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WO2022027239A1 - Use of primidone as pro-inflammatory cytokine inhibitor - Google Patents

Use of primidone as pro-inflammatory cytokine inhibitor Download PDF

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WO2022027239A1
WO2022027239A1 PCT/CN2020/106844 CN2020106844W WO2022027239A1 WO 2022027239 A1 WO2022027239 A1 WO 2022027239A1 CN 2020106844 W CN2020106844 W CN 2020106844W WO 2022027239 A1 WO2022027239 A1 WO 2022027239A1
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primidone
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treatment
pneumonia
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查运红
胡昕倩
何小燕
李敏
魏钧
牟彦
祝国锋
王君
赵海龙
黄明
余雅婕
张宏冰
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First People's Hospital Of Yichang People's Hospital Of China Three Gor
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    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

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  • the invention relates to the application of primidone as a pro-inflammatory cytokine inhibitor, belonging to the technical field of medicine.
  • Systemic inflammatory response syndrome is triggered by a series of sterile inflammations and is caused by severe damage to the body to infectious or non-infectious factors such as infection, trauma, burns, surgery, and ischemia-reperfusion.
  • the systemic non-specific inflammatory response eventually leads to a set of clinical symptoms manifested by the body's uncontrolled inflammatory response, including fever, tachycardia, shortness of breath, and increased peripheral blood leukocytes.
  • Its major pathological processes include a "cytokine storm” in which overproduction of pro-inflammatory cytokines such as TNF- ⁇ and IL-1 ⁇ triggers vascular dysfunction and organ damage.
  • Cytokine storm appears in chemotherapy, H1N1 infection, and novel coronavirus pneumonia. At present, there is no effective treatment plan for similar diseases in clinical practice. Generally, hormone therapy, antibiotic or antiviral therapy, and symptomatic and supportive therapy are used.
  • Sepsis is a systemic inflammatory response syndrome (SIRS) caused by infection, with clinically confirmed bacterial presence or highly suspicious infection foci.
  • SIRS systemic inflammatory response syndrome
  • drugs that can block TNF- ⁇ or IL-1R signaling in patients with systemic inflammatory response syndrome or sepsis are of great significance for the treatment of systemic inflammatory response syndrome and sepsis-related diseases.
  • cytokine storm that occurs in chemotherapy, H1N1 infection or new coronavirus pneumonia is an important mechanism for the transformation of chemotherapy patients, pneumonia patients, and new coronary pneumonia patients from mild to severe and critical. Inhibition of excessive cytokine storm is expected to prevent and treat sepsis in patients with new coronavirus pneumonia, inhibit inflammatory cytokine storm, and improve the survival prognosis of patients with new coronavirus pneumonia, and it is also expected to improve the survival prognosis of patients with chemotherapy and pneumonia.
  • Primidone English name: primidone, alias Missourin, primidone, primidone, is an odorless white crystalline powder chemical.
  • Primidone is an anti-epileptic drug, which is mainly used clinically for the single or combined treatment of tonic-clonic seizures (grand mal), simple partial seizures and complex partial seizures. It is also used in the treatment of essential tremor and senile tremor.
  • the technical problem to be solved by the present invention is to provide an application of primidone as a pro-inflammatory cytokine inhibitor.
  • the technical scheme adopted in the present invention is:
  • Pro-inflammatory cytokines include TNF- ⁇ and/or IL-1 ⁇ .
  • primidone as a therapeutic agent for systemic inflammatory response syndrome.
  • primidone as a cytokine storm inhibitor in chemotherapy, H1N1 infection or novel coronavirus pneumonia.
  • the invention has the following beneficial effects: using TNF- ⁇ tail vein injection to induce the mouse model of SIRS, primidone can significantly reduce the mortality rate and improve the hypothermia, thereby treating SIRS, sepsis, pneumonia and new coronary pneumonia .
  • the pathogenesis of sepsis, pneumonia, and new coronary pneumonia is the same as that of SIRS, so the discovery that primidone can act as a pro-inflammatory cytokine inhibitor is important for systemic inflammatory response syndrome, sepsis, pneumonia, new coronary pneumonia and other related diseases. Treatment is very important.
  • Fig. 1 is the accompanying drawing that primidone can significantly reduce the mortality of TNF- ⁇ -induced systemic inflammatory response syndrome mice and improve the lowering of body temperature in the present invention
  • Fig. 2 is the accompanying drawing showing that primidone in the present invention significantly reduces lung inflammation in SIRS mice.
  • This example discloses the application of primidone as a pro-inflammatory cytokine inhibitor.
  • Pro-inflammatory cytokines include TNF- ⁇ and/or IL-1 ⁇ .
  • primidone as a therapeutic agent for systemic inflammatory response syndrome.
  • primidone as a cytokine storm inhibitor in chemotherapy, H1N1 infection or novel coronavirus pneumonia.
  • FIG. 1A shows that primidone can significantly reduce the mortality of TNF- ⁇ -induced systemic inflammatory response syndrome mice
  • Figure 1B shows that primidone can improve the hypothermia of SIRS mice.
  • Vehicle group ie control group
  • Primidone group ie primidone group
  • Primidone group ie primidone group
  • PEG300 PEG300
  • SIRS was induced by tail vein injection of mTNF- ⁇ , and the survival rate of mice was counted at different times.
  • Data are presented in Tables 1 and 2, analyzed by Survival analysis (**p ⁇ 0.05, ***p ⁇ 0.005; ****p ⁇ 0.0001).
  • mice in the primidone treatment group had significantly less pulmonary inflammation, and the infiltration and exudation of inflammatory cells were significantly reduced.
  • primidone can treat pneumonia, new coronary pneumonia and other diseases with lung inflammation as the main symptom, and relieve the clinical symptoms of related diseases.
  • primidone can significantly reduce the mortality rate and improve the hypothermia of the mouse model of SIRS induced by TNF- ⁇ tail vein injection, thereby treating SIRS.

