CN116829157A - Application of polyanionic fiber diglycoside compound - Google Patents
Application of polyanionic fiber diglycoside compound Download PDFInfo
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- CN116829157A CN116829157A CN202180080201.5A CN202180080201A CN116829157A CN 116829157 A CN116829157 A CN 116829157A CN 202180080201 A CN202180080201 A CN 202180080201A CN 116829157 A CN116829157 A CN 116829157A
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Abstract
The application of the polyanionic cellobioside compound is shown in a formula II in the preparation of a medicament for treating 2019-nCoV infection-induced related diseases or symptoms. The compound is safe, can obviously improve related diseases or symptoms caused by 2019-nCoV infection, and can achieve treatment effect on acute respiratory distress syndrome caused by other reasons.
Description
The present application claims priority from Chinese patent application 202011384873.9 with the filing date 2020/12/1. The present application incorporates the entirety of the above-mentioned chinese patent application.
The application relates to application of a polyanionic cellobioside compound.
The new coronavirus pneumonia (Corona Virus Disease, 2019) is a new acute respiratory infectious disease, is caused by SARS-CoV-2 (also known as 2019-nCoV), and has been caused to infect more than 2 hundred million people worldwide by the current time since the bottom of 12 months in 2019, and has become a global serious public health event at present, and has great influence on the world.
According to the new diagnosis and treatment scheme (revised eighth edition) of coronavirus pneumonia released in 2021 in China, the pneumonia infected by 2019 new coronavirus can be classified into light, common, heavy and dangerous according to the degree of illness. The light clinical symptoms are mild, only low fever, slight hypodynamia and the like, and no pneumonia is caused. The common type has symptoms such as fever, respiratory tract and the like (cough, pharyngalgia, nasal obstruction, shortness of breath, hypodynamia and the like), and the symptoms of pneumonia can be seen in imaging. Heavy subjects show dyspnea, shortness of breath, hypoxia, somnolence and convulsion; severe patients may rapidly progress to acute respiratory distress syndrome, sepsis, septic shock and multiple organ failure, and even die.
Pathological studies of acute respiratory distress syndrome have found that numerous proteins and various inflammatory cells, predominantly neutrophils, are present in the edema fluid in the alveolar and pulmonary interstitium. Activation and recruitment of neutrophils is thought to play a role in the progression of acute respiratory distress syndrome.
After a patient is infected with a novel coronavirus, because the virus injury and the immune injury caused by inflammation are interwoven, clinical pathological manifestations mainly comprising lung injury and affected by multiple organs of the whole body can appear, especially severe patients, and the patients are represented by acute respiratory distress syndrome and can develop into sepsis, septic shock, multiple organ failure and even death. For epidemic prevention and control, effective vaccines and antiviral drugs are needed for prevention and control, and "life-saving drugs" for treating immune injury of organisms caused by virus infection are also urgently needed.
Disclosure of Invention
The application aims to solve the technical problem that the existing medicine for treating acute respiratory distress syndrome and novel coronavirus pneumonia has a single structure, and therefore, the application provides application of a polyanion fiber diglycoside compound. The compound is safe, can obviously improve related diseases or symptoms caused by 2019-nCoV infection, and can achieve treatment effect on acute respiratory distress syndrome caused by other reasons.
The first aspect of the application provides the use of a compound of formula II (1-O-methyl 2,2', 3',4', 6' -hepta-O-sulfonyl-beta-cellobiose heptasodium salt) for the manufacture of a medicament for the treatment of a disease or disorder associated with 2019-nCoV infection;
the "2019-nCoV" refers to a 2019 novel coronavirus named by world health organization, and is also called SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). 2019-nCoV described in the application comprises various strains, such as all strains recorded by NCBI or GISAID (global shared influenza data initiative), particularly important variants with strong transmissibility, pathogenicity or immune evasion, such as WHO specified Alpha, beta, gamma, delta, eta, iota, kappa, lambda or Omicron variants, and important variants specified later.
