problems, this application provides the following technical solutions:

[0008] The present application provides the use of olanzapine combined with quercetin in the preparation of a drug for treating and / or improving schizophrenia.

[0009] The present application provides the use of olanzapine combined with quercetin in the preparation of a drug for improving metabolic disorders in schizophrenia.

[0010] The present application provides a drug for treating schizophrenia, which comprises olanzapine and quercetin. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 Effects of MK-801 on the activity of mice (a: total movement distance, b: average movement speed in the peripheral area, c: total rest time, d: number of transitions).

[0012] Figure 2 Effects of MK-801 on cognitive function in mice (e: exploration time, f: exploration index).

[0013] Figure 3 Effects of MK-801 on sensory gating function in mice (g: prepulse inhibition rate).

[0014] Figure 4. Results of olanzapine combined with quercetin improving hyperactivity in MK-801 mice (a: total distance traveled, b: average locomotor speed in the peripheral area, c: total rest time, d: number of transitions).

[0015] Figure 5 Results of olanzapine combined with quercetin improving cognitive impairment in MK-801 mice (e: exploration time, f: exploration index).

[0016] Figure 6 shows the results of olanzapine combined with quercetin improving the sensory gating function of MK-801 mice (g: prepulse inhibition rate).

[0017] Figure 7 Quercetin improves the weight gain of olanzapine-induced model mice.

[0018] Figure 8: Quercetin improves the increased food intake of model mice induced by olanzapine.

[0019] Figure 9 shows the results of quercetin improving the increased blood glucose in model mice induced by olanzapine. DETAILED DESCRIPTION

[0020] This application provides the use of olanzapine combined with quercetin in the preparation of a drug for treating and / or ameliorating schizophrenia. The olanzapine combined with quercetin described in this application improves MK-801-induced hyperactivity, cognitive impairment, and perceptual impairment in mice, demonstrating significant efficacy in ameliorating and / or treating schizophrenia.

[0021] This application provides the use of olanzapine combined with quercetin in the preparation of a drug for ameliorating metabolic disorders in schizophrenia. The quercetin described in this application improves olanzapine-induced weight gain, increased food intake, and increased blood sugar, and has a significant therapeutic effect on metabolic disorders caused by olanzapine in the treatment of schizophrenia.

[0022] In the present application, the dosage of quercetin is 45-110 mg / kg, preferably 50-100 mg / kg; the dosage of olanzapine is 1-10 mg / kg, preferably 3-8 mg / kg.

[0023] The application also provides a medicine for treating schizophrenia, and the medicine includes olanzapine and quercetin. The medicine described in the application also includes a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier described in the application includes but is not limited to isotonicity agents, buffers, flavoring agents, excipients, fillers, adhesives, disintegrants, lubricants, emulsifiers, solubilizers, antibacterial agents, analgesics and antioxidants, etc., and this type of adjuvant can effectively improve the stability and solubility of the compound in pharmaceutical preparations or change the release rate and absorption rate of the compound, so as to improve the metabolism of the compound in the organism, and then enhance the administration effect of the composition. The dosage form of the medicine described in the application includes but is not limited to tablets, granules, capsules, pills, injections, sustained-release agents, aqueous powder injections, powders, patches, suppositories, emulsions, creams, gels, aerosols, sprays, powder mists, sustained-release agents or controlled-release agents, etc., preferably tablets, granules, capsules, pills, injections.

[0024] In this application, unless otherwise specified, all raw material components are commercially available products well known to those skilled in the art. Beneficial effects:

[0025] This application combines olanzapine and quercetin to improve hyperactivity, cognitive impairment, and perceptual impairment caused by schizophrenia, and the effect of the two drugs combined is significantly better than olanzapine. At the same time, the quercetin described in this application can improve the metabolic damage caused by schizophrenia, and can also improve the adverse reactions such as weight gain, increased food intake, and increased blood sugar caused by olanzapine in the treatment of schizophrenia, indicating that quercetin has good prospects in alleviating metabolic dysfunction caused by second-generation antipsychotic drugs. No relevant research has been found to show that quercetin can reduce metabolic dysfunction caused by antipsychotic drugs.

[0026] The present application will be further described below with reference to the accompanying drawings and embodiments.

[0027] Unless otherwise specified, the methods used in the following examples are all conventional methods.

[0028] Example 1 Effect of olanzapine combined with quercetin on schizophrenia

[0029] 1. Construction of a schizophrenia-like mouse model

[0030] Animals: 6-week-old C57BL / 6 mice were provided by Henan Sikebes Biotechnology Co., Ltd., animal certificate numbers: 410983221100034856, 410983221100057087, and 370726221100374687.

