CN104688727A - Application of artesunate in preparing medicine for treating middle-late sepsis - Google Patents
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Abstract
The invention discloses application of artesunate in treating middle-late sepsis. The artesunate can promote proinflammatory factors, activate the immune function and effectively lower the death rate, caused by secondary strike of germs, of middle-late sepsis patients.
Description
Technical field
The invention belongs to field of medicaments, be specifically related in Artesunate, late period pyemic purposes.
Background technology
Sepsis (sepsis) is the systemic inflammatory response syndrome (SIRS) caused by infective agent, be the common complication of the critically ill patients such as War injury, burn, severe patient occurs that septic shock, multiple organ dysfunction syndrome (MODS) are even dead.Sepsis disease progression is rapid, case fatality rate is high, it is the major reason causing the personnel reduction in wartime or burn patient death, the generation of timely diagnosis of sepsis disease and disease progression thereof, and take effectively to give treatment to measure, significant to the survival rate improving sepsis patient.
In early days the research of pathogenesis of sepsis mechanism is shown, pyemic generation activates with the innate immune system that infective agent or severe tissue damage are induced thus to cause inflammatory mediator excessively to discharge relevant, and the activation of complement system and the overactivity of cellular immunization are pyemic features.Wherein being present in the total genomic DNA (CpGDNA) of the lipopolysaccharide (LPS) on Grain-negative Mycoderma, the Peptidoglycan (PGN) of gram positive bacteria, gram-negative bacteria and positive bacteria is all the important virulence factor of antibacterial, equal innate immune system of inducing activates, thus cause a large amount of releases of inflammatory mediator, the generation of incite inflammation storm, finally causes septic shock even dead.Clinical research shows, inflammatory factor IL-6, IL-8, TNF-α, IL-1 obviously raise in sepsis patient blood plasma, and CD11b/CD18, HLA-DR etc. also obviously increase, and is the early stage comparatively sensitive indicator of sepsis.The prognosis of sepsis patient can not be improved based on monoclonal antibody, the glucocorticoid etc. " immunosuppressant " such as inflammatory mediator TNF-α, IL-1 of " antiinflammatory theoretical " and anti-inflammatory treatment measure, even make case fatality rate increase.Above-mentioned situation illustrates, only excessive inflammation is not pyemic essence and all processes.
Recent study confirms, in pyemic generation evolution, cause inflammation and be in shifting process with antiinflammatory network factors, therefore body is not in excessive inflammation state always.As far back as the nineties, have clinical research to show, sepsis patient can enter immunosuppressive condition after excessive inflammation state.Along with going deep into of research, the immunosuppressive condition of sepsis patient more and more comes into one's own: immunosuppressant causes the sepsis patient main causes of death after accepting such as antibacterial, fungus etc. " two-hit ".
Research finds, the water fall effect of inflammatory mediator, the normal stress of body will be inspired, namely the activation of body anti-inflammatory mechanisms is caused, cause anti-inflammatory factors significantly to raise, proinflammatory factor obviously reduces, and makes antiinflammatory/proinflammatory factor unbalance, make body immune system occur immunosuppressant, as neutrophilic granulocyte paralysis, Th1 cell increase to Th2 transformation, lymphocyte and dendritic cell apoptosis thereupon.Find after performing an autopsy on sb. to the sepsis patient of death in recent years, the sepsis later stage shows as serious immunological paralysis: the expression of patient's splenocyte and pulmonary epithelial cells surface C D4, CD8, costimulatory molecules CD28 and HLA-DR obviously reduces and even lacks; In patient, late period time, the inflammatory factors such as TNF-α, IL-6, IL-1 and γ-IFN obviously reduce, and the anti-inflammatory factors such as IL-10 obviously raise.When immunosuppressant or immunological paralysis, body can not effectively be removed constitutional pathogenic microorganism, easily suffer the two-hit of the conditioned pathogen such as Pseudomonas aeruginosa, escherichia coli, staphylococcus aureus, cause organismic internal environment further disorderlyly, serious will cause septic shock, multiple organ failure, MOF finally causes death.Therefore, for sepsis patient immunosuppressive condition, not only effect is not had with the therapeutic strategy blocking inflammatory reaction and Immunosuppression, cause that sb.'s illness took a turn for the worse, the increase of mortality rate on the contrary, so judge accurately to have very important significance to the pyemic cure rate of raising to the sepsis patient state of an illness.Therefore, based on sepsis patient immunological paralysis in late period state research and development new drug, likely become effective antagonism sepsis and reduce the available strategy of mortality rate.
