CN116983294A - Application of treprostinil and analogue thereof in treating sepsis shock - Google Patents

Abstract

The present application relates to the use of treprostinil and its analogs in the treatment of septic shock. In the application, treprostinil can be used singly or in combination with liquid resuscitation and vasoactive drugs, has obvious treatment effects, can obviously reduce the death rate, improve the survival rate of patients with sepsis shock, prolong the survival time and improve the cardiac output.

Description

Application of treprostinil and analogue thereof in treating sepsis shock

Technical Field

The application relates to the technical field of medicines, in particular to application of treprostinil and analogues thereof in treating sepsis shock.

Background

In broad terms, sepsis (sepis) is a type of dynamically-altered syndrome of clinical significance, with infection as a starter factor leading to a subsequent series of complex linkage effects. Sepsis defines the initial intent to maximize the differentiation of commonly light, localized infected patients from those with overactive systemic inflammatory response (systemic inflammatory response syndrome, SIRS) to facilitate better identification and timely intervention by medical personnel. Sepsis hypocardiac output and shock refers to sepsis with severe circulatory, cellular and metabolic disturbances, with a higher risk of death than sepsis alone.

Sepsis low heart rate and shock (i.e., sepsis shock) are currently an important issue in acute critical medicine, and recent epidemiological data show that patients suffering from sepsis worldwide have over 1900 thousands of patients each year, more than 600 thousands of patients die, the death rate is about 30% -50%, severe patients develop sepsis low heart rate and shock, and the death rate can be as high as 80%. Patients with severe sepsis and hypocardiac output are associated with cardiovascular dysfunction, reduced cardiac function, reduced blood pressure, and multiple organ dysfunction of the liver and kidney.

Currently, there is no satisfactory therapeutic for septic shock. Thus, there is an urgent need in the art to develop drugs effective in treating or ameliorating septic shock.

Disclosure of Invention

The application aims to provide a medicine for effectively treating or improving sepsis shock and application thereof.

In a first aspect of the application, there is provided the use of treprostinil and its analog for the preparation of a medicament for the treatment of septic shock.

In another preferred embodiment, the septic shock is shock caused by sepsis due to a microbial infection.

In another preferred embodiment, the septic shock is characterized by one or more of the following:

(a) Low heart row: heart index lower than 1.8L/min/m ² ；

(b) Heart function decreases: cardiac output is lower than 4.0L/min;

(c) Blood pressure drop: mean Arterial Pressure (MAP) <65mmHg;

(d) Sepsis: rapid sequential organ failure score (qSOFA) > 2.

In another preferred embodiment, the treprostinil or its analog comprises treprostinil or its pharmaceutically acceptable salt.

In another preferred embodiment, the medicament contains (A1) a first active ingredient selected from the group consisting of: treprostinil and its analogs; and (B) a pharmaceutically acceptable carrier.

In another preferred embodiment, the pharmaceutical composition further comprises (A2) a second active ingredient selected from the group consisting of: vasoactive drugs, dopamine, norepinephrine, epinephrine, milrinone, amirinone, prostacyclin, or combinations thereof.

In another preferred embodiment, the pharmaceutical dosage form is a liquid or solid.

In another preferred embodiment, the medicament comprises an injection.

In another preferred embodiment, the drug is administered intravenously.

In another preferred embodiment, the medicament is an intravenous injection.

In another preferred embodiment, the drug is administered subcutaneously.

In another preferred embodiment, the medicament is a subcutaneous injection.

In another preferred embodiment, the medicament is administered by intra-airway inhalation.

In another preferred embodiment, the medicament is an intra-airway inhalation formulation.

In another preferred embodiment, the medicament is for:

(Z1) increasing cardiac output in a sepsis shocked patient;

(Z2) increasing the ejection fraction of sepsis shock patients and bringing them into a compensatory range;

(Z3) reducing pulmonary circulatory resistance in patients with septic shock;

(Z4) increasing stroke volume in patients with septic shock; and/or

(Z5) increasing blood oxygen saturation in sepsis shock patients;

(Z6) improving renal function (increasing urine volume) in patients with septic shock.

In a second aspect of the application, there is provided a kit comprising:

(a) A pharmaceutical composition comprising prostaglandins and analogues thereof and a pharmaceutically acceptable carrier;

(b) A rapid sequential organ failure scoring (qSOFA) tool; and

(c) Instructions describing administration of the pharmaceutical composition to a sepsis shock patient.

