WO2021179555A1

WO2021179555A1 - Marker for viral pneumonia and application thereof

Info

Publication number: WO2021179555A1
Application number: PCT/CN2020/113939
Authority: WO
Inventors: 李尹雄; 陈彦; 游凯; 谭圣林
Original assignee: 中国科学院广州生物医药与健康研究院
Priority date: 2020-03-09
Filing date: 2020-09-08
Publication date: 2021-09-16
Also published as: CN113376386A

Abstract

A marker for viral pneumonia and application thereof, applied in the field of drugs. The marker for viral pneumonia is prostaglandin E2 and/or prostaglandin M. By taking the prostaglandin E2 and/or prostaglandin M as a marker for viral pneumonia, the use of a cyclooxygenase II inhibitor can effectively and quickly reduce prostaglandins, thus reversing the progression of common and severe illness, preventing the occurrence of critical illness, and accelerating virus elimination, pneumonia inflammation reduction, and recovery. Once the efficacy is further confirmed, the scope of clinical use of the drug can be expanded, and the treatment method can be applied to clinical diagnosis and treatment, so as to provide a new strategy and diagnosis and treatment method for comprehensive treatment of COVID-19.

Description

A marker of viral pneumonia and its application

Technical field

This application relates to the field of drug applications, in particular to a marker for viral pneumonia and its application.

Background technique

Coronavirus is a large virus family, known to cause colds and more serious diseases such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS). Common signs of people infected with coronavirus include respiratory symptoms, fever, cough, shortness of breath, and difficulty breathing. In more severe cases, the infection can lead to pneumonia, severe acute respiratory syndrome, kidney failure, and even death. There is currently no specific treatment for the disease caused by the new coronavirus.

Celecoxib (Celecoxib) has a unique mechanism of action that specifically inhibits COX-2, and its chemical name is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1hydro-1 -Pyrazol-1-yl]benzenesulfonamide, its molecular formula is C17H14F3N3O2S, molecular weight is 381.38; Celecoxib is the first specific cyclooxygenase II (COX-2) inhibitor jointly developed by Sealle and Pfizer Celecoxib capsule was first approved for marketing in the United States in January 1999. It is used to relieve arthritis-related pain. It is currently the world's most prescribed non-steroidal anti-inflammatory analgesic. Inflammatory stimulation can induce the production of COX-2, which leads to the synthesis and accumulation of inflammatory prostaglandins, especially prostaglandin E2, which in turn causes inflammation, edema and pain. Celecoxib can prevent the production of inflammatory prostaglandins by inhibiting COX-2, and achieve anti-inflammatory, analgesic and antipyretic effects. Celecoxib is clinically used to treat bones and joints, rheumatoid arthritis, acute pain, ankylosing spondylitis and so on.

Regarding the application of cyclooxygenase II inhibitors, especially celecoxib in coronavirus pneumonia, there are no relevant reports.

Summary of the invention

This application provides a marker for viral pneumonia and its application. This application provides a new way and choice for the treatment of viral pneumonia, especially coronavirus pneumonia.

To achieve this goal, this application adopts the following technical solutions:

In the first aspect, this application provides a marker for viral pneumonia, and the marker for viral pneumonia is prostaglandin E2 (PGE2) and/or prostaglandin M (PGEM).

In this application, the inventors analyzed the clinical data and the gene function research of the novel coronavirus, SARS-CoV and MERS-CoV. The three coronaviruses share one protein: the nucleocapsid N protein, which directly binds to COX- 2 gene promoter, start the gene transcription of COX-2, cause the increase of COX-2 expression in the lung, it can be seen that COX-2 is positively correlated with the concentration of nucleocapsid N protein, and the catalytic product of COX-2 is prostaglandin (PGE The production of D, F, TBX) is increased, and the degradation of lung parenchyma is reduced, causing excessive accumulation of prostaglandins. It is speculated that cyclooxygenase II (COX-2) is the key target, and the increased prostaglandin is the cause of viral pneumonia The pathological basis shows that PGE2 and PGEM can be used as markers of viral pneumonia.