Arteannuin and derivant thereof are used for treating as artesunate the history that heating that malaria is correlated with has had more than 1,000 year, are mainly used in drug resistance pernicious malaria clinically now.Efferth TM, Wang X etc. are at its article " Antiviral activity of artesunate towards wild-type, recombinantandganciclovir-resistant human cytomegalovimses " (J Mol Med.2002; 80 (4): p223-224) describe Herba Artemisiae Annuae class material in and also have as relievingd asthma, anticancer, schistosomicide and to effects such as immune adjustments.Both at home and abroad about the research of arteannuin and derivant thereof mainly concentrates on malaria, anticancer, antischistosomal Function and its mechanisms.
Li Chunying etc. are at its article " inhibitory action of the nitric oxide synthesis of artesunate induced by endotoxin induction " (CHINA JOURNAL OF CHINESE MATERIA MEDICA .2001; 26 (11): p770-773.) describing artemisinin derivative artesunate in stimulates the synthesis of Turnover of Mouse Peritoneal Macrophages NO to have obvious inhibitory action to LPS and merging interferon; to the Turnover of Mouse Peritoneal Macrophages RAW264.7 that LPS stimulates, also there is similar protective effect, and the inhibitory action that NO synthesizes also is strengthened along with the increase artesunate of artesunate concentration.Beam Aiwa, Xue Baoyun, Wang Jinhua etc. are at its article " inflammatory factor of artesunate induced by endotoxin induction synthesizes inhibiting research " (Chinese combination of Chinese and Western medicine first aid magazine .2001; 8 (5): p262.-265) describing artesunate in and have obvious inhibitory action at 25 ~ 100mg/L to the TNF-α generation that LPS induces, is 43% ~ 58% with the independent Application comparison suppression ratio of LPS.
The open arteannuin of CN1833644 and derivant thereof are as artesunate pepperyly can reduce colibacillus deactivating to septicopyemia, antibacterial attacks (comprising Grain-negative, positive bacteria) mice mortality rate; mice serum cytokine TNF-α and IL-6 significantly can be suppressed to discharge, and to the main organs (heart, liver, intestinal, lung, kidney) of colibacillus deactivating, germ attack mice, there is remarkable protective effect.But this research still excessively discharges the stage based on sepsis early metaphase inflammatory mediator, artesunate plays therapeutic effect mainly through the release of the inflammation-inhibiting factor.
The middle and advanced stage of sepsis patient after excessive inflammation state, enters immunosuppressive condition, and now, the inflammatory factors such as TNF-α, IL-6, IL-1 and γ-IFN obviously reduce, and the anti-inflammatory factors such as IL-10 obviously raise.When immunosuppressant or immunological paralysis, body can not effectively be removed constitutional pathogenic microorganism, easily suffer the two-hit of the conditioned pathogen such as Pseudomonas aeruginosa, escherichia coli, staphylococcus aureus, cause organismic internal environment further disorderlyly, serious will cause septic shock, multiple organ failure, MOF finally causes death.Along with going deep into of research, the immunosuppressive condition of sepsis patient more and more comes into one's own: immunosuppressant causes the sepsis patient main causes of death after accepting such as antibacterial, fungus etc. " two-hit "..Therefore, based on sepsis patient immunological paralysis in late period state research and development new drug, likely become effective antagonism middle and advanced stage sepsis and reduce the available strategy of mortality rate.
Summary of the invention
The object of this invention is to provide a kind of artesunate in the purposes prepared in treatment middle and advanced stage medication for treating pyemia or utilization.
Specifically, object of the present invention be exactly during artesunate is used for the treatment of or late period pyemic purposes, particularly treat late period pyemic purposes.
Purposes of the present invention, artesunate is in the purposes manufactured in treatment mid-term or late period medication for treating pyemia or utilization.
The purposes of the invention described above, described sepsis is preferably pus disease patient in late period.
The purposes of the invention described above, described mid-term or late period sepsis refer to the state that the inflammatory factor secretion in sepsis patient body obviously reduces, or refer to that the immunity of sepsis patient is suppressed or immunity is in palsy.