In another preferred embodiment, the instructions describe the use of the pharmaceutical composition in patients with rapid sequential organ failure score (qSOFA). Gtoreq.2.

In another preferred embodiment, the rapid sequential organ failure scoring (qSOFA) tool is a scoring card.

In another preferred embodiment, the instructions describe a rapid sequential organ failure score (qSOFA) criterion: qSOFA comprises 3 items including conscious state change, systolic pressure less than or equal to 100mmHg and respiratory frequency more than or equal to 22 times/min, and accords with 2 items or more, namely, if the qSOFA score is more than or equal to 2, the qSOFA is a sepsis shock patient or a suspected sepsis shock patient.

In a third aspect of the application, there is provided a method of treating or preventing septic shock, the method comprising the steps of: (a) administering treprostinil and its analog to a subject.

In another preferred embodiment, the method further comprises the steps of: (b) Determining cardiac output, cardiac stroke volume and/or cardiac ejection fraction of the subject.

In another preferred embodiment, the subject includes human and non-human mammals (e.g., pigs).

In another preferred embodiment, the subject is a sepsis patient.

In another preferred embodiment, the subject is a septic shock patient.

It is understood that within the scope of the present application, the above-described technical features of the present application and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.

Drawings

Figure 1 shows the effect of treprostinil on short term survival in sepsis shocked pigs.

Figure 2 shows the effect of treprostinil on sepsis shocking pig haemodynamics. Wherein, the ∈two represents the data of the control group. ■ Experimental group data are presented in which MPAP mean pulmonary arterial pressure, PVR pulmonary circulatory resistance, CO cardiac output, RVSV right ventricular stroke volume, RVEF right ventricular ejection fraction, SVR systemic resistance.

Figure 3 shows the effect of treprostinil on urine volume in sepsis shocked pigs.

Detailed Description

The present inventors have made extensive and intensive studies and have unexpectedly developed a drug which can be used for effectively treating or ameliorating septic shock for the first time. Studies by the present inventors have shown that treprostinil and its analogs, including alone or in combination (e.g., in combination with liquid resuscitation and vasoactive drugs), can unexpectedly significantly treat and ameliorate septic shock. The present application has been completed on the basis of this finding.

Experiments show that treprostinil and analogues thereof can reduce heart work for patients or subjects suffering from sepsis shock, so that liquid in a right heart system can smoothly reach a left heart system, circulation can be effectively improved, liquid infusion quantity can be reduced, right heart load can be lightened, liquid treatment effect of patients suffering from sepsis is improved, right heart failure incidence rate is reduced, and sepsis low heart discharge and shock are effectively treated.

Terminology

The terms used herein have the conventional meaning in the medical field.

As used herein, the term "sepsis" refers to life threatening organ dysfunction due to a deregulation of the host's response to infection. Typically, sepsis is a type of dynamically-diffracted syndrome of clinical significance, with infection as a starter factor leading to a subsequent series of complex linkage effects.

Sepsis shock

As used herein, the terms "sepsis shock", "sepsis hypocardiac stress and shock" are used interchangeably to refer to a disorder that results in or incorporates very severe circulatory disorders, significant decreases in cardiac output, and the like, resulting in shock or a significantly increased risk of shock in a patient.

Clinically, the risk of death of septic shock is far higher than sepsis. Statistics indicate that patients, once they develop sepsis low heart rate and shock, have a mortality rate of up to about 80%.

Rapid sequential organ failure scoring (qSOFA) is commonly used as a screening tool for sepsis to identify suspected infected patients with poor prognosis. qSOFA consists of 3 items including conscious state change, contraction pressure less than or equal to 100mmHg and breathing frequency more than or equal to 22 times/min, and accords with 2 items or more, namely that the qSOFA score is more than or equal to 2 and is suspected sepsis.

Heart index

As used herein, the term "cardiac index" (CI) is the left ventricular Cardiac Output (CO) per minute calculated as Body Surface Area (BSA) of a parameter involved in hemodynamics, thereby comparing cardiac pump function between different individuals. The units of measurement are liters per square meter per minute (L/min/m) ² )。

The index is typically calculated using the following formula:

wherein:

CI: heart Index (cardioac Index)

BSA: body surface area (Body Surface Area)

SV: stroke Volume (Stroke Volume)

HR: heart Rate (Heart Rate)

CO: cardiac Output (cardioac Output)

The heart index is 2.6-4.2L/min/m in normal range of general population ² 。

Heart index is often used and measured in intensive care medicine and coronary care units. The heart index is an index for judging the blood pumping function of the heart under the condition that the metabolic rates of people with different body surface areas (such as high, low, fat and thin) are different, so that the cardiac output is also different.