According to the application, the marker is abnormally elevated in the urine of patients with viral pneumonia.

In this application, the inventor tested the presence of a high amount of prostaglandin E2 (PGE2) in the urine of patients with new coronary pneumonia, and its concentration can reach 1000-6000ng/ml, while the level of normal people (in our current test samples) It is 0-30ng/ml, and the inventor further measured the prostaglandin and its metabolite PGEM (prostaglandin E metabolite) in the patient’s serum and/or urine, and its concentration far exceeded the normal concentration of 0-20ng/ml. , Thus verifying that the prostaglandin concentration is related to coronavirus pneumonia, and COX-2 inhibitors can reduce the prostaglandin concentration, thereby realizing the treatment of coronavirus pneumonia.

According to the present application, the prostaglandin E2 in the marker is abnormally increased in the early and mid-stage of viral pneumonia, and the concentration of the prostaglandin E2 in the marker is positively correlated with the progression of the viral pneumonia.

In this application, the increase rate of PGE2 in the urine of patients with viral pneumonia is 100%, the change of PGE2 is 1-3 days earlier than the CT image diagnosis, and the correct rate of predicting the disease trend is more than 85%.

According to the present application, the prostaglandin M in the markers is abnormally increased in the middle and late stages of viral pneumonia, and the concentration of prostaglandin M in the markers is positively correlated with the severity of viral pneumonia. When the PGEM rises, it is an early warning of viral pneumonia. Entering the critically ill or critically ill stage, the function of multiple organs in the whole body declines or fails.

In this application, the inventor found that both PGE2 and PGEM will increase during the course of pneumonia patients. The increase in the concentration of PGE2 is positively correlated with the exacerbation of pneumonia, and the increase in the concentration of PGEM is positively correlated with the severity of pneumonia.

According to the application, the viral pneumonia is coronavirus pneumonia, preferably influenza, bird flu, coronavirus SARS-CoV-2 infected pneumonia, coronavirus SARS-CoV infected pneumonia, or coronavirus MERS-CoV infection Any one or a combination of at least two of the pneumonia is preferably pneumonia infected by the coronavirus SARS-CoV-2.

In the second aspect, the present application provides the marker as described in the first aspect as a marker for any one or a combination of at least two of viral pneumonia early warning, curative effect observation and prognosis judgment. Preferably, prostaglandin E2 is used as a marker in the marker Viral pneumonia early warning, curative effect observation and prognosis judgment any one or a combination of at least two markers.

In the third aspect, the present application provides the marker as described in the first aspect as a severe viral pneumonia and/or critical viral pneumonia marker, preferably prostaglandin M in the marker is used as severe viral pneumonia and/or viral pneumonia Critical illness markers.

In this application, the main cause of death in patients with coronavirus infection is acute respiratory distress syndrome. Coronavirus infection causes an increase in the expression of COX-2 in the lungs, which catalyzes the transformation of arachidonic acid into prostaglandins; at the same time, the function of lung tissue cells is decreased due to infection. , Can not degrade prostaglandin, the two add up, resulting in excessive accumulation of prostaglandin in the lungs, which is also the key pathological basis of coronavirus pneumonia and respiratory distress syndrome. Excessive prostaglandin promotes the pathological development of new coronavirus pneumonia (new coronary pneumonia): (1) Increased inflammatory secretions, alveolar surface edema, and the formation of a water film covering the alveoli, hindering blood oxygen exchange, resulting in a decrease in blood oxygen; ( 2) Causes high-strength contraction of small bronchi and small blood vessel smooth muscles, leading to small bronchospasm, increasing airway resistance, and even lung lobes dilation; hemodynamic disorders, respiratory rate and heart rate are fast and inefficient, and gradually develop to cause breathing Distress and multiple organ failure; (3) Inhibition of the function and number of lymphocytes, especially T cells, leads to a decrease in the total number and proportion of idiosyncratic lymphocytes, which is conducive to the replication and expansion of the virus, which is the cause of coronavirus pneumonia The pathological evolution process in the early and mid-term, entering the critical stage can trigger a storm of immune factors, which is life-threatening.