[0031] Female C57BL / 6J mice (6 weeks old, weighing 19 ± 1 g) were randomly divided into two groups. The control group received intraperitoneal injections of normal saline, while the experimental group received intraperitoneal injections of 0.1 ml / 10 g (dose 0.6 mg / kg) of dizocillin (MK-801) for 14 consecutive days. MK-801 was provided by Sigma. Mice were housed in cages (two per cage) under controlled environmental conditions (22°C, 70% humidity, specific pathogen-free, 12 / 12 h light / dark cycle) and allowed free access to food and water.

[0032] Groups: normal saline group (Control group) and MK-801 group, intraperitoneal injection was performed continuously for 14 days according to body weight.

[0033] Methods: 24 hours after the last administration, the mice were behaviorally evaluated to see whether the model was successfully established.

[0034] Open field test (OFT): Each group of mice was placed in the behavioral measurement room three hours in advance for acclimatization. The test room was located in a black square acrylic box (50*50*50cm). The test mice were allowed to move freely in the box for 15 minutes, with the first five minutes being the acclimatization phase and the last 10 minutes being the recording phase. The movement trajectory and distance of the mice were recorded using Smart 3.0. To eliminate the odor left by the previous mice, the experimental area was wiped with 75% alcohol before each mouse was tested to reduce olfactory cues.

[0035] The novel object recognition (NORT) task is used to assess memory consolidation and depends on the ability of rodents to explore new objects rather than familiar objects in the absence of external reinforcement. During training, each mouse was placed in the center of an open rectangular arena and acclimated for 5 minutes. The next day, a familiarization test was performed, in which each animal in the experimental group was exposed to two identical objects placed in the apparatus for 5 minutes. After 1 hour, the animals were exposed to the two objects again, and in the second (choice) test, one of the objects was replaced by a new object. In both tests, exploration of each object was defined as sniffing, licking, chewing, or having active whiskers while pointing the nose ≤ 1 cm away from the object. The objects and experimental arena were wiped with 75% ethanol between trials to reduce olfactory cues. The novel object recognition index (NOI) of mice = time exploring the novel object / (time exploring the novel object + time exploring the familiar object) × 100%.

[0036] The prepulse inhibition test (PPI) is a commonly used method to detect sensory gating function in animal models of schizophrenia. Mice are placed in a shock box in the test box, which is connected to a dynamic sensor to record the amplitude of the mouse's shock. The test box is soundproof and lightproof, and has a built-in speaker that can produce sound stimuli of different intensities. The environment is kept quiet throughout the experiment. The experiment set up background noise (65dB), prepulse stimulation (73dB, 77dB, 81dB) and shock stimulation (120dB). The whole process includes four stages: adaptation period and Block 1-3. During the adaptation period, mice adapt to the background noise of 65dB for 5 minutes to reduce the interference of background noise on the results. In Block 1, a 120dB shock stimulus is given for a total of 10 times. Block 2 consisted of six patterns: ① 65dB background noise alone; ② 120dB startle stimulus alone; ③ 73dB, 77dB, or 81dB prepulse stimulus alone; ④-⑥ 73dB, 77dB, or 81dB prepulse stimulus followed by a 120dB startle stimulus with a 100ms interval. These six patterns were presented pseudo-randomly for a total of 40 times. The strength of the prepulse inhibition (PPI) was measured as follows: PPI% = (response amplitude to the startle stimulus - response amplitude to the prepulse combined with the startle stimulus) / response amplitude to the startle stimulus × 100%.

[0037] Results from the open field test showed that MK-801-treated mice exhibited increased movement distance and speed, and decreased rest time (Figure 1). In the novel object recognition test, the exploration time and exploration index of MK801-injected mice were significantly lower than those of the control group (Figure 2). Prepulse inhibition experiments showed that the PPI% of 73, 77, and 81 dB prepulses combined with a 120 dB pulse were significantly higher in MK801-injected mice compared to the control group (Figure 3). In summary, MK-801-injected mice exhibited schizophrenia-like behaviors.

[0038] 2. Olanzapine combined with quercetin improves schizophrenia-like behavior in MK-801 mice

[0039] Grouping: Mice injected with MK-801 were randomly divided into the following four groups: (a) Vehicle group (MK group): vehicle at the corresponding dose; (b) O group: 6 mg / kg olanzapine; (c) O+Q(l): 6 mg / kg olanzapine + 50 mg / kg quercetin; (d) O+Q(h): 6 mg / kg olanzapine + 100 mg / kg quercetin; Control group: saline. Mice were orally administered with the corresponding doses of drugs and saline daily for 6 consecutive weeks.