If the heart index is lower than 1.8L/min/m ² Patients may develop cardiogenic shock.

Heart discharge blood volume below normal value can be regarded as low heart discharge.

Cardiac output

As used herein, the term "cardiac output" (CO) is a term used in cardiac physiology to describe the amount of blood pumped by the two ventricles of the heart per unit time (typically measured per minute). Cardiac Output (CO) is the product of Heart Rate (HR), i.e. the number of beats per minute (bpm), and Stroke Volume (SV), i.e. the amount of blood pumped from the left ventricle per stroke, giving the formula: co=hr×sv.

The cardiac output value is typically expressed as L/min. For healthy people weighing 70 kg, the cardiac output at rest averages about 5L/min; assuming a heart rate of 70 beats/min, the stroke volume is about 70 ml. The cardiac output of normal adults is 4.0-8.0 liters/min. If it is less than 4.0L/min, it is considered that the heart function is lowered.

Hypotension

As used herein, the term "diagnosis of hypotension" is first to obtain blood pressure by a sphygmomanometer noninvasively or arterial catheter invasively (mainly in an intensive care unit). Another method belonging to hypotension measurement is to use MAP (mean arterial pressure) of arterial catheters or continuous non-invasive hemodynamic monitoring, measuring intra-operative blood pressure continuously throughout the procedure, if systolic pressure <90mmHg or diastolic pressure <60 mmHg. MAP <65mmHg is considered hypotension. Intra-operative hypotension <65mmHg may lead to an increased risk of acute kidney injury, myocardial injury or post-operative stroke.

For most adults, the ideal blood pressure is at or below 120/80mmHg. Small decreases in blood pressure, even as low as 20mmHg, can result in transient hypotension.

In addition to the determined threshold, a sudden drop in systolic blood pressure of about 30mmHg from a typical mean systolic blood pressure of a person may also be diagnosed as hypotension.

Active ingredient

As used herein, the terms "active ingredient of the present application", "first active ingredient of the present application" are used interchangeably and refer to treprostinil and its analogs. Typically, the term includes treprostinil and its pharmaceutically acceptable salts.

Treprostinil is a stable prostacyclin analogue that produces prostacyclin (PGI 2) -like effects, including pulmonary hypertension, inhibition of platelet aggregation, and inhibition of smooth muscle cell proliferation. Intravenous formulations (treprostinil injections) have been approved by the U.S. FDA in month 5 of 2002 for the treatment of patients with pulmonary hypertension. The molecular structure is as follows:

pharmaceutical compositions and methods of administration

The application also provides a pharmaceutical composition, which may be therapeutic or prophylactic. The pharmaceutical composition of the present application comprises (a) a safe and effective amount of a first active ingredient of the present application (treprostinil and its analog or its pharmaceutically acceptable salt); and (b) a pharmaceutically acceptable carrier or excipient.

For the purposes of the present application, an effective dose is about 0.1 nanograms to 200 nanograms per kg/min, with a typical dose of 10 to 100 nanograms per kg/min of the first active ingredient of the application administered to a subject. In addition, the first active ingredient of the present application may be used alone or in combination with other therapeutic agents (e.g., formulated in the same pharmaceutical composition).

The term "pharmaceutically acceptable carrier" refers to a carrier for administration of a therapeutic agent. The term refers to such agent carriers: they do not themselves induce the production of antibodies harmful to the individual receiving the composition and do not have excessive toxicity after administration. Such vectors are well known to those of ordinary skill in the art. A sufficient discussion of pharmaceutically acceptable excipients can be found in Remington's Pharmaceutical Sciences (Mack Pub.Co., N.J.1991). Such vectors include (but are not limited to): saline, buffer, dextrose, water, glycerol, ethanol, adjuvants, and combinations thereof. In addition, auxiliary substances such as wetting or emulsifying agents, pH buffering substances and the like may also be present in these carriers.

In general, the compositions of the present application may be formulated as an injectable, e.g., liquid solutions or suspensions; it can also be made into solid form suitable for formulation into solution or suspension, and liquid excipient prior to injection.

The composition can be made into unit or multiple dosage forms. Each dosage form contains a predetermined amount of active substance calculated to produce the desired therapeutic effect, and suitable pharmaceutical excipients.

