WO2010055711A1

WO2010055711A1 - Peptide composition for saving the life of sirs patient

Info

Publication number: WO2010055711A1
Application number: PCT/JP2009/061872
Authority: WO
Inventors: 秀親岡田; 有武岡田
Original assignee: 株式会社蛋白科学研究所
Priority date: 2008-11-11
Filing date: 2009-06-29
Publication date: 2010-05-20
Also published as: JP2010116325A

Abstract

Disclosed is a composition for saving a life, which can be administered to a patient having a serious condition associated with systemic inflammatory response syndrome (SIRS) including sepsis after the patient is suffering from the serious condition in order to save the life of the patient. The composition comprises a peptide depicted in SEQ ID NO:1 or SEQ ID NO:2.

Description

Peptide composition for saving SIRS patients

The present invention relates to a therapeutic agent capable of saving a patient's life by administering to a patient who has suffered from a serious medical condition due to systemic inflammatory response syndrome (SIRS) including zepsis after having suffered from such a serious medical condition. About.

Systemic Inflammatory Response Syndrome (SIRS), including zepsis, is a fatal disease that causes 300,000 patients to die every year in North America, and there is still no effective therapeutic agent. In the United States, 750,000 people develop zepsis annually and 220,000 people die, but there is no special lifesaving medicine. Activated protein C (APC) can only improve 30% mortality to 24%. In Zepsis, pathogenic bacteria have increased in the body, so even if bacteria are suppressed with antibiotics, endotoxin (LPC) cannot be removed. Antibiotic administration and treatment with symptomatic treatment such as heparin and steroids remain.

Zepsis is a type of systemic inflammatory response syndrome (SIRS), which causes disseminated intravascular coagulation (DIC) and multiple organ failure (MOF), which are very fatal. A central role in SIRS of C5a anaphylatoxin, a 74-amino acid peptide released by C5 convertase generated during complement activation from the fifth component of complement (C5) (has been proposed (Non-patent Documents 1 and 2). ).

C5a is a 74-amino acid peptide that is released from complement fifth component (C5) by C5 convertase generated during complement activation (Non-patent Documents 1 and 2). C5a anaphylatoxin is an in vivo inflammation stimulating substance having a strong activity that acts even at a low concentration of 10 ⁻¹¹ M, and stimulates the production of TNFα and other inflammatory cytokines (Non-patent Documents 3-5).

Although C5a anaphylatoxin is considered an effective target for the treatment of excessive inflammation, attempts to limit the effects of C5a with C5a5receptor (C5aR) antagonists have not been successful. This is because C5aR is expressed not only in inflammatory leukocytes but also in many other cell types (Non-patent Document 4). Furthermore, the number of C5aR increases in an acute inflammatory state (Non-patent Document 6).

Antibodies to C5a anaphylatoxins have been shown to be effective in the treatment of experimental zepsis primate models (Non-Patent Documents 3 and 7), and C5a anaphylatoxin inhibitors are severe systemic inflammatory response syndrome (SIRS). It has been shown that it may be useful for the treatment of patients suffering from (Non-patent Document 8).

However, the antibody against C5a anaphylatoxin has problems such as remaining in the body after treatment, and it is not easy to apply to humans.

Amino acids 37 to 53 of C5a (RAARISLGPRCIKAFTE) are antisense peptides to the antisense homology box (AHB) peptide (Non-patent Document 9) of the C5a receptor (C5aR) and are referred to as PL37 (Non-patent Document 10). ). This region of C5a anaphylatoxin is presumed to be a potential site for C5aR stimulation (Non-patent Document 11). Using the computer program MIMETIC (Non-Patent Documents 12-14), we created a complementary peptide to PL37 called PepA (ASGAPAPGPAGPLRPMF) (SEQ ID NO: 1), which binds to C5a anaphylatoxin and complements it. It was confirmed that body-mediated lethal shock was prevented in rats (Patent Document 1, Non-Patent Document 15). In the system of Patent Document 1, PepA or a peptide called AcPepA (SEQ ID NO: 2) generated by acetylation of N-terminal alanine of PepA is administered before the onset of systemic symptoms to prevent the onset of zepsis itself prophylactically. ing. However, it is unclear what effect PepA or AcPepA has on a subject who has already developed a lethal shock.
JP 2004-269520 A Annu. Rev. Immunol. 12: 775-808 (1994) Immunopharmacology, 38: 3-15 Nature.Med. 5, 788-792 (1999) Annu Rev. Immunol. 23, 821-852 (2005) Immunol. Rev. 180, 177-189 (2001) J. Clin. Invest. 110: 101-108 J. Clin. Invest. 77, 1812-1816 (1986) Nature. Med. 9, 517-24 (2003) Nature Med. 1, 894-901 (1995) J. Immunol. 157, 4591-4601 (1996) Neuroscience 86, 903-911 (1998) Microbiol. Immunol. 46, 211-215 (2002) Biochem. Biophys. Res. Comm. 324, 236-240 (2004) Microbiol. Immunol. 47, 241-245 (2003) J. Immunol. 172, 6382-6387 (2004)