In a fourth aspect, the present application provides a medicine for treating viral pneumonia, which inhibits the rise of prostaglandins.

According to the present application, the active ingredient of the drug is a cyclooxygenase II inhibitor or a pharmaceutically acceptable salt, ester, or solvate thereof.

According to the present application, the cyclooxygenase II inhibitor is a non-steroidal compound, preferably a coxib compound, and more preferably celecoxib.

In this application, the inventor found that non-steroidal drugs, especially coxib drugs, as anti-inflammatory drugs, are a type of cyclooxygenase II antagonist, which can reduce the production of prostaglandins, thereby realizing the treatment of viral pneumonia.

In a specific embodiment, the drug can also be added to one or more pharmaceutically acceptable carriers, which include conventional excipients, diluents, carriers, flavoring agents, binders and fillers in the pharmaceutical field. Any one or a combination of at least two of the agents.

In a specific embodiment, the drug is introduced into the body by injection, jetting, penetration, absorption, physical or chemically mediated methods alone, and the body includes but not limited to muscle, intradermal, subcutaneous, vein, and mucosal tissues; The medicine can also be introduced into the body after being mixed or wrapped by other substances.

In this application, the cyclooxygenase II inhibitor or its pharmaceutically acceptable salt, ester, or solvate as the active ingredient can be prepared into injections, tablets, powders, granules, capsules, oral liquids, etc. Various forms of the above-mentioned various dosage forms of drugs can be prepared according to conventional methods in the field of pharmacy.

In the fifth aspect, the present application provides a pharmaceutical composition for treating viral pneumonia, the composition including a cyclooxygenase II inhibitor and an antiviral drug.

Compared with the prior art, this application has the following beneficial effects:

(1) It is found in this application that the increase rate of PGE2 in the course of patients with new coronary pneumonia is 100%, and the increase in PGE2 concentration is positively correlated with the exacerbation of pneumonia. The change of PGE2 is 1-3 days earlier than the CT image diagnosis, and the correct rate of predicting the disease is 85. % Above, PGEM increases in the late stage of viral pneumonia, which is closely related to the severity of viral pneumonia. It can be seen that changes in PGE2 and/or PGEM indicators can be used as markers of viral pneumonia;

(2) This application monitors the changes in the concentration of PGE2 in the urine of the patient, which can warn the progress of the disease 1-3 days in advance, so that corresponding treatment measures can be taken in advance. The use of regular doses of celecoxib to inhibit type II cyclooxygenase can be effective Quickly reduce prostaglandins, reverse the progression of common and severe disease, block the occurrence of critical illness, promote virus conversion, pneumonia absorption and health recovery.

Description of the drawings

Figure 1 is a mass spectrum showing that the urine PGE2 of patients with new coronary pneumonia is significantly higher than that of normal people. Figure 1(A) shows the specific peaks of PGE2 standard by liquid phase mass spectrometry; Figure 1(B) shows the mass spectrometry quantitative standard curve; Figure 1(C) shows the specific peaks of urine PGE2 of COVID-19 patients; Figure 1(D) shows that the urine PGE2 concentration of COVID-19 patients is significantly higher than that of the normal population. **, p<0.01;

Figure 2 shows changes in the urine PEG2 level. Figure 2(A) shows the peak value of PEG2 in urine above 1000ng/ml. Figure 2(B) shows the patient's PEG2 rising above 1000ng/ml. The CT results of the peak value. Figure 2(C) is the graph of the drop of PEG2 in the urine from the peak value of more than 1000ng/ml. Figure 2(D) is the CT result of the patient's PEG2 falling from the peak of more than 1000ng/ml in the case. Figure 2( E) is a small-amplitude vibration image of PEG2 in urine below 100ng/ml baseline, Figure 2(F) is a CT result of a patient's PEG2 with small-amplitude vibration below 100ng/ml baseline in the case;