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Abstract

A use of primidone as a pro-inflammatory cytokine inhibitor; a use of primidone in inhibiting pro-inflammatory cytokines, the pro-inflammatory cytokines comprising TNF-α and/or IL-1β; and a use of primidone in treating systemic inflammatory response syndrome, sepsis, pneumonia and Covid-19.

Description

扑米酮作为促炎性细胞因子抑制剂的应用Application of primidone as pro-inflammatory cytokine inhibitor 技术领域technical field

本发明涉及一种扑米酮作为促炎性细胞因子抑制剂的应用，属于医药技术领域。The invention relates to the application of primidone as a pro-inflammatory cytokine inhibitor, belonging to the technical field of medicine.

背景技术Background technique

全身炎症反应综合征(systemic inflammatory response syndrome，SIRS)由一系列无菌炎症触发，是机体对感染、创伤、烧伤、手术以及缺血-再灌注等感染性或非感染性因素的严重损伤所产生的全身性的非特异性炎症反应，最终导致机体对炎症反应失控所表现的一组临床症状，包括发热、心动过速、呼吸急促和外周血白细胞增加等。其主要的病理过程包括“细胞因子风暴”促炎性细胞因子如TNF-α和IL-1β的过量产生会触发血管功能障碍和器官损伤。“细胞因子风暴”在化疗、H1N1感染、新型冠状病毒肺炎中出现。目前临床对于类似疾病的治疗尚无有效方案，一般进行激素治疗、抗生素或抗病毒治疗以及对症支持治疗等。Systemic inflammatory response syndrome (SIRS) is triggered by a series of sterile inflammations and is caused by severe damage to the body to infectious or non-infectious factors such as infection, trauma, burns, surgery, and ischemia-reperfusion. The systemic non-specific inflammatory response eventually leads to a set of clinical symptoms manifested by the body's uncontrolled inflammatory response, including fever, tachycardia, shortness of breath, and increased peripheral blood leukocytes. Its major pathological processes include a "cytokine storm" in which overproduction of pro-inflammatory cytokines such as TNF-α and IL-1β triggers vascular dysfunction and organ damage. "Cytokine storm" appears in chemotherapy, H1N1 infection, and novel coronavirus pneumonia. At present, there is no effective treatment plan for similar diseases in clinical practice. Generally, hormone therapy, antibiotic or antiviral therapy, and symptomatic and supportive therapy are used.