An object of the present invention is to provide a drug with no side effects or few side effects that can effectively save a patient who has already suffered from a shock state due to SIRS such as Zepsis.

We conducted experiments in cynomolgus monkeys in shock induced by injection of lethal doses of LPS. The present inventors administered acetylated PepA (AcPepA) (SEQ ID NO: 2) to monkeys in lethal endotoxic shock as a model for shock patients. 100% life-saving treatment effect was exerted on monkeys that were shocked with lethal endotoxin.
The present inventors also induced an actual bacterial infection into the abdominal cavity by experiments in a porcine neonatal peritonitis model (CLP), and confirmed the lifesaving effect of AcPepA in a model in a shock state caused by the bacterial infection.
Since AcPepA according to the present invention is rapidly decomposed in the body, there is little risk of accumulated toxicity even in a large dose in an emergency.

Therefore, the present invention provides a lifesaving composition comprising the peptide shown in SEQ ID NO: 1 or 2, which saves a subject from SIRS death when administered after such diagnosis in a subject diagnosed with SIRS. A subject diagnosed with SIRS is preferably a subject diagnosed with zepsis. Preferably the composition comprises the peptide shown in SEQ ID NO: 2. The present invention also shows in SEQ ID NO: 1 or 2 for the manufacture of a life saving composition that saves a subject from SIRS, particularly death from zepsis, when administered after such diagnosis in a subject diagnosed with SIRS. Provide the use of peptides.

The present invention also provides a method for saving a subject from death due to SIRS, comprising administering to the subject diagnosed with SIRS the peptide shown in SEQ ID NO: 1 or 2 after such diagnosis. A subject diagnosed with SIRS is preferably a subject diagnosed with zepsis. Preferably the peptide is as shown in SEQ ID NO: 2.

In the composition of the present invention or the method of the present invention, the peptide shown in SEQ ID NO: 1 or 2 is preferably promptly, specifically within 1 hour, preferably within 30 minutes after being diagnosed with SIRS. More preferably, it is administered for the first time within 10 minutes. The dose is not limited and should be determined by a physician based on the patient's sex, age, symptoms, etc. For example, in the case of the peptide shown in SEQ ID NO: 2, the initial dose is preferably 1 to 4 mg / kg. Body weight, more preferably the initial dose is 2-4 mg / kg body weight. More preferably, the peptide shown in SEQ ID NO: 2 is 1 to 4 mg / kg body weight / hour after initial administration, more preferably 2 to 4 mg / kg body weight / hour, preferably 2 to 6 hours, more preferably 3 to Administration is continued for 6 hours. Particularly preferably, administration is performed until each parameter described in Table 1 below, which is a diagnostic criterion for SIRS, returns to the normal range.
Table 1. Diagnostic criteria for S I R S

In the present specification and claims, “SIRS (Systemic Inframmatory Response Syndrome)” means a fatal pathological condition in which an excessive inflammatory reaction occurs systemically and various organ damages are induced by inflammation.
In the present specification and claims, “zepsis” refers to SIRS caused by infectious diseases.
The diagnostic criteria for “SIRS” are as shown in Table 1 above.
Among the pathological conditions diagnosed with SIRS, those caused by infection are diagnosed as zepsis. Whether or not the cause is an infection is determined by confirmation of an infection focus by a pathogenic microorganism or an abnormal increase in CRP (10 or more).
In the present specification and claims, the peptide of SEQ ID NO: 1 is the peptide consisting of the amino acid sequence of SEQ ID NO: 1 as well as the peptide consisting of the amino acid sequence of SEQ ID NO: 1 stabilized by chemical modification or the like Is also included.
In the present specification and claims, the peptide of SEQ ID NO: 1 or 2 includes a salt of the peptide of SEQ ID NO: 1 or 2.