Figure 3 is a graph showing the results of using celecoxib to accelerate the improvement of common patients. Figure 3(A) shows the change of PEG2 level in control case 1, and Figure 3(B) shows the change in PEG2 level of case 31 in the experimental group. , Figure 3 (C) is the CT result of the control case 1, and Figure 3 (D) the CT result of the experimental group case 31;

Figure 4 shows the results of using Celecoxib to accelerate the improvement of severe patients. Figure 4(A) shows the change of PEG2 level in control case 2, and Figure 4(B) shows the change in PEG2 level of case 22 in the experimental group. , Figure 4 (C) is the CT result of the control case 2, and Figure 4 (D) the CT result of the experimental group case 22;

Figure 5 is a graph showing the improvement of the patient's condition with adjuvant celecoxib for more than 10 days after admission to the hospital. Figure 5(A) shows the change of PEG2 level in case 1, and Figure 5(B) shows the change in PEG2 level of case 6 , Figure 5(C) is the CT result of case 1, and Figure 5(D) is the CT result of case 6;

Figure 6 shows the results of patients who discontinued celecoxib treatment. Figure 6(A) shows the change of PEG2 level in case 5, Figure 6(B) shows the change in PEG2 level of case 14, and Figure 6(C) shows the case CT results of 5, Figure 6(D) CT results of case 14.

Detailed ways

In order to further illustrate the technical means adopted by this application and its effects, the technical solutions of this application will be further described below with reference to the drawings and specific implementations, but this application is not limited to the scope of the embodiments.

The process, conditions, reagents, experimental methods, etc. of the implementation of this application, except for the content specifically mentioned below, are all common knowledge and common knowledge in the field, and there is no particular limitation on the content of this application.

Unless otherwise specified, the meanings of all professional terms and scientific terms used in this specification are the same as those generally understood by those skilled in the technical field to which this application belongs. However, in case of conflict, the specification including definitions shall prevail.

Example 1 Quantitative detection of urine PGE2 water concentration by high performance liquid phase mass spectrometry

The Agilent 1290 Infinity II high-performance liquid chromatograph and the Agilent 6470 triple quadrupole mass spectrometer combined system were used. Chromatographic conditions: Chromatographic column Agilent Zorbax Eclipse plus C18 3.0×150mm, 1.8μm pore size; mobile phase A: water (containing 0.1% HCOOH), mobile phase B: CH3CN (containing 0.1% HCOOH); flow rate 0.4 mL/min, gradient wash Take off; the injection volume is 20μL, and the column temperature is 30°C. Mass spectrometry conditions: ESI source, negative ion, MRM mode. PGE2 monitoring m/z 351.1 → m/z 271.3.

Standard curve preparation: use artificial urine (Leagene, article number: CZ0350) to prepare PGE2 (Cayman, article number: 14010) standard series concentration: 5, 10, 25, 50, 75, 100, 250 and 500ng/mL; then add 3 Double the volume of anhydrous ethanol, add an equal volume of anhydrous methanol after mixing, 13000rcf, centrifuge for 30 minutes at 4°C, take the supernatant, dilute it with 0.01% formic acid (Dikma, 50144) aqueous solution 5 times, mix and load the sample.

Sample pretreatment: Urine is directly connected to a collection tube containing 3 times the volume of absolute ethanol for inactivation, after mixing, add an equal volume of anhydrous methanol, centrifuge at 13000rcf, 4℃ for 30 minutes, take the supernatant, and use 0.01% formic acid Dilute the aqueous solution 5 times, mix well and load the sample.