脓毒症(sepsis)是指由感染引起的全身炎症反应综合征(systemic inflammatory response syndrome,SIRS)，临床上证实有细菌存在或有高度可疑感染灶。Sepsis is a systemic inflammatory response syndrome (SIRS) caused by infection, with clinically confirmed bacterial presence or highly suspicious infection foci.

因此，能在全身炎症反应综合征或脓毒症患者中阻断TNF-α或IL-1R信号传导的药物，对于全身炎症反应综合征、脓毒症相关疾病的治疗具有十分重要的意义。Therefore, drugs that can block TNF-α or IL-1R signaling in patients with systemic inflammatory response syndrome or sepsis are of great significance for the treatment of systemic inflammatory response syndrome and sepsis-related diseases.

目前研究发现，化疗、H1N1感染或新型冠状病毒肺炎中出现的细胞因子风暴是化疗患者、肺炎患者、新冠肺炎患者由轻症向重症及危重症转化的重要机制。抑制过激的细胞因子风暴，有望防治新型冠状病毒肺炎患者脓毒症、抑制炎症细胞因子风暴、改善新型冠状病毒肺炎患者的生存预后，并且也有望改善化疗患者以及肺炎患者的生存预后。Current research has found that the cytokine storm that occurs in chemotherapy, H1N1 infection or new coronavirus pneumonia is an important mechanism for the transformation of chemotherapy patients, pneumonia patients, and new coronary pneumonia patients from mild to severe and critical. Inhibition of excessive cytokine storm is expected to prevent and treat sepsis in patients with new coronavirus pneumonia, inhibit inflammatory cytokine storm, and improve the survival prognosis of patients with new coronavirus pneumonia, and it is also expected to improve the survival prognosis of patients with chemotherapy and pneumonia.

扑米酮，英文名称：primidone，别名密苏林、扑痫酮、普里米酮，是一种无气味的白色结晶粉末化学品。化学名称5-乙基-5-苯基-二氢-4,6(1H,5H)-嘧啶 二酮，分子式为C 12H 14N 2O 2，分子量为325.4242，熔点281～282℃，略苦味道，无酸性，在乙醇中微溶，水、丙酮或苯中几乎不溶。 Primidone, English name: primidone, alias Missourin, primidone, primidone, is an odorless white crystalline powder chemical. Chemical name 5-ethyl-5-phenyl-dihydro-4,6(1H,5H)-pyrimidinedione, molecular formula is C 12 H 14 N 2 O 2 , molecular weight is 325.4242, melting point is 281-282 ° C, slightly Bitter taste, no acidity, slightly soluble in ethanol, almost insoluble in water, acetone or benzene.

扑米酮为抗癫痫药，临床上主要用于癫痫强直阵挛性发作(大发作)，单纯部分性发作和复杂部分性发作的单药或联合用药治疗。也用于特发性震颤和老年性震颤的治疗。Primidone is an anti-epileptic drug, which is mainly used clinically for the single or combined treatment of tonic-clonic seizures (grand mal), simple partial seizures and complex partial seizures. It is also used in the treatment of essential tremor and senile tremor.

发明内容SUMMARY OF THE INVENTION

本发明所要解决的技术问题是，提供一种扑米酮作为促炎性细胞因子抑制剂的应用。The technical problem to be solved by the present invention is to provide an application of primidone as a pro-inflammatory cytokine inhibitor.

为解决上述技术问题，本发明采用的技术方案为：In order to solve the above-mentioned technical problems, the technical scheme adopted in the present invention is:

扑米酮作为促炎性细胞因子抑制剂的应用。Use of primidone as a proinflammatory cytokine inhibitor.

扑米酮在抑制促炎性细胞因子中的应用。The use of primidone in inhibiting pro-inflammatory cytokines.

促炎性细胞因子包括TNF-α和/或IL-1β。Pro-inflammatory cytokines include TNF-α and/or IL-1β.

扑米酮作为TNF-α抑制剂的应用。Use of primidone as a TNF-α inhibitor.