Pathological research finds that middle and advanced stage sepsis patient is after inflammatory factor excessively discharges, inflammatory factor obviously reduces, fuselage immunologic function is suppressed or immunity is in palsy, now, body can not effectively be removed constitutional pathogenic microorganism, easily suffer the two-hit of the conditioned pathogen such as Pseudomonas aeruginosa, escherichia coli, staphylococcus aureus, cause organismic internal environment further disorderlyly, serious will cause sepsis patient shock, multiple organ failure, MOF finally causes death.The discovery that the present inventor is surprised, artesunate is when fuselage immunologic function is suppressed or immunity is in palsy, the no longer release of the inflammation-inhibiting factor, the release promoting inflammatory factor on the contrary, recover or elevator body immunity function, thus improve body to the opposing of Pseudomonas aeruginosa, escherichia coli, staphylococcus aureus, body effectively can be prevented to suffer the two-hit of antibacterial, fungus etc., reduce sepsis patient mortality rate.
Accompanying drawing explanation
The content of the inflammatory factor of each matched group of Fig. 1 embodiment 2.
The content of the lung of the LPS tolerant mice of Fig. 2 embodiment 4, spleen and the serum inflammatory factor.
The LPS tolerant mice of Fig. 3 embodiment 5 suffers the mortality rate after antibacterial two-hit.
In Fig. 4 embodiment 6, LPS tolerant mice suffers the quantity of antibacterial PA in lung after antibacterial two-hit, spleen, serum.
Detailed description of the invention
Following examples are used for further describing and understanding the present invention, and do not limit the scope of the invention.
Embodiment 1 screens the fatal dose of LPS
120 mices are divided into 6 groups, and often organize 20, often organize respectively by 10,20,30,40,50 and 80mg/kg intravenous injection LPS, observe and respectively organize viable counts in 7 days, and screening LPS causes the lowest dose level of normal mouse 100% death.The results are shown in Table 1, experimental result is known: 50mg/kg of LPS can cause normal mouse 100% dead.
Table 1 accepts the amount of survival of mice every day in 7 days of various dose LPS
Embodiment 2 sets up LPS tolerant mice model
Mice is divided into 3 groups, often organize mice 6, one group of LPS giving (lumbar injection) 0.3mg/kg every day, one group give the LPS of (lumbar injection) 1.0mg/kg every day, give the LPS of (lumbar injection) 3.0mg/kg one group of every day, give pre-LPS 3 days continuously, 4th day each group of LPS all giving (lumbar injection) 50mg/kg, to observe after injection LPS each group mouse survival quantity in 7 days.The results are shown in Table 2.
The burst size of LPS tolerant mice inflammatory factor: get mice 24, be divided into 4 groups, often organize mice 6, normal group (NS), gives the normal saline of same volume; LPS (0.3) group: inject LPS by 0.3mg/kg, for three days on end, the 4th day lumbar injection 50mg/kg LPS; LPS (50) group: the normal saline giving same volume, for three days on end, the 4th day lumbar injection 50mg/kg LPS.Each group of the 12nd hour of giving the last time after LPS, gets the lung (A) of mice, spleen (B) and serum (C), detects inflammatory factor IL-1 β, the expression of IL-6 and TNF-α.The results are shown in Figure 1A (in lung inflammatory Cytokines Expression amount), Figure 1B (in spleen inflammatory Cytokines Expression amount), Fig. 1 C (in blood inflammatory Cytokines Expression amount), *, p<0.05 and in figure
*, p<
p<0.01 vs LPS (50).
After the administration of table 2 LPS tolerant mice group, in 7 days, each group mice to survive number every day
Experimental result from table 2 and Fig. 1: compare with LPS50 group, LPS0.3+LPS50 (tolerance group) mouse death rate is 0%, and in lung, spleen, blood, the expression of inflammatory factor IL-1 β, IL-6 and TNF-α obviously reduces.Result shows to adopt the continuous lumbar injection of 0.3mg/kg/day LPS 3 days, within the 4th day, adopts fatal dose 50mg/kg LPS can successfully set up LPS Tolerance Model.Therefore, LPS0.3+LPS50 group is selected to be LPS tolerant mice model.According to the result of table 2 and Fig. 1, determine that LPS (0.3+50) group is LPS tolerant mice model, below by LPS tolerant mice model referred to as " LPS tolerant mice ".