Results: Mass spectrometry detection of urine PGE2 showed that patients with new coronary pneumonia were significantly higher than normal

In order to detect the level of PGE2 in urine, a method for the detection of PGE2 by liquid phase mass spectrometry was first established. The synthetic PGE2 is used as the standard, and the artificial urine containing the basic components of human urine is used to dilute the standard. The mass spectrometry results showed that the standard product showed a single specific peak pattern (Figure 1A), and the standard curve was linear (goodness of fit value R ² >0.99) (Figure 1B); urine samples from COVID-19 patients showed PGE2 Specific peak (peak time is 1.437 min), the integrated sum of the area of this specific peak represents the concentration of PGE2 (Figure 1C, arrow shown). The levels of PGE2 in urine samples of 8 normal people and 10 COVID-19 patients were summarized. Taking into account the development of the disease and the influence of medication on the detection of PGE2 concentration, try to select the urine of patients who were admitted within 2 days for testing. Of course, these patients are likely to have used anti-fever drugs such as Bunofen before or within two days of admission. Even so, the test results showed that the level of PGE2 in the urine of early COVID-19 patients was significantly higher than that of normal people (170±40ng/mL vs 18.8±3.8ng/mL, P<0.01) (Figure 1D). Based on the above test results, it is preliminarily determined that the normal threshold of PGE2 in normal human urine samples is less than 20 ng/mL. If the level of PGE2 in urine continues to be greater than 100ng/mL, it indicates that the body's inflammatory response is active, and 100ng/mL is set as the risk threshold.

Example 2 Initial clinical trial of celecoxib

In this example, on the basis of conventional treatment following the guidelines, in cooperation with the Eighth People's Hospital of Guangzhou City, a clinical study of the type II cyclooxygenase inhibitor celecoxib in the treatment of new coronary pneumonia was carried out, and the adjuvant celecoxib was used For clinical research, take oral medication for 10-14 days, 200 mg twice a day, each time, the specific cases are as follows:

In the first batch, 8 cases were included in the experimental group (4 cases of severe disease, 4 cases of ordinary type) and 7 people in the control group (7 cases of ordinary type). Follow-up evaluations were conducted on the 4th and 10th days of treatment and found that the disease had returned All were improved, and there was no serious disease; in the control group, the return of the disease was in aggravation, no change and improvement in the three categories of 42%, 14% and 42%, respectively. The curative effect of the experimental group was significantly better than that of the control group. According to the medical ethics and international standards of clinical trials, the control status of patients with worsening conditions in the control group was terminated and transferred to the experimental group for treatment; the parallel grouping method was abandoned and most new patients were included in the experimental group.

Example 3 Expansion of celecoxib clinical trial

In this example, in order to further verify the clinical study of the type II cyclooxygenase inhibitor celecoxib in the treatment of new coronary pneumonia, the enrolled population was further increased. The specific cases are as follows:

As of February 23, 2020, 31 cases were formally enrolled in the test group (6 cases of severe disease, 25 cases of common type). The specific medication situation and results are shown in Table 1 below:

It can be seen from Table 1 that in all 38 cases including the test group and the control group, 84.2% (32/38) of the patients were admitted to the hospital with milder disease (light or normal CT imaging manifestations), 15.7% ( 6/38) patients were admitted to the hospital with a severe condition (severe), after treatment (1) 31/31 cases improved (improvement rate 100%); (2) 31/31 cases of virus turned negative (turning negative rate 100%) (3) 0/31 cases were aggravated (exacerbation rate 0%); (4) 0/31 cases had no change (no change rate: 0%); (5) 15 cases have been discharged from the hospital, and 16 cases are still in hospital for treatment; ( 6) Except for 1 case of discontinuation due to excessive sweating and suspected side effects, no side effects were observed in the rest. Observations in a limited number of clinical trial groups suggest that the use of regular doses of celecoxib (0.2 g/time bid) can effectively reduce prostaglandins, reverse the progression of common and severe disease, block the occurrence of critical illness, and promote virus conversion. , Pneumonia absorption and health recovery.

Example 4 Clinical diagnosis of PGE2

In this example, in order to further verify the clinical study of the type II cyclooxygenase inhibitor celecoxib in the treatment of new coronary pneumonia, and to further analyze the correlation between PGE2 and changes in the condition of new coronary pneumonia, this example tracks and detects patients with new coronary pneumonia every day The level of PGE2 in urine was compared with CT results, and the results are shown in Figure 2.