[0040] Methods: After the last administration of drug or saline, the mice were tested for behavior (open field test, novel object recognition test, prepulse inhibition test).

[0041] The experimental procedures for improving hyperactivity in MK-801 mice by combining olanzapine with quercetin refer to the open field test in step 1 of this example; the experimental procedures for improving cognitive impairment in MK-801 mice by combining olanzapine with quercetin refer to the novel object recognition test in step 1 of this example; the experimental procedures for improving sensory gating function impairment in MK-801 mice by combining olanzapine with quercetin refer to the prepulse inhibition test in step 1 of this example.

[0042] The above experimental results show that olanzapine combined with quercetin treatment does not affect the efficacy of olanzapine itself. In addition, combined quercetin treatment may be more effective than olanzapine treatment alone. For example, in the open field test, the total movement distance and peripheral movement speed of mice treated with combined drugs decreased, and the total rest time was extended more significantly (Figure 4). In the new object recognition experiment, compared with olanzapine alone, the exploration time and exploration index of mice in the combined quercetin treatment group increased (Figure 5). In addition, in the prepulse inhibition experiment, the PPI% of mice in the olanzapine combined with quercetin treatment group with 73, 77, and 81dB prepulses combined with 120dB pulses increased (Figure 6).

[0043] Example 2 Effect of Quercetin on Olanzapine-Induced Metabolic Dysfunction in Schizophrenia

[0044] 1. Statistics of experimental data on the effect of quercetin on the weight gain of model mice induced by olanzapine: The weight of each group of mice in Example 1 was recorded at 9:00 am every day, and the average weight of the mice was calculated after 2 weeks, 4 weeks, and 6 weeks.

[0045] 2. Quercetin improves olanzapine-induced increased food intake in model mice. Experimental data statistics: For each group of mice in Example 1, two mice were placed in a cage. The food intake of the mice was recorded at 9:00 am every day, and the average food intake of each group was calculated.

[0046] 3. Experimental Study on Quercetin's Effect on Improvement of Olanzapine-Induced Hyperglycemia in Mice: Blood glucose was measured using a Roche blood glucose meter and active blood glucose test strips. An oral glucose tolerance test (OGTT) was performed 24 hours after the last oral administration of 2g / kg glucose solution. After a 12-hour fast, blood was collected from the tail tip (baseline, 0 hours). The first drop of blood was discarded, and the second drop was used for blood glucose testing.

[0047] These experimental results show that olanzapine can cause increases in body weight, food intake, and blood sugar, but combined treatment with quercetin can alleviate metabolic disorders. Combining olanzapine with quercetin, especially high-dose quercetin, can significantly alleviate abnormal increases in body weight, food intake, and blood sugar (Figures 7-9).

[0048] In summary, the above experiments show that olanzapine combined with quercetin can alleviate the metabolic dysfunction caused by olanzapine without affecting its efficacy. Therefore, quercetin has good prospects in alleviating the metabolic dysfunction caused by second-generation antipsychotic drugs.

[0049] The above is only a preferred embodiment of the present application. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present application. These improvements and modifications should also be regarded as the scope of protection of the present application.

Claims

1. Use of olanzapine combined with quercetin in the preparation of drugs for treating and / or improving schizophrenia.

2. The use according to claim 1, characterized in that Olanzapine combined with quercetin improves hyperactivity, cognitive impairment, and perceptual disturbances caused by schizophrenia.

3. Application of olanzapine combined with quercetin in the preparation of drugs for improving metabolic disorders in schizophrenia.

4. The use according to claim 3, characterized in that Quercetin improved olanzapine-induced weight gain, increased food intake, and increased blood sugar.

5. The use according to any one of claims 1 to 4, characterized in that: The dosage of the quercetin is 45-110 mg / kg, and the dosage of the olanzapine is 1-10 mg / kg.

6. The use according to claim 5, characterized in that The dosage of the quercetin is 50-100 mg / kg, and the dosage of the olanzapine is 3-8 mg / kg.

7. A drug for treating schizophrenia, characterized in that: The drugs include olanzapine and quercetin.

8. The drug according to claim 7, characterized in that The medicament further includes a pharmaceutically acceptable carrier.

9. The drug according to claim 7, characterized in that The dosage form of the drug includes tablets, granules, capsules, pills, injections or sustained-release preparations.

Images