The peptide of the present application can save a patient and reduce the mortality rate when administered to a patient who has developed a shock caused by zepsis.

The peptide of the present invention is useful for treating SIRS patients including zepsis. The half-life in the body of the peptide of the present invention is short (about 2 minutes), and even if a large dose is saved in an emergency, it is rapidly decomposed and disappeared if treatment is stopped, and there is little risk of accumulated toxicity.

Levels of TNFα in the plasma of monkeys that received 4 mg / kg LPS followed by saline treatment instead of therapeutic agent (upper panel) and monkeys that were treated with AcPepA after LPS injection (lower panel). AcPepA treatment suppressed THFα levels to approximately 60% that of saline treatment. TNFα in plasma disappeared within 4 hours of LPS injection in treated monkeys, whereas it took 5 hours in saline treated control monkeys. TNFα in monkey plasma was measured using an ELISA kit purchased from Quantikine Immunoassay® (Minneapolis, Minn.). Macrophage migration inhibitory factor (MIF) levels in plasma. MIF levels in plasma of monkeys treated only with saline after LPS injection (# 1, # 4, # 10) and monkeys treated with AcPepA after LPS injection (# 3, # 5, # 8) Were tested. MIF levels in AcPepA-treated monkeys were maintained at low levels (less than 30 ng / ml), whereas MIF levels in saline-treated control monkeys increased above 30 ng / ml. MIF was measured using an ELISA kit prepared by Sapporo Immuno Diagnostic Laboratory (Sapporo, Japan). Increased HMGB1 in the plasma of LPS injected monkeys. Monkeys treated with saline after LPS sputum injection (# 1, # 10) showed an increase in plasma HMGB1 sputum levels, and monkeys treated with AcPepA sputum after LPS sputum injection (# 5, # 8) showed no rise . For HMGB1 measurement, an ELISA kit from Shino-Test Co. (Sagamihara, Kanagawa, Japan) was used. The serum HMGB1 level in a porcine neonatal peritonitis model is shown. Figure 2 shows serum TNF-α levels in a porcine neonatal peritonitis model. The survival curve (upper left), serum IL-6 level (upper right), serum IL-10 (lower left) and serum HMGB1 level (lower right) in a porcine neonatal peritonitis model are shown. The half-life measurement result in rats of AcPepA is shown. The half-life was 2 minutes (1/2 t = 1.9).

AcPepA is a peptide AcPepA (SEQ ID NO: 2) in which the N-terminal alanine of PepA, which is a 17 amino acid peptide (ASGAPAPGPAGPLRPMF) (SEQ ID NO: 1), is acetylated. Both show the same effect on C5a, but AcPepA is more stable than PepA (Japanese Patent Laid-Open No. 2004-269520).

The method for producing the peptides of SEQ ID NOs: 1 and 2 of the present invention is not particularly limited. For example, the peptide of SEQ ID NO: 1 is prepared by a conventional chemical synthesis method, and then the N-terminal alanine is acetylated by a conventional method. Can be created. A method of using acetylated alanine in advance for N-terminal alanine is also possible. The peptide of the present invention or a salt thereof can be mixed with sterile water, human serum albumin (HSA), physiological saline or other known physiologically acceptable carriers. If necessary, the peptide of SEQ ID NO: 2 or a salt thereof of the present invention can be powdered by lyophilization. In lyophilization, stabilizers such as sorbitol, mannitol, dextrose, maltose, trehalose, glycerol and the like can be added.

The subject of administration of the peptide of SEQ ID NO: 1 or 2 of the present invention is a mammal, particularly a human, already presenting symptoms of SIRS or zepsis.

Administration method, administration route, and dosage form are not particularly limited, but it is preferable to administer a liquid preparation containing the peptide of the present invention by intravenous injection into a subject. The peptides of the present invention can be administered parenterally or topically to mammals (eg, humans). For example, the peptide of the present invention can be administered parenterally by intravenous injection or intramuscular injection. Formulation of an injection is performed according to a conventional method using, for example, physiological saline or an aqueous solution containing glucose and other adjuvants.