It can be seen from Figure 2 that there are three patterns of changes in PGE2 levels between two adjacent CT detections: 1) Figure 2(A) has a climbing peak exceeding 1000ng/ml; 2) Figure 2(C) The drop from the peak value of more than 1000ng/ml; 3) Figure 2(E) shows a small amplitude vibration below the baseline of 100ng/ml; corresponding analysis of the two adjacent CT results, the same corresponding to the occurrence of three disease regressions, As shown in Figure 2(B), Figure 2(D) and Figure 2(F), we have defined three types of PGE2 changes and follow-up CT diagnosis results that are completely consistent with the worsening, improvement and no change of pneumonia.

In the case of excluding other interfering factors such as inflammatory diseases, we retrospectively analyzed 58 PGE2 concentration dynamic change events, and correspondingly analyzed the CT image results of patients before and after the PGE2 change. Among them, 47 events had PGE2 advance change patterns and predicted subsequent CT The diagnosis results showed that the return of the disease was completely consistent. The correct rate of predicting the direction and progress of the disease in advance reached 81%, and the advance time was 1-3 days, indicating that the concentration of urine PGE2 was positively correlated with the process of pneumonia, and had a predictive effect. Judgment of early warning effect.

Example 5 Clinical trial results of celecoxib in the treatment of common patients

In this example, in order to further verify the clinical study of the type II cyclooxygenase inhibitor celecoxib in the treatment of new coronary pneumonia, this example analyzes and compares two common cases with similar disease and course (control case 1 and experimental Group case 31) PGE2 and lung CT image changes, the results are shown in Figure 3.

It can be seen from Figure 3 that the PGE2 level of case 1 in the control group was maintained at a high level of 1000 ng/ml from the 5th to 9th days of admission (Figure 3(A)), while the PGE2 level of case 31 in the experimental group was second from admission to the hospital. It is more than 1000ng/ml every day, and it stably drops to about 100ng/ml within two days (Figure 3(B)); the corresponding CT results show that the absorption of pneumonia foci in case 31 of the experimental group is faster than that of control case 1 (Figure 3 (C)-Figure 3(D)).

Analyzing the efficacy of ordinary new coronary pneumonia, none of the 25 ordinary patients in the test group progressed to severe disease. Compared with the control group, under the treatment of celecoxib, the concentration of PGE2 in the test group can be effectively controlled, and the absorption of pneumonia is relatively fast. It can be seen that the use of celecoxib to assist conventional treatment may accelerate the improvement of ordinary patients.

Example 6 Clinical trial results of celecoxib in the treatment of critically ill patients

In this example, in order to further verify the clinical study of the type II cyclooxygenase inhibitor celecoxib in the treatment of new coronary pneumonia, this example analyzes and compares the control group (control case 2) and the experimental group (experimental group case 22) The PGE2 and lung CT image changes of 1 patient each, the results are shown in Figure 4.

It can be seen from Figure 4 that the PGE2 level of the control case 2 has been fluctuating within the concentration range of 1000ng/ml from the 5th to the 12th day of admission (Figure 4(A)), while the PGE2 level of the case 22 was Coxib decreased steadily under the control, and finally maintained at a concentration range of less than 100ng/ml (Figure 4(B)); CT imaging results showed that pneumonia recurred in the control group, while the absorption rate of pneumonia in case 22 of the test group was significantly faster than that of the test group. Control case 2 (Figure 4 (C)-Figure 4 (D)).

It can be seen that in the 6 severe patients in the experimental group, none of the patients progressed to critical illness after celecoxib treatment. The use of celecoxib in adjuvant conventional treatment may block the occurrence of critical illness.

Example 7 Clinical trial results of celecoxib in the treatment of severely ill patients who were admitted to the hospital for more than 10 days and continued to aggravate the disease

In this example, in order to further verify the clinical study of the type II cyclooxygenase inhibitor celecoxib in the treatment of new coronary pneumonia, this example analyzes and compares two patients (case 1 and case 6). The two patients were admitted to the hospital. After 12-15 days of conventional treatment, the condition worsened from ordinary to severe, and celecoxib was used on the basis of the original conventional treatment. The PGE2 and lung CT image changes of the two patients were compared. The results are shown in Figure 5. Show.