The 2019-nCoV infection related diseases or conditions described by the application include, but are not limited to: one or more of symptoms of pneumonia, organ damage, respiratory distress, hypoxia, thrombosis and embolism, microcirculation disturbance, acute respiratory distress syndrome, acute respiratory failure, sepsis, septic shock, multiple organ failure, fever, respiratory tract (cough, pharyngalgia, nasal obstruction, shortness of breath, debilitation, etc.), dyspnea, somnolence and convulsion; preferably, wherein the pneumonia is a covd-19, more preferably a heavy or critical covd-19. Further, the acute respiratory distress syndrome may be a lipopolysaccharide-initiated acute respiratory distress syndrome.
It will be appreciated by those skilled in the art that there may be differences in the definition and identification of the clinical typing of the covd-19 by different countries or organizations, and that the present application includes all of the clinical typing of heavy or critical covd-19 (expressed in english as Severe covd-19 or Severe covd-19 pneumaria) defined by different countries or organizations, for example, in our country "new coronavirus pneumonia diagnosis and treatment scheme (trial eighth edition revision).
As used herein, "COVID-19" refers to pneumonia caused by infection with 2019-nCoV.
Organ damage includes, but is not limited to: one or more of lung injury, kidney injury, myocardial injury, and liver injury. The lung injury may include: lung capillary endothelial cell injury and/or alveolar epithelial cell injury.
The pathological basis of the acute respiratory distress syndrome is diffuse alveolar injury, and the pathological characteristic is that capillary endothelial cells of lung tissues are widely damaged by inflammation, so that exudation of capillaries is increased; and alveolar epithelial cell injury, resulting in increased lung permeability, alveolar and pulmonary interstitial filling with protein-rich pulmonary edema fluid, hyaline membrane formation, and inflammatory cell infiltration, resulting in severe deregulation of the ventilation/blood ratio. Acute respiratory distress syndrome is manifested clinically as respiratory distress and refractory hypoxemia, pulmonary imaging presents as a non-uniform exudative lesion, the early stages of which are generally considered to be acute lung injury, and moderate or severe are referred to as acute respiratory distress syndrome.
Sepsis generally refers to a life-threatening multiple organ dysfunction caused by an inflammatory response of the body to infection (e.g., 2019-nCoV) that is overactive throughout the body, further developing septic shock and multiple organ failure; the multi-organ failure includes, but is not limited to: lung failure, kidney failure and liver failure.
The application also provides an application of the pharmaceutical composition in preparing medicines;
the pharmaceutical composition comprises a compound of formula II (1-O-methyl 2,2', 3',4', 6' -hepta-O-sulfonyl-beta-cellobiose heptasodium salt) and pharmaceutically acceptable auxiliary materials;
the medicine is used for treating 2019-nCoV infection-induced related diseases or symptoms.
Further, the 2019-nCoV infection-induced related disease or disorder is as described above, such as heavy or critical type COVID-19, and also such as lipopolysaccharide-induced acute respiratory distress syndrome.
The pharmaceutical compositions may be formulated for administration by solid or liquid forms, including but not limited to: injection (e.g., subcutaneous, intramuscular, intravenous, or epidural), mucosal, transdermal, or topical administration, nasal or oral inhalation administration, and ocular administration.
Pharmaceutically acceptable excipients in the art include, but are not limited to: diluents, fillers, disintegrants, wetting agents, lubricants, pH adjusters, buffers, colorants, flavorants, preservatives or other conventional additives.
In one embodiment of the present application, the pharmaceutical composition may be an injectable pharmaceutical composition. Further, the pharmaceutical composition for injection may be prepared in the form of a powder or a concentrated solution (it will be understood by those skilled in the art that the powder and the concentrated solution are generally sterile) which may be dissolved or dispersed in a pharmaceutically acceptable carrier for clinical use. The pharmaceutically acceptable carrier may be a solvent or dispersion medium including, but not limited to: water, ringer's solution, isotonic saline, phosphate buffer, ethanol or polyols, and the like.
In some embodiments of the application, the concentrated solution has a pH of about 7.0 to about 8.0, further 7.4 to about 7.6, and still further 7.5, and the pH is adjusted by adding a buffer selected from the group consisting of phosphate buffer, citrate buffer, and acetate buffer.