Once formulated into the compositions of the present application, they may be administered by conventional routes including, but not limited to: intravenous, intramuscular, intraperitoneal, subcutaneous, intradermal, oral or topical administration. The subject to be prevented or treated may be an animal; especially human and non-human mammals (e.g., pigs).

When the composition of the present application is used for actual treatment, various different dosage forms of the pharmaceutical composition may be employed according to the use condition. These pharmaceutical compositions may be formulated by mixing, diluting or dissolving according to conventional methods, and occasionally adding suitable pharmaceutical additives such as excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents (isotonides), preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizers and cosolvents, and the formulation process may be carried out in a conventional manner according to dosage forms.

The pharmaceutical compositions of the present application may also be administered in the form of a slow release formulation. For example, treprostinil or its salt can be incorporated into a pellet or microcapsule that is supported on a slow release polymer, which is then surgically implanted into the tissue to be treated. Examples of the slow release polymer include ethylene-vinyl acetate copolymer, polyhydroxymethacrylate (polyhydroxymethacrylate), polyacrylamide, polyvinylpyrrolidone, methylcellulose, lactic acid polymer, lactic acid-glycolic acid copolymer, and the like, and preferably biodegradable polymers such as lactic acid polymer and lactic acid-glycolic acid copolymer.

When the pharmaceutical composition of the present application is used for actual treatment, the dose of treprostinil or its pharmaceutically acceptable salt as the first active ingredient can be reasonably determined according to the weight, age, sex, and symptom degree of each patient to be treated.

Typically, treprostinil is administered at a rate of 0.1-200 nanograms/kg/min for septic shock.

The main advantages of the application include:

(1) The treprostinil drug can obviously reduce the death rate, improve the survival rate of patients with sepsis shock, prolong the survival time and improve the cardiac output.

(2) Treprostinil can improve the low heart rate index of septic shock.

(3) By the application of treprostinil, the work of the heart is reduced, so that the liquid in the right heart system can smoothly reach the left heart system, the circulation can be effectively improved, the liquid infusion quantity can be reduced, the right heart load can be lightened, the liquid treatment effect of a patient suffering from sepsis is improved, the occurrence rate of right heart failure is reduced, and the aims of effectively treating low heart discharge and shock of sepsis are fulfilled.

The application will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.

Example 1 construction of sepsis shock pig model

The study was approved by the animal welfare committee. The local Bama miniature pig is adopted for 24 heads, the weight is 22-37kg, and the male and female pigs are not restricted. Levoketamine 4mg/kg and midazolam 0.2mg/kg are intramuscular injected. After waiting for 5 minutes, a 20G intravenous needle (anesthetic pump) was placed in the right ear margin vein of the pig after the drug had been effective. Immediately, cardiac electrical activity was monitored using a 5-lead electrocardiogram, and blood oxygen saturation was monitored on the pig tongue using a finger pulse oxygen detection probe.

The tracheal intubation (model 6-7# of tracheal catheter) is adopted for assisting in breathing, the breathing machine adopts a capacity control ventilation mode, the parameters are set to 10ml/kg of Tidal Volume (TV), the frequency (F) is 16-20 times/min, the Positive End Expiratory Pressure (PEEP) is 3mmHg, and the oxygen partial pressure (FiO 2) is 40%. And (3) adjusting the parameters of the breathing machine according to the blood gas analysis result to maintain the partial pressure of arterial blood carbon dioxide within the range of 40-45 mmHg. The anesthesia maintenance adopts propofol (6-8 mg/kg/h), remifentanil (7-10 mug/kg/h) and cis-atracurium (1 mg/kg/h). Fentanyl (30 μg) or midazolam (5 mg) were additionally injected as necessary. Under the guidance of B ultrasonic, a 4F Picco arterial catheter was inserted into the right femoral artery (invasive blood pressure monitoring), and an 18G single-cavity central venous catheter was placed into the right femoral vein, which was used for fluid infusion and treprostinil pumping in experiments. The right internal jugular vein was punctured, an 8.5F sheath was placed (LPS was pumped in), and then a 7.5F Swan-Gaze catheter was placed in the pulmonary artery. Urine collection adopts bladder puncture under the guidance of B ultrasonic wave. 10% ringer's lactic acid and 10% glucose (G10%) were infused, PCWP was maintained at 6-8 mmHg, blood glucose was controlled at 3.5-5.0 mmol/L, and blood temperature was maintained at about 38℃with a warming blanket. Wait for the system to stabilize for 1 hour.