扑米酮作为IL-1β抑制剂的应用。Use of primidone as an IL-1β inhibitor.

扑米酮作为TNF-α和IL-1β抑制剂的应用。Use of primidone as an inhibitor of TNF-α and IL-1β.

扑米酮在治疗全身炎症反应综合征中的应用。Application of primidone in the treatment of systemic inflammatory response syndrome.

扑米酮作为全身炎症反应综合征治疗药剂的应用。Application of primidone as a therapeutic agent for systemic inflammatory response syndrome.

扑米酮在治疗脓毒症中的应用。The application of primidone in the treatment of sepsis.

扑米酮作为脓毒症治疗药剂的应用。The use of primidone as a sepsis treatment agent.

扑米酮在治疗肺炎中的应用。The use of primidone in the treatment of pneumonia.

扑米酮作为肺炎治疗药剂的应用。The use of primidone as a therapeutic agent for pneumonia.

扑米酮在治疗新冠肺炎中的应用。The application of primidone in the treatment of new coronary pneumonia.

扑米酮作为新冠肺炎治疗药剂的应用。Application of primidone as a therapeutic agent for new coronary pneumonia.

扑米酮在治疗化疗、H1N1感染或新型冠状病毒肺炎中出现的细胞因子风暴中的应用。The use of primidone in the treatment of cytokine storms arising from chemotherapy, H1N1 infection or novel coronavirus pneumonia.

扑米酮作为细胞因子风暴抑制剂的应用。Use of primidone as a cytokine storm inhibitor.

扑米酮作为在化疗、H1N1感染或新型冠状病毒肺炎中出现的细胞因子风暴抑制剂的应用。The use of primidone as a cytokine storm inhibitor in chemotherapy, H1N1 infection or novel coronavirus pneumonia.

扑米酮在改善全身炎症反应综合征或脓毒症患者体温降低中的应用。The use of primidone in improving hypothermia in patients with systemic inflammatory response syndrome or sepsis.

扑米酮作为全身炎症反应综合征患者体温降低调节剂的应用。Use of primidone as a hypothermic regulator in patients with systemic inflammatory response syndrome.

扑米酮作为脓毒症患者体温降低调节剂的应用。本发明具有以下有益效果：采用TNF-α尾静脉注射诱导SIRS的小鼠模型，扑米酮可显著降低其死亡率，并改善其体温降低情况，从而治疗SIRS、脓毒症、肺炎以及新冠肺炎。Use of primidone as a hypothermic regulator in septic patients. The invention has the following beneficial effects: using TNF-α tail vein injection to induce the mouse model of SIRS, primidone can significantly reduce the mortality rate and improve the hypothermia, thereby treating SIRS, sepsis, pneumonia and new coronary pneumonia .

脓毒症、肺炎以及新冠肺炎与SIRS的发病机理相同，故扑米酮可作为促炎性细胞因子抑制剂这一发现对于全身炎症反应综合征、脓毒症、肺炎、新冠肺炎等相关疾病的治疗具有十分重要的意义。The pathogenesis of sepsis, pneumonia, and new coronary pneumonia is the same as that of SIRS, so the discovery that primidone can act as a pro-inflammatory cytokine inhibitor is important for systemic inflammatory response syndrome, sepsis, pneumonia, new coronary pneumonia and other related diseases. Treatment is very important.

附图说明Description of drawings

图1为本发明中扑米酮可显著降低TNF-α诱导的全身炎症反应综合症小鼠的死亡率以及改善其体温降低情况的附图；Fig. 1 is the accompanying drawing that primidone can significantly reduce the mortality of TNF-α-induced systemic inflammatory response syndrome mice and improve the lowering of body temperature in the present invention;

图2为本发明中扑米酮明显减轻SIRS小鼠肺部炎症的附图。Fig. 2 is the accompanying drawing showing that primidone in the present invention significantly reduces lung inflammation in SIRS mice.

具体实施方式detailed description

下面结合附图对本发明作更进一步的说明。The present invention will be further described below in conjunction with the accompanying drawings.

本实施例公开了扑米酮作为促炎性细胞因子抑制剂的应用。This example discloses the application of primidone as a pro-inflammatory cytokine inhibitor.