The preparation containing the peptide of the present invention or a salt thereof may also contain other physiologically acceptable active ingredients such as salts, diluents, carriers, buffers, binders, surfactants and preservatives. Good. Preparations for parenteral administration are ampoules in sterile aqueous solutions or suspensions with physiologically acceptable solvents, or sterile powders that can be used diluted with physiologically acceptable diluents (usually freezing peptide solutions). Provided as ampoules (obtained after drying).

Summary of Example 1 Intravenous injection of 4 mg / kg of endotoxin (LPS) into cynomolgus monkeys caused severe systemic inflammatory response syndrome (SIRS), which resulted in all animals within 2 days. To death. SIRS monkeys injected with LPS were saved by administration of 2 mg / kg AcPepA. However, this peptide did not significantly inhibit TNF-α induction. On the other hand, this peptide inhibited the induction of HMG box 1 (HMGB1) and macrophage migration inhibitory factor (MIF) in plasma. Inactivation of C5a anaphylatoxin sustained by complement activation by LPS in the SIRS state appears to suppress a lethal cytokine storm, including induction of HMGB1 that amplifies the inflammatory response (Am. J. Physiol Cell. Physiol. 290, C917-924 (2006), Shock, 26, 174-179 (2006), Science 285, 248-251 (1999), Proc. Natl. Acad. Sci. 101, 296-301 (2004) )).

Details of Example 1 AcPepA (ASGAPAPGPAGPLRPMF) (SEQ ID NO: 2) in which the N-terminal alanine of PepA was acetylated was synthesized and purified by Biologica Co. Ltd. (Nagoya, Japan) (purity exceeding 95%). Peptide AcPepA was dissolved in saline at a concentration of 2 mg / ml and passed through a 0.22 μm Millipore filter prior to intravenous administration with an automated injection pump. Cynomolgus monkeys were provided by breeding colonies maintained by the Society for Preventive Hygiene (CPRLP, Tsukuba, Japan). Research protocols by the Institute for Longevity Medicine, the Institutional Animal Ethical Committee of the Welfare Village Hospital, the Tsukuba Primate Research Center, and the Animal Experiment Committee of the Pharmaceutical Board Research Institute Was approved.

Animals weighing 4 to 5.5 kg were hematocrit that exceeded 36% and were not affected by infections including tuberculosis. Animals were housed in CPRLP for 1 month prior to the lethal LPS study with LPS. After sedation with ketamine hydrochloride sputum (14 mg / kg, subcutaneous), monkeys were anesthetized with pentobarbital sodium administered intravenously via a percutaneous catheter to maintain a light level of surgical anesthesia. Oral intubation allowed the animal to breathe naturally. Under anesthesia with sodium pentobarbital, 4 mg / kg LPS was administered intravenously to monkeys within 30 minutes. Thirty minutes after LPS injection, monkeys received intravenous saline (untreated control) sputum or AcPepA (2 mg / kg for 2 minutes, then 4 hours, 2 mg / kg / hour). Six hours after LPS sputum administration, the anesthesia was terminated and the monkeys were returned to their homerooms (except for animals sacrificed for necropsy) and their condition observed without further interference. All three control monkeys died in 2 days, but all AcPepA-treated monkeys returned to health by the next day. Blood samples were collected for analysis including blood cell count, CPK assay, and cytokine levels.

Under anesthesia, cynomolgus monkeys were intravenously injected with a lethal dose of LPS (4 mg / kg, 30 minutes). After LPS injection, 3 monkeys received saline alone as an untreated control, and all animals died within 2 days (2 on

day

1 and 1 on day 2). On the other hand, 30 minutes after LPS injection, all monkeys treated with 2 mg / kg of AcPepA for 2 minutes and then 2 mg / kg / hour of AcPepA for 4 hours with SIRS appearing. Rescued and recovered to health the next day (Table 2), but also marked in AcPepA-treated monkeys, leukopenia (less than 3000 / mm ³ after 1 hour), thrombocytopenia (less than 25000 / mm ³ after 3 hours) ), Decreased blood pressure (80 mmHg after 30 minutes), and release of creatinine phosphokinase (CPK) (1000 IU / L after 4 hours), all of which were related to their SIRS status. Leukopenia in AcPepA-treated monkeys increased to 15000 / mm ³ after 24 hours, and thrombocytopenia decreased to 1000 / mm ³ after 24 hours, but reached the normal range of 460000 / mm ³ after 72 hours. It was recovering. The decrease in blood pressure in the monkeys treated with AcPepA recovered to 100 mmHg the next day, and the release of creatinine phosphokinase (CPK), which had increased to 2500 IU / L after 6 hours, has decreased to 1300 IU / L the next day. It was.