Case 1 stopped taking celecoxib due to sweating on the 5th day of treatment with celecoxib. Even though there was only a 5-day course of treatment, the patient continued to improve and was discharged from the hospital (Figure 5(A)). Case 6 continued to be administered Next, the patient's condition improved (Figure 5(B)), and the CT imaging results showed that: the condition gradually stabilized and improved (Figure 5(C)-Figure 5(D)).

It can be seen that after the use of celecoxib, PGE2 is controlled, and the condition improves steadily from cloth to cloth. The use of celecoxib treatment reverses the progress of severe illness and blocks the occurrence of critical illness.

Example 8 Clinical trial results of patients with discontinuation of celecoxib in the treatment of patients

In this example, in order to further verify the clinical study of the type II cyclooxygenase inhibitor celecoxib in the treatment of new coronary pneumonia, this example analyzes and compares two patients (case 5 and case 14), these two patients are using Celecoxib was discontinued after 11 days of treatment, and the PGE2 and lung CT image changes of the two patients were compared. The results are shown in Figure 6.

It can be seen from Figure 6 that case 5 showed a slight aggravation on the 3rd day after the drug was stopped, and then recovered on its own (Figure 6(A)); while case 14 only experienced a slight aggravation on the 6th day after the drug was stopped. In the case of (Figure 6(B)), the CT results also showed repeated symptoms (Figure 6(C)-Figure 6(D)).

It can be seen that after stopping the use of celecoxib, the condition has been repeated.

Example 9 Clinical diagnosis of PGEM

In this example, in order to further verify the clinical study of the type II cyclooxygenase inhibitor celecoxib in the treatment of new coronary pneumonia, and to further analyze the correlation between PEGM and changes in the condition of new coronary pneumonia, this example tracks and detects patients with new coronary pneumonia every day The level of PEGM in urine, the results are shown in Table 2.

Table 2 Daily patient urine PGEM (ng/mL)

It can be seen from Table 2 that PGEM is abnormally elevated, PGEM is elevated in the middle and late stages of the disease course, and the concentration of PGEM is related to the severity of pneumonia.

In summary, according to the observations of a limited number of clinical trial groups, this application suggests that changes in PGE2 indicators may have the effects of early warning, observation of curative effects and prognostic judgments. At the same time, celecoxib can effectively reduce the level of PGE2 in patients. Promote the improvement of patients with ordinary and severe COVID-19 new coronary pneumonia, and prevent the disease from progressing to severe or critical illness.

The applicant declares that this application uses the above-mentioned embodiments to illustrate the detailed methods of this application, but this application is not limited to the above-mentioned detailed methods, which does not mean that this application must rely on the above-mentioned detailed methods to be implemented. Those skilled in the art should understand that any improvement to this application, the equivalent replacement of each raw material of the product of this application, the addition of auxiliary components, the selection of specific methods, etc., fall within the scope of protection and disclosure of this application.

Claims

A marker for viral pneumonia, wherein the marker for viral pneumonia is prostaglandin E2 and/or prostaglandin M.
The marker according to claim 1, wherein the marker is abnormally elevated in the urine of patients with viral pneumonia;

Preferably, the prostaglandin E2 in the marker is abnormally increased in the early and mid-course of viral pneumonia;

Preferably, the concentration of prostaglandin E2 in the marker is positively correlated with the progression of viral pneumonia;

Preferably, the prostaglandin M in the marker is abnormally increased in the middle and late stages of the course of viral pneumonia;

Preferably, the concentration of prostaglandin M in the marker is positively correlated with the severity of viral pneumonia;