Heart Rate (HR), mean Arterial Pressure (MAP), mean Pulmonary Arterial Pressure (MPAP), central venous pressure (CVP, right atrial chamber of Swan-size catheter), pulmonary Arterial Wedge Pressure (PAWP) were monitored by a BeneView T9 monitor (acquisition frequency 0.2 Hz). Central venous oxygen saturation (SVO 2), cardiac Output (CO), right heart stroke volume (RVSV), and right heart end diastole volume (RVEDV) were monitored using a Vigilance monitor. The right heart ejection fraction was calculated from the stroke volume and end diastole volume of the right heart (rvef=rvsv/RVEDV), the pulmonary circulation resistance (PVR) was calculated from pulmonary artery mean pressure, pulmonary artery wedge pressure, cardiac output (pvr=80 x (MPAP-PAWP)/CO), and the peripheral circulation resistance (SVR) was calculated from mean arterial pressure, central venous pressure and cardiac output (svr=80 x (MAP-CVP)/CO). Blood gas analysis was performed by danish Rate ABL90 (Radiometer ABL 90).

Establishing a sepsis shock model: all animals were given ringer's lactate 3mL/kg/h as a maintenance solution at T0-T10. After stabilization for 1 hour, 24 pigs were continuously infused with LPS (Sigma; E.coli lipopolysaccharide, 0111: B4, L2630-100 mg,129K 4025) from a sheath of 8.5F starting at T0 h. The infusion rate was 30. Mu.g/kg/h for 1h, then dropped to 20. Mu.g/kg/h, and the infusion was continued for 1h, then at a rate of 10. Mu.g/kg/h for the remaining observation time (T2 h-T10 h).

Example 2 treprostinil improves survival time and survival rate in sepsis shocked pigs

Starting at T2h, the experimental animals were randomly divided into 2 groups of 6 pigs each using a random block grouping method (weight and age are similar, sex differences are equally distributed between groups). The LPS infusion was started from 0h and continued until the end of the experiment (10 h). The control group was infused with LPS only and maintained in a physiologically desirable amount of ringer's lactate 3ml/kg/h. The experimental group was subjected to treprostinil treatment (80 ng/kg/min) starting from 2h, except for LPS and maintenance fluid, for the end of the experiment (10 h). Each data point is represented by a mean and a mean standard error, and data is collected every half hour. Wilcoxon's rank-sum test was used to compare the variability of the measurements of the experimental and control groups at the same time point.

The results are shown in Table 1 and FIG. 1. Pigs in the control group developed death due to septic shock during the course of the experiment. The number of pigs surviving the control group within 10 hours was as follows: at 0h, n=6; at 5h, n=5; at 6.5h, n=4; at 9h, n=3; n=2 at 10 h. The cause of death in 4 pigs in the control group (6) was identified as circulatory failure or ventricular fibrillation, respectively (table 1).

Experimental group 6 experimental pigs survived during the observation period (10 h) and the improvement of the hemodynamics was evident.

TABLE 1 survival time and cause of death of subjects in 10h of control group

Example 3 treprostinil improves hemodynamic and blood-qi index in sepsis shocked pigs

Starting at T2h, the experimental animals were randomly divided into 2 groups of 6 pigs each using a random block grouping method (weight and age are similar, sex differences are equally distributed between groups). The LPS infusion was started from 0h and continued until the end of the experiment (10 h). The infusion rate of LPS was 30. Mu.g/kg/h for 1h, then dropped to 20. Mu.g/kg/h, the infusion was continued for 1h, then at a rate of 10. Mu.g/kg/h for the remaining observation time (T2 h-T10 h).

Group 1, in which only 3ml/kg/h of maintenance solution was administered;

group 2, continuous infusion of treprostinil 80ng/kg/min from the central venous catheter of the femoral vein on a maintenance fluid basis.

Hemodynamic data was collected every half hour. Arterial blood was drawn at 9 time points T0, 1, 2, 3, 4, 5, 6, 8, 10 for blood gas analysis.

The hemodynamic results are shown in fig. 2. Treprostinil reduces pulmonary arterial pressure (t >4h, p < 0.05) and pulmonary circulatory resistance (t >5h, p < 0.05), improves cardiac output (5 h-9h, p < 0.05), stroke volume (6 h-7h, p < 0.05) and ejection fraction (7 h-8h, p < 0.05) (+.LPS control; ■ treprostinil treatment).

The results of the blood gas analysis are shown in Table 2.