扑米酮在抑制促炎性细胞因子中的应用。The use of primidone in inhibiting pro-inflammatory cytokines.

促炎性细胞因子包括TNF-α和/或IL-1β。Pro-inflammatory cytokines include TNF-α and/or IL-1β.

扑米酮作为TNF-α抑制剂的应用。Use of primidone as a TNF-α inhibitor.

扑米酮作为IL-1β抑制剂的应用。Use of primidone as an IL-1β inhibitor.

扑米酮作为TNF-α和IL-1β抑制剂的应用。Use of primidone as an inhibitor of TNF-α and IL-1β.

扑米酮在治疗全身炎症反应综合征中的应用。Application of primidone in the treatment of systemic inflammatory response syndrome.

扑米酮作为全身炎症反应综合征治疗药剂的应用。Application of primidone as a therapeutic agent for systemic inflammatory response syndrome.

扑米酮在治疗脓毒症中的应用。The application of primidone in the treatment of sepsis.

扑米酮作为脓毒症治疗药剂的应用。The use of primidone as a sepsis treatment agent.

扑米酮在治疗肺炎中的应用。The use of primidone in the treatment of pneumonia.

扑米酮作为肺炎治疗药剂的应用。The use of primidone as a therapeutic agent for pneumonia.

扑米酮在治疗新冠肺炎中的应用。The application of primidone in the treatment of new coronary pneumonia.

扑米酮作为新冠肺炎治疗药剂的应用。Application of primidone as a therapeutic agent for new coronary pneumonia.

扑米酮在治疗化疗、H1N1感染或新型冠状病毒肺炎中出现的细胞因子风暴中的应用。The use of primidone in the treatment of cytokine storms arising from chemotherapy, H1N1 infection or novel coronavirus pneumonia.

扑米酮作为细胞因子风暴抑制剂的应用。Use of primidone as a cytokine storm inhibitor.

扑米酮作为在化疗、H1N1感染或新型冠状病毒肺炎中出现的细胞因子风暴抑制剂的应用。The use of primidone as a cytokine storm inhibitor in chemotherapy, H1N1 infection or novel coronavirus pneumonia.

扑米酮在改善全身炎症反应综合征或脓毒症患者体温降低中的应用。The use of primidone in improving hypothermia in patients with systemic inflammatory response syndrome or sepsis.

扑米酮作为全身炎症反应综合征患者体温降低调节剂的应用。Use of primidone as a hypothermic regulator in patients with systemic inflammatory response syndrome.

扑米酮作为脓毒症患者体温降低调节剂的应用。如图1所示，图1A为扑米酮可显著降低TNF-α诱导的全身炎症反应综合症小鼠的死亡率的附图，图1B为扑米酮可改善SIRS小鼠体温降低情况的附图，将20只8周龄C57BL/6分为Vehicle组(即对照组)(10只)、Primidone组(即扑米酮组)(10只)，分别提前30min给与PEG300、50mg/kg Primidone灌胃处理，后采用尾静脉注射mTNF-α诱导SIRS，并在不同时间统计小鼠存活率。数据见表1和表2，经Survival analyses分析(**p<0.05，***p<0.005；****p<0.0001)。Use of primidone as a hypothermic regulator in septic patients. As shown in Figure 1, Figure 1A shows that primidone can significantly reduce the mortality of TNF-α-induced systemic inflammatory response syndrome mice, and Figure 1B shows that primidone can improve the hypothermia of SIRS mice. Figure, 20 8-week-old C57BL/6 were divided into Vehicle group (ie control group) (10 animals), Primidone group (ie primidone group) (10 animals), and were given PEG300 and 50mg/kg Primidone 30min earlier After gavage treatment, SIRS was induced by tail vein injection of mTNF-α, and the survival rate of mice was counted at different times. Data are presented in Tables 1 and 2, analyzed by Survival analysis (**p<0.05, ***p<0.005; ****p<0.0001).