The plasma TNFα level obtained during the experiment on monkeys treated with AcPepA was reduced by only about 30% compared with the saline-treated control monkey (FIG. 1). However, elevated levels of macrophage migration inhibitory factor (MIF) (Figure 2) and HMG box 1 HM (HMGB1) (Figure 3) after LPS injection were suppressed in AcPepA treated monkeys. Some monkeys were sacrificed under anesthesia 6 hours after LPS sputum injection for autopsy. By pathological analysis of the organ tissue, severe inflammatory changes including leukocyte infiltration were observed in the lungs of AcPepA-treated monkeys. This inflammatory change was similar to that in the saline-treated control simian monkey. This result shows that at 6 hours when the fatal response progressed after LPS sputum injection and was euthanized for necropsy, the monkey was in severe SIRS sputum, even in AcPepA treated monkeys. It is shown that once a lethal response occurred, the progression may have been limited by AcPepA. Although the mechanisms involved in the inhibition of MIF and HMGB1 induction have not yet been elucidated, they are thought to be directly related to the therapeutic effects of AcPepA. In particular, HMGB1 has been shown to respond to Toll-Like Receptor (TLR) -4 and TLR-2 of inflammatory cells such as leukocytes, causing inflammatory exacerbation feedback by the action of HMGB1 as an inflammation enhancing factor, It is thought to progress SIRS pathology.

Table 2. Therapeutic effects of AcPepA on monkeys inoculated with lethal doses of LPS (4mg / kg)

Leukopenia was observed after 1 hour and CPK elevation was observed after 6 hours. Blood pressure reduction (80 mmHg) started 30 minutes after the administration of AcPepA. Even when AcPepA was administered, it was in SIRS pathology at 6 hours, but it is thought that it recovered rapidly thereafter. In monkeys to which AcPepA had been administered, MIF and HMGB1 did not rise at 6 hours, and therefore, vigorous food back was prevented from increasing, and it was considered that the monkeys were removed from SIRS.

Summary of Example 2 The lifesaving effect of AcPepA of the present invention was confirmed in a porcine neonatal peritonitis model close to the actual pathological condition of zepsis infection.
A piglet suffering from fatal peritonitis induced by cecal ligation and puncture (CLP) in a preliminary experiment died within about 9 hours due to severe zepsis, but the animal was started at 3 mg after 3 hours of CLP surgery. When intravenous administration of AcPepA at kg / hour was performed, HMGB1 did not increase and survived for 24 hours. These results indicate that the administration of AcPepA is a useful method for the treatment of patients with severe SIRS, especially Zepsis.

Details of Example 2 The incision was made in the abdomen of 8 pig newborns who were anesthetized with ketamine (0.1 mg / kg body weight), and the ileocecum was ligated, then a hole was made in the intestine with an 18-gauge needle. Leakage into the abdominal cavity and then surgery to close the abdomen after returning the intestine to the abdominal cavity (Cecum Ligation and Puncture: CLP) caused peritonitis in the leaked feces, 9 to 14 hours (9.5 +/- 0.4 Died later). In these CLP-treated pigs, HMGB1 was released into the blood (CLP). No HMGB1 release was observed in animals that had undergone laparotomy and did not undergo CLP surgery (SHAM).
Another neonatal pig undergoing CLP surgery survived up to 18 hours after continuous administration of AcPepA intravenously at 2 mg / kg / hour from 3 hours later. In the newborn pigs treated with AcPepA, the increase in blood HMGB1 was suppressed (AcPepA). AcPepA also suppressed the release of HMGB1 and exerted a life-saving effect even in newborn pigs with a lethal septic pathology model in which enterobacteria leaked into the abdominal cavity by CLP (FIG. 4).

In the newborn pigs that underwent CLP (Cecum Ligation and Puncture) surgery, 30 minutes after the operation, continuous administration of AcPepA at 2 mg / kg / hour intravenously suppressed the increase in TNFα completely (FIG. 5).