TABLE 2 influence of treprostinil on sepsis shock pig haemodynamics

Comment ×: p <0.05vs. control group

The result shows that treprostinil improves the oxygenation index of the sepsis shock pig, reduces the hematocrit (without significant difference) and has no obvious influence on other blood and qi indexes

Example 4 treprostinil improves urine output in sepsis shocked pigs

Urine collection adopts bladder puncture under the guidance of B ultrasonic wave. Urine amounts of the LPS control group and treprostinil treated group were 1.6ml/kg/h and 3.8ml/kg/h (p < 0.05), respectively.

The results are shown in figure 3, treprostinil significantly improved urine volume in septic shock.

Discussion of the application

The main treatments of sepsis, sepsis hypocresis and shock at present comprise identification of infection sources and anti-infection (root of sepsis treatment), liquid resuscitation treatment, vasoactive drugs, glucocorticoids, immune conditioning, anticoagulation and other early target-oriented treatments, and especially the use of liquid resuscitation and vasoactive drugs is two-basic stone for hemodynamic management of sepsis patients. After early targeted therapy was proposed from river et al, there is a constant search for more optimal liquid resuscitation strategies. Based on ProCESS, ARISE and ProMISE et al studies, the 2016 version of the sepsis guideline eliminates the goal-directed fluid treatment regimen and the best regimen for fluid treatment requires more study. Norepinephrine is still the first boost drug recommended by the current guidelines for sepsis, but at present, the timing, dosage, etc. of its application need further study confirmation. In short, the sepsis low heart rate and shock still have higher mortality under the current treatment methods, and the sepsis low heart rate and shock have no definite treatment scheme, so that the development of clinical medicines for treating sepsis is urgent.

Existing fluid resuscitation and vasoactive drug based therapies are similar to Ma Jiabian for patients who have been in the late stages of sepsis, develop hypocardiac drainage and shock. The proposal increases the front load and the back load of the heart on one hand, and continues the contraction function of overdraft cardiac muscle on the other hand to improve the blood discharge amount of the heart, thereby improving shock.

Based on the existing treatment scheme, sepsis, low heart rate of sepsis and shock still have higher illness mortality, and are still main causes of worldwide health threat, the medical field is urgent to formulate global sepsis control measures, and further the disease burden of patients and countries is relieved.

The research of the application suggests that treprostinil or the analogue thereof can reduce the work of the heart in the process of pumping blood flow from the right heart to the left heart, thereby improving the blood pumping function of the heart and improving the blood discharge quantity of the heart. The pharmacological mechanism of the traditional therapeutic medicine is different from that of the traditional therapeutic medicine, namely, the load before and after the heart is not increased, and the contraction function of the cardiac muscle is not increased, so that the burden of a circulatory system is lightened, the effect of sepsis shock treatment is improved, and the survival rate and the survival time of sepsis shock patients are improved.

All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (10)

1. The use of treprostinil and its analogues for the preparation of a medicament for the treatment of septic shock.

2. The use of claim 1, wherein the septic shock is shock caused by sepsis due to a microbial infection.

3. The use of claim 1, wherein the septic shock is characterized by one or more of the following:

(a) Low heart row: heart index lower than 1.8L/min/m ² ；

(b) Heart function decreases: cardiac output is lower than 4.0L/min;

(c) Blood pressure drop: mean Arterial Pressure (MAP) <65mmHg;

(d) Sepsis: rapid sequential organ failure score (qSOFA) > 2.

4. The use according to claim 1, wherein the treprostinil and its analog comprises treprostinil or a pharmaceutically acceptable salt thereof.

5. The use according to claim 1, wherein the medicament comprises (A1) a first active ingredient selected from the group consisting of: treprostinil and its analogs; and (B) a pharmaceutically acceptable carrier.

6. The use according to claim 1, wherein the pharmaceutical composition further comprises (A2) a second active ingredient selected from the group consisting of: dopamine, norepinephrine, epinephrine, milrinone, amirinone, prostacyclin, or a combination thereof.

7. The use according to claim 1, wherein the pharmaceutical dosage form is liquid or solid.

8. The use according to claim 1, wherein the medicament is an intravenous injection, or a subcutaneous injection, or an intra-airway inhalation.

9. A kit, comprising:

(a) A pharmaceutical composition comprising prostaglandins and analogues thereof and a pharmaceutically acceptable carrier;

(b) A rapid sequential organ failure scoring (qSOFA) tool; and

(c) Instructions describing administration of the pharmaceutical composition to a sepsis shock patient.

10. A method of treating or preventing septic shock comprising the steps of: (a) administering treprostinil and its analog to a subject.