阅读说明：本技术 脱水亚硝基尼索地平在制备防治脓毒症的药物中的应用 (Application of dehydrated nitrosonisoldipine in preparation of medicine for preventing and treating sepsis ) 是由 高翔 林兆宇 王鼎玉 陈芊月 郑嘉烁 于 2019-12-16 设计创作，主要内容包括：本发明属于医药领域,涉及脱水亚硝基尼索地平(dehydronitrosonisoldipine,NTS)在制备防治脓毒症的药物中的应用,其中所述的脓毒症既包括内毒素血症,也包括多细菌感染性的脓毒症。具体机制涉及NTS对细胞焦亡(pyroptosis)的抑制。该应用中所述的药物为腹腔注射液,注射液的剂量范围是14.8～44.4mg/kg体重。在脓毒症小鼠模型中,该药物能抑制血浆炎症因子的表达、延长小鼠生存时间、提高小鼠生存率。(The invention belongs to the field of medicines, and relates to application of dehydrated Nitrosonisoldipine (NTS) in preparation of a medicine for preventing and treating sepsis, wherein the sepsis comprises endotoxemia and multiple-bacterium infectious sepsis. A particular mechanism involves the inhibition of cellular apoptosis (pyroptosis) by NTS. The medicine in the application is an intraperitoneal injection, and the dosage range of the injection is 14.8-44.4 mg/kg of body weight. In a sepsis mouse model, the medicament can inhibit the expression of plasma inflammatory factors, prolong the survival time of mice and improve the survival rate of mice.)

1. Application of dehydrated nitrosonisoldipine in preparing medicine for preventing and treating sepsis is provided.

2. Use according to claim 1, wherein the sepsis endotoxemia or multiple bacterial infectious sepsis.

3. Application of dehydrated nitrosonisoldipine in preparation of cell apoptosis inhibitor is provided.

4. Application of dehydrated nitrosonisoldipine in preparing sepsis anti-inflammatory drug is provided.

Technical Field

The invention belongs to the field of medicine, and relates to a prevention and treatment effect of dehydrated Nitrosonisoldipine (NTS) on sepsis; a particular mechanism involves NTS ameliorating the inflammatory state of the body by inhibiting cellular apoptosis (pyroptosis).

Background

Sepsis (sepsis) is a serious complication of surgical infection and the most lethal disease in intensive care units; on average, one death occurs in every four sepsis patients; approximately 3150 million sepsis occurs worldwide each year, with 530 million people lost to sepsis. The pathological process of sepsis is extremely complex and until the last thirty years, it has not been generally understood. The pathological process of sepsis can be divided into two stages, an early inflammatory storm stage and a late immunosuppressive stage. Early inflammatory storms begin with an excessive response of the innate immune system to autologous damaged tissues and pathogens that is beyond the control of the immune system and forms an inflammatory storm under the effect of cascade amplification. The immunosuppression at the late stage is manifested by paralysis of the immune system, which is insensitive to the stimulation of pathogens; this is closely related to immune depletion and cell death caused by early inflammatory storms.

Cell apoptosis is a new programmed cell death mode discovered in recent years, and mainly occurs in professional phagocytes such as macrophages, monocytes, DCs, neutrophils and the like. Unlike apoptosis (apoptosis), when a cell is burnt out, the whole cell membrane is burst and releases a large amount of proinflammatory factors; of all necrotic cell deaths, the induction of cellular apoptosis is most rapid and the inflammatory response activated is also most violent. A great deal of research has been carried out to show that cell apoptosis plays an important driving role in the inflammatory storm stage of sepsis, and related genes of an apoptosis signal pathway are knocked out, so that the prognosis of a mouse model of sepsis can be improved (Kayagaki N, Stowe I B, Lee B L, et al, caspase-11 clear gasdermin D for non-cancerous inflaming signalling [ J ]. Nature,2015,526(7575): 666-71; Hagar JA, Powe D A, Aachoui Y, et al, cytoplastic LPS activity caspase-11: ligands in TLR 4-indendependental oxosample [ J ]. Science,2013, 341(6151): 1250-3).

NTS is a major component of the photolysis product of the dihydropyridine calcium antagonist nisoldipine (nisoldipine).

The drug toxicity of NTS has been reported in the literature (preparation and pharmacological action of photolysis products of nisoldipine [ J ]. proceedings of hebei medical university, 1990, (1): 8-9). The study showed that NTS had less toxic side effects than nisoldipine itself. In the mouse gavage experiment, nisoldipine is used at the dose of 300mg/kg body weight, so that 10 mice die completely; however, NTS does not cause death of one mouse at a dose of 300-2000 mg/kg (10 mice in total). In the intraperitoneal experiment, nisoldipine causes 7/10 mice to die at a dose of 100mg/kg, while NTS only causes 1/10 mice to die at the same dose (100 mg/kg). The research shows that the toxic and side effects of NTS are small, but the effects of the geniposide and the NTS in the aspects of inhibiting the apoptosis of cells and preventing and treating sepsis are not reported at present.

Disclosure of Invention

The invention aims to provide application of NTS in preparation of medicines.

The invention discloses an application of dehydrated nitrosonisoldipine in preparing a medicament for preventing and treating sepsis.

Sepsis in the context of the present invention includes endotoxemia and also sepsis of multiple bacterial infections.

The invention provides an application of NTS in preparation of a cell apoptosis inhibitor.

The invention provides application of NTS in preparation of sepsis anti-inflammatory drugs.

The invention provides a dosage range of NTS when used as an intraperitoneal injection for preventing and treating sepsis, namely 14.8-44.4 mg/kg of body weight.

The invention provides application of NTS in preparation of a medicament for preventing and treating sepsis, and particularly relates to inhibition of NTS on cell apoptosis (pyroptosis). In a sepsis mouse model, the medicament can inhibit the expression of plasma inflammatory factors, prolong the survival time of mice and improve the survival rate of mice.

Drawings

FIG. 1 shows that NTS inhibits endotoxin-induced apoptosis of THP-1 cells of the human monocyte cell line.

FIG. 2 shows that NTS inhibits Nigeria toxin-induced apoptosis of iBMDM cells in mouse macrophage cell line.

Figure 3 is the survival of mice with LPS-improved sepsis.

FIG. 4 is IL-1 β from mice with LPS-improved sepsis by NTS.

FIG. 5 is IL-6 improvement by NTS in LPS septic mice.

FIG. 6 is TNF- α from mice with LPS-improved sepsis by NTS.

Figure 7 is a graph of NTS extended survival of multiple bacterial infected septic mice.

FIG. 8 is an example of the improvement of IL-1 β by NTS in polybacterial infected septic mice.

FIG. 9 is IL-6 from a polybacterial infected septic mouse that was not affected by NTS.

FIG. 10 is TNF- α from a polybacterial infected septic mouse that was not affected by NTS.

Detailed Description