The sensitivity of embodiment 3 LPS tolerant mice antibacterial
Normal mouse 8 groups (NS1-8 group), often organize 6, each group gives (NS1 group) 5.0 × 10 successively
5(NS2 group), 1.0 × 10
6(NS2 group), 5.0 × 10
6(NS3 group), 1.0 × 10
7(NS4 group), 5.0 × 10
7(NS5 group), 1.0 × 10
8(NS6 group), 5.0 × 10
8(NS7 group), 1.0 × 10
9bacillus pyocyaneus (the being called for short PA) induction of (NS8 group) dosage, the LPS tolerant mice 8 groups (LPS1-8 group) of embodiment 2, often organizes 6, and each group is given successively with 5.0 × 10
5(LPS1 group), 1.0 × 10
6(LPS2 group), 5.0 × 10
6(LPS3 group), 1.0 × 10
7(LPS4 group), 5.0 × 10
7(LPS5 group), 1.0 × 10
8(LPS6 group), 5.0 × 10
8(LPS7 group), 1.0 × 10
9bacillus pyocyaneus (PA) induction of (LPS8 group) dosage.Observe induction rear 0.5th day, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days and the 7th day mouse survival quantity, the results are shown in Table 3.
The sensitivity experiments result of table 3 normal mouse and LPS tolerant mice antibacterial
Experimental result from table 3: 5.0 × 10
8the bacillus pyocyaneus of CFU/kg can cause normal mouse 100% dead, and 1.0 × 10
7the bacillus pyocyaneus of CFU/kg just can cause LPS tolerant mice 100% dead, shows that the sensitivity of LPS tolerant mice to antibacterial is higher, and LPS tolerant mice more easily suffers the two-hit of the conditioned pathogens such as antibacterial and dead.
Embodiment 4 artesunate (referred to as AS) is on the impact of LPS tolerant mice lung, spleen, serum inflammatory factor expression
42 mices are divided and are divided into 7 groups:
Normal group (NS group), gives the normal saline of same volume;
LPS (0.3) group, by 0.3mg/kg tail vein injection LPS;
LPS (50) group, by 50mg/kg tail vein injection LPS;
LPS (0.3)+LPS (50) group, i.e. the LPS tolerant mice of embodiment 2;
LPS (0.3)+LPS (50)+AS (2.5) group, 0 hour after LPS tolerant mice last LPS induction and the 4th hour are to LPS tolerant mice intramuscular injection 2.5mg/kg artesunate (AS);
LPS (0.3)+LPS (50)+AS (5) group, 0 hour after LPS tolerant mice last LPS induction and the 4th hour are to LPS tolerant mice intramuscular injection 5mg/kg artesunate (AS);
LPS (0.3)+LPS (50)+AS (10) group, 0 hour after LPS tolerant mice last LPS induction and the 4th hour are to LPS tolerant mice intramuscular injection 10mg/kg artesunate (AS).
Below, after respectively organizing 12 hours after LPS induction the last time, get the lung of mice, spleen, blood sample, detect IL-1 β, the expression of IL-6 and TNF-α.The results are shown in Figure 2, Fig. 2 A (in lung inflammatory Cytokines Expression amount), Fig. 2 B (in spleen inflammatory Cytokines Expression amount), Fig. 2 C (in blood inflammatory Cytokines Expression amount), the data in Fig. 2 are meansigma methods+standard deviation, wherein, *, p<0.05 and * *
p<0.05 and
p<0.01 vs LPS (0.3)+LPS (50).
Experimental result from Fig. 2: compare with LPS0.3+LPS50 (tolerance group), the AS of 2.5,5,10mg/kg can raise the expression of LPS tolerant mice lung, spleen, serum inflammatory factor IL-1 β, IL-6 and TNF-α.Experimental result shows, AS can raise the expression of LPS tolerant mice lung, spleen, the serum inflammatory factor.
Embodiment 5 AS can reduce LPS tolerant mice suffer antibacterial two-hit after mortality rate
68 mices are divided and are divided into 4 groups, often organize 17 mices:
PA group injects PA1.0 × 10 to normal mouse
7cFU/kg;
LPS (0.3)+LPS (50)+PA group, to LPS tolerant mice injection PA1.0 × 10
7cFU/kg;
LPS (0.3)+LPS (50)+PA+AS (5) group, to 6 h infusion PA1.0 × 10 after LPS tolerant mice the last time LPS induction
7cFU/kg, respectively at first 2 hours of infusion PA and 6 hours intramuscular injection 5mg/kg artesunate (AS);
LPS (0.3)+LPS (50)+AS (10) group, to 6 h infusion PA1.0 × 10 after LPS tolerant mice the last time LPS induction
7cFU/kg, respectively at first 2 hours of infusion PA and 6 hours intramuscular injection 10mg/kg artesunate (AS);
Observe in 7 days and respectively organize mouse death rate, the results are shown in Figure * * in 3, Fig. 3,
p<0.01vs LPS (0.3)+LPS (50)+PA.From Fig. 3 experimental result: compare with LPS (0.3)+LPS (50)+PA, the AS of 5,10mg/kg can reduce LPS tolerant mice suffer antibacterial two-hit after mortality rate.