The upper left panel of Fig. 6 shows an incision in the abdomen of a newborn pig with general anesthesia with ketamine (0.1mg / kg body weight). It is a postoperative survival curve when performing an operation (Cecum Ligation and Puncture: CLP) to return the intestine into the abdominal cavity and close the abdomen after leaking. Survival curves of CLP (Cecum Ligation and Puncture), no treatment (□), post-CLP AcPepA treatment (○), and neonatal pig newborns (△) who did not perform CLP but only laparotomy (this group was euthanized at 24 hours) ) When CLP was performed, peritonitis was caused by the leaked intestinal bacteria in the feces, and if not treated, it died after 9 to 14 hours (survival time 9.5 時間 +/- 0.4) (□). 30 minutes after the CLP operation of another 8 newborn pigs, some patients survived up to 24 hours after intravenous administration of AcPepA at 2 mg / kg / hour (survival time was 18 +/- 3.9 hours) ) (○). CLP revealed that AcPepA exerted a life-saving effect even in a newborn pig with a lethal septic disease model caused by intestinal bacteria leaking into the abdominal cavity. Some pig neonates treated with AcPepA at 30 mg to 2 mg / kg / hr after CLP surgery survived for more than 24 hours.

The upper right panel of FIG. 6 is the transition of serum IL6 value, the lower left panel is the transition of serum IL10 value,
The lower right panel shows the transition of the serum HMGB1 value.

Half-life in a rat model of AcPepA
Administration of AcPepA and blood sampling over time Male male Wistar rats weighing 250 g were intravenously injected with 2.5 mg of AcPepA (10 mg / kg), and then wetted with heparin after 1, 3, 5, 10 and 20 minutes. 0.4 ml of blood was collected from each vein using a syringe, and each blood was immediately centrifuged to collect plasma.
Measurement of plasma concentration 0.25 mL of acetonitrile was added to 0.1 mL of plasma, stirred, and centrifuged at 15,000 rpm (Himac CF15D, HITACHI) for 5 minutes (4 ° C). The unchanged substance concentration in the obtained supernatant was analyzed by LC-MS method.
LC / MS measurement method Alliance 2695 HPLC system (Waters) was used as the HPLC system. A TSQ Quantum LC-MS / MS system (ThermoFinnigan, Probe: TurboIonSpray, Data processing system: Xcalibar LCquan ver. 1.3) was used as the MS apparatus. For ionization, electrospray ionization (ESI) was performed by positive ionization detection, and the selected ion monitoring (SIM) method using the set precursor ion was used. The column is Super ODS (2μm, 2.0 mmID x 50 mm, Tosoh), the column temperature is set to 40 ° C, and liquid A is used as the mobile phase [CH3CN: H2O: CH3COOH (10: 90: 0.1, v / v)] And B solution [CH3CN: H2O: CH3COOH (90: 10: 0.1, v / v)] were analyzed by isocratic method (flow rate 0.2 and 0.4 mL / min).

LC / MS / MS conditions
[LC condition]
Column: Super ODS (2 μm, 2.0 mmID × 50 mm, Tosoh)
Column Temperature: 40 ℃
Injection volume: 10 μL
Mobile Phase: A: CH3CN / H2O / CH3COOH = 10/90 / 0.1
B: CH3CN / H2O / CH3COOH = 90/10 / 0.1
Gradient conditions:

[MS condition]
Spray Voltage: 4.8kV
Sheath Gas Pressure: 5Psi
Aux Gas Pressure: 12 Unit
Capillary Temp .: 215 ℃
Collision Pressure: 1.5 mTorr
Selected ion monitoring parameters:

*: Multivalent (divalent) ions are detected because the MS range (up to 1500) is exceeded.

Results are shown in FIG. AcPepA showed low plasma stability with a half-life of 1.93 minutes.

The PepA and AcPepA (SEQ ID NOs: 1 and 2) according to the present invention can be used as a therapeutic drug for saving a patient suffering from a serious disease state.

Claims

A life-saving composition comprising the peptide shown in SEQ ID NO: 1 or 2 for saving a subject from SIRS death when administered after such diagnosis in a subject diagnosed with SIRS.
The composition according to claim 1, wherein SIRS is Zepsis.
The composition according to claim 1 or 2, comprising the peptide represented by SEQ ID NO: 2.
4. The composition according to any one of claims 1 to 3, which is first administered within 1 hour after diagnosis of SIRS or zepsis.
The composition according to claim 4, wherein the initial dose is 1 to 4 mg / kg body weight.
6. The composition according to claim 4 or 5, which is continuously administered at 1 to 4 mg / kg body weight / hour for 2 to 6 hours after the initial administration.