如图2所示，在SIRS模型小鼠以50mg/kg灌胃后，扑米酮治疗组小鼠与模型组小鼠相比，肺部炎症明显减轻，炎性细胞的浸润和渗出显著减少。提示了扑米酮可治疗肺炎、新冠肺炎等以肺部炎症为主要症状的疾病，缓解相关疾病的临床症状。As shown in Figure 2, after the SIRS model mice were given 50 mg/kg orally, compared with the mice in the model group, the mice in the primidone treatment group had significantly less pulmonary inflammation, and the infiltration and exudation of inflammatory cells were significantly reduced. . It is suggested that primidone can treat pneumonia, new coronary pneumonia and other diseases with lung inflammation as the main symptom, and relieve the clinical symptoms of related diseases.

表1.在mTNF-α诱导SIRS小鼠模型中不同处理小鼠存活只数比较Table 1. Comparison of surviving mice with different treatments in mTNF-α-induced SIRS mouse model

Figure PCTCN2020106844-appb-000001
Figure PCTCN2020106844-appb-000001

表2.在mTNF-α诱导SIRS小鼠模型中不同处理小鼠体温的比较(Mean±SD)Table 2. Comparison of body temperature of mice with different treatments in mTNF-α-induced SIRS mouse model (Mean±SD)

Figure PCTCN2020106844-appb-000002
Figure PCTCN2020106844-appb-000002

Figure PCTCN2020106844-appb-000003
Figure PCTCN2020106844-appb-000003

由此可见，采用TNF-α尾静脉注射诱导SIRS的小鼠模型，扑米酮可显著降低其死亡率，并改善其体温降低情况，从而治疗SIRS。It can be seen that primidone can significantly reduce the mortality rate and improve the hypothermia of the mouse model of SIRS induced by TNF-α tail vein injection, thereby treating SIRS.

由于SIRS与脓毒症的细胞因子风暴发病机理相同，故扑米酮可治疗脓毒症。Since SIRS and sepsis have the same pathogenesis of cytokine storm, primidone can treat sepsis.

以上所述仅是本发明的优选实施方式，应当指出：对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。The above is only the preferred embodiment of the present invention, it should be pointed out: for those skilled in the art, under the premise of not departing from the principle of the present invention, several improvements and modifications can also be made, and these improvements and modifications are also It should be regarded as the protection scope of the present invention.

Claims (9)

扑米酮作为促炎性细胞因子抑制剂的应用。Use of primidone as a pro-inflammatory cytokine inhibitor. 根据权利要求1所述的应用，其特征在于，扑米酮在抑制促炎性细胞因子中的应用。The use according to claim 1, wherein the use of primidone in inhibiting pro-inflammatory cytokines. 根据权利要求2所述的应用，其特征在于，促炎性细胞因子包括TNF-α和/或IL-1β。The use according to claim 2, wherein the pro-inflammatory cytokines include TNF-α and/or IL-1β. 根据权利要求1所述的应用，其特征在于，扑米酮在治疗全身炎症反应综合征中的应用。The application according to claim 1, wherein the application of primidone in the treatment of systemic inflammatory response syndrome. 根据权利要求1所述的应用，其特征在于，扑米酮在治疗脓毒症中的应用。The application according to claim 1, wherein the application of primidone in the treatment of sepsis. 根据权利要求1所述的应用，其特征在于，扑米酮在治疗肺炎中的应用。The application according to claim 1, wherein the application of primidone in the treatment of pneumonia. 根据权利要求1所述的应用，其特征在于，扑米酮在治疗新冠肺炎中的应用。The application according to claim 1, wherein the application of primidone in the treatment of new coronary pneumonia. 根据权利要求1所述的应用，其特征在于，扑米酮在治疗化疗、H1N1感染或新型冠状病毒肺炎中出现的细胞因子风暴中的应用。The application according to claim 1, characterized in that, the application of primidone in the treatment of cytokine storm occurring in chemotherapy, H1N1 infection or novel coronavirus pneumonia. 根据权利要求1所述的应用，其特征在于，扑米酮在改善全身炎症反应综合征或脓毒症患者体温降低中的应用。The application according to claim 1, characterized in that, the application of primidone in improving systemic inflammatory response syndrome or hypothermia in patients with sepsis.
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