Embodiment 6
AS can reduce LPS tolerant mice suffer antibacterial two-hit after lung, spleen, quantity 24 mices of antibacterial are divided into 4 groups in serum, often organize 6 mices:
NS group, to normal mouse injection and to the normal saline of LPS group same volume accumulated amount.
PA group injects PA1.0 × 10 to normal mouse
7cFU/kg;
LPS (0.3)+LPS (50)+PA group, to LPS tolerant mice injection PA1.0 × 10
7cFU/kg;
LPS (0.3)+LPS (50)+PA+AS (10) group, to 6 h infusion PA1.0 × 10 after LPS tolerant mice the last time LPS induction
7cFU/kg, respectively at first 2 hours of infusion PA and 6 hours intramuscular injection 10mg/kg artesunate (AS);
Often organize and get 3 mices after injection PA 2 hours and 6 hours respectively, get the blood of mice, lung and spleen, collection lung and spleen tissue and and blood in PA, and detect the CFU value of PA.The results are shown in Figure in 4, Fig. 4, * *,
p<0.01 vs LPS (0.3)+LPS (50)+PA
From Fig. 4 experimental result: compare with LPS (0.3)+LPS (50)+PA group, the AS of 10mg/kg can reduce the quantity that LPS tolerant mice suffers antibacterial in lung after antibacterial two-hit, spleen, serum.
To sum up, artesunate animal experiment shows, artesunate in sepsis patient, late period can promote that inflammatory factor discharges, and activates immunity of organisms, strengthen patient and support antibacterial ability, in can effectively reducing, mortality rate that late period, sepsis patient caused because of antibacterial two-hit.
Claims (4)
1. artesunate is manufacturing the purposes in treatment mid-term or late period medication for treating pyemia.
2. purposes as claimed in claim 1, described sepsis is pus disease patient in late period.
3. purposes as claimed in claim 1, described mid-term or late period sepsis refer to that the inflammatory factor in sepsis patient body secretes less state.
4. purposes as claimed in claim 1, described mid-term or late period sepsis refer to that the immunity of sepsis patient is suppressed or immunity is in palsy.
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| CN201510130689.4A CN104688727A (en) | 2015-03-24 | 2015-03-24 | Application of artesunate in preparing medicine for treating middle-late sepsis |
| PCT/CN2015/092808 WO2016150151A1 (en) | 2015-03-24 | 2015-10-26 | Use of artesunate in preparation of medicine for treating medium-term and advanced sepsis |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111135291A (en) * | 2020-02-27 | 2020-05-12 | 遵义医科大学 | Immunosuppressive drug composition for treating glucocorticoid induction and application thereof |
| CN111362964A (en) * | 2020-03-19 | 2020-07-03 | 中国人民解放军陆军军医大学 | Amber derivative of artesunate, preparation method and application in medicine thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1833644A (en) * | 2005-03-18 | 2006-09-20 | 中国人民解放军第三军医大学 | Abrotine, its derivative dihydro-abrotine, artemether, arteether and arte sunate in use of pharmacy |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102781471B (en) * | 2009-10-16 | 2016-10-12 | 奥默罗斯公司 | Method by suppression MASP-2 dependent complement activation treatment disseminated inravascular coagulation |
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- 2015-03-24 CN CN201510130689.4A patent/CN104688727A/en active Pending
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1833644A (en) * | 2005-03-18 | 2006-09-20 | 中国人民解放军第三军医大学 | Abrotine, its derivative dihydro-abrotine, artemether, arteether and arte sunate in use of pharmacy |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111135291A (en) * | 2020-02-27 | 2020-05-12 | 遵义医科大学 | Immunosuppressive drug composition for treating glucocorticoid induction and application thereof |
| CN111362964A (en) * | 2020-03-19 | 2020-07-03 | 中国人民解放军陆军军医大学 | Amber derivative of artesunate, preparation method and application in medicine thereof |
| CN111362964B (en) * | 2020-03-19 | 2022-03-08 | 中国人民解放军陆军军医大学 | Amber derivative of artesunate, preparation method and application in medicine thereof |
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Application publication date: 20150610 |