Preferably, the viral pneumonia is coronavirus pneumonia, influenza or avian influenza, more preferably coronavirus SARS-CoV-2 infected pneumonia, coronavirus SARS-CoV infected pneumonia, or coronavirus MERS-CoV infection Any one or a combination of at least two of the pneumonia is more preferably the pneumonia infected by the coronavirus SARS-CoV-2.
The use of the marker according to claim 1 or 2 for any one or a combination of at least two of viral pneumonia early warning, curative effect observation and prognosis judgment.
The use according to claim 3, wherein the marker is prostaglandin E2;

Preferably, the marker is used as a severe viral pneumonia and/or critical viral pneumonia marker.
The use according to claim 3, wherein the marker is prostaglandin M, and the prostaglandin M is used as a severe viral pneumonia and/or critical viral pneumonia marker.
The use according to any one of claims 3-5, wherein the viral pneumonia is coronavirus pneumonia, influenza or bird flu, preferably pneumonia infected by the coronavirus SARS-CoV-2, coronavirus Any one or a combination of at least two of SARS-CoV-infected pneumonia or coronavirus MERS-CoV-infected pneumonia, more preferably coronavirus SARS-CoV-2 infection.
The use according to claim 3, wherein if the concentration of prostaglandin E2 in the urine of the patient increases, the patient suffers from viral pneumonia, preferably coronavirus SARS-CoV-2 infected pneumonia, more preferably coronavirus Early and mid-stage pneumonia infected by the virus SARS-CoV-2; and/or

If the concentration of prostaglandin M in the urine of the patient increases, the patient has viral pneumonia, preferably coronavirus SARS-CoV-2 infected pneumonia, more preferably coronavirus SARS-CoV-2 infected pneumonia in the middle and late stages .
The use according to claim 3, wherein if the concentration of prostaglandin E2 in the urine of the patient is greater than or equal to 100 ng/ml, the patient has viral pneumonia, preferably pneumonia infected by the coronavirus SARS-CoV-2 , More preferably early to mid-stage pneumonia infected by coronavirus SARS-CoV-2; and/or

If the concentration of prostaglandin M in the urine of the patient is greater than or equal to 20 ng/ml, the patient is suffering from viral pneumonia, preferably coronavirus SARS-CoV-2 infected pneumonia, more preferably coronavirus SARS-CoV-2 infection Mid-to-late pneumonia.
The use according to claim 4, wherein if the concentration of prostaglandin E2 in the urine of the patient is greater than or equal to 1000 ng/ml, the patient has severe or critically ill viral pneumonia.
A medicine for treating viral pneumonia, wherein the medicine inhibits the increase of prostaglandin.
The drug according to claim 10, wherein the drug is a cyclooxygenase II inhibitor or a pharmaceutically acceptable salt, ester, or solvate thereof;

Preferably, the cyclooxygenase II inhibitor is a non-steroidal compound, preferably a coxib compound, and more preferably celecoxib.
The medicine according to claim 10 or 11, wherein the medicine further comprises pharmaceutically acceptable excipients;

Preferably, the adjuvant is any one or a combination of at least two of excipients, diluents, carriers, flavoring agents, binders and fillers.
The medicament according to any one of claims 10-13, wherein the viral pneumonia is coronavirus pneumonia, preferably influenza, bird flu, coronavirus SARS-CoV-2 infected pneumonia, coronavirus Any one or a combination of at least two of SARS-CoV-infected pneumonia or coronavirus MERS-CoV-infected pneumonia is preferably coronavirus SARS-CoV-2 infected pneumonia.
A pharmaceutical composition for treating viral pneumonia, which includes a cyclooxygenase II inhibitor and an antiviral drug.
The pharmaceutical composition according to claim 14, wherein the cyclooxygenase II inhibitor is a non-steroidal compound, preferably a coxib compound, and more preferably celecoxib;

Preferably, the viral pneumonia is coronavirus pneumonia, preferably influenza, bird flu, coronavirus SARS-CoV-2 infected pneumonia, coronavirus SARS-CoV infected pneumonia, or coronavirus MERS-CoV infected pneumonia Any one or a combination of at least two of the pneumonia is preferably pneumonia infected by the coronavirus SARS-CoV-2.