In some embodiments of the application, the concentration of the compound of formula II in the concentrated solution may be 50-500mg/mL, further 60-100mg/mL, preferably 65-85mg/mL, more preferably 68-80mg/mL (e.g., 70 mg/mL), and may be administered by intravenous infusion after dilution according to the clinical protocol, which dilution may be performed using the following reagents: water, ringer's solution, isotonic saline, and the like.
In some embodiments, the concentrated solution may be infused at a rate of 15 to 120mg/hr, preferably 20 to 90mg/hr, for example, at the time of clinical use (i.e. diluted solution of the concentrated solution): 25mg/hr, 30mg/hr, 35mg/hr, 40mg/hr, 45mg/hr, 50mg/hr, 55mg/hr, 58.3mg/hr, 60mg/hr, 65mg/hr, 70mg/hr, 75mg/hr, 80mg/hr, 87.5mg/hr or 90mg/hr; infusion times may be 1-120hr, for example: 2hr, 4hr, 6hr, 8hr, 10hr, 12hr, 24hr, 36hr, 48hr, 60hr, 72hr, 84hr, 96hr, 108hr, etc. The numerical values include intermediate values of all point values.
In some embodiments of the application, the pharmaceutical composition may be administered directly to the airway of a subject in the form of an aerosol or by nebulization. For use as an aerosol, the solution or suspension of the pharmaceutically acceptable composition of the application may be packaged in a pressurized aerosol container together with a suitable propellant, for example a hydrocarbon propellant such as propane, butane or isobutane, and conventional adjuvants. Such compositions may also be administered in non-pressurized form, for example in a nebulizer or atomizer.
The application also provides in a third aspect the use of a compound of formula II (1-O-methyl 2,2', 3',4', 6' -hepta-O-sulfonyl- β -cellobiose heptasodium salt) in the manufacture of a medicament for the treatment of acute respiratory distress syndrome or acute respiratory failure;
further, the acute respiratory distress syndrome may be an acute respiratory distress syndrome induced by infection or an acute respiratory distress syndrome induced by lipopolysaccharide, and may be an acute respiratory distress syndrome induced by 2019-nCoV infection.
In a fourth aspect the application also provides a method of treating a disease or condition associated with 2019-nCoV infection as described above, comprising administering to a patient a therapeutically effective amount of a compound of formula II (1-O-methyl 2,2', 3',4', 6' -hepta-O-sulfonyl- β -cellobioside heptasodium salt);
further, the 2019-nCoV infection may cause related diseases or conditions such as COVID-19, and also such as heavy or critical COVID-19.
Further, the 2019-nCoV infection may be associated with a disease or condition such as acute respiratory distress syndrome or acute respiratory failure, and may be associated with acute respiratory distress syndrome caused by lipopolysaccharide.
Preferably, intravenous continuous infusion is used, the infusion rate may be 15 to 120mg/hr, preferably 20 to 90mg/hr, for example: 25mg/hr, 30mg/hr, 35mg/hr, 40mg/hr, 45mg/hr, 50mg/hr, 55mg/hr, 58.3mg/hr, 60mg/hr, 65mg/hr, 70mg/hr, 75mg/hr, 80mg/hr, 87.5mg/hr or 90mg/hr; infusion times may be 1-120hr, for example: 2hr, 4hr, 6hr, 8hr, 10hr, 12hr, 24hr, 36hr, 48hr, 60hr, 72hr, 84hr, 96hr, 108hr, etc. The numerical values include intermediate values of all point values.
The present application also provides in a fifth aspect a method of treating acute respiratory distress syndrome or acute respiratory failure comprising administering to a patient a therapeutically effective amount of a compound of formula II (1-O-methyl 2,2', 3',4', 6' -hepta-O-sulfonyl- β -cellobioside heptasodium salt);
further, the acute respiratory distress syndrome may be an acute respiratory distress syndrome induced by infection or an acute respiratory distress syndrome induced by lipopolysaccharide, and may be an acute respiratory distress syndrome induced by 2019-nCoV infection.
Acute respiratory distress syndrome is a non-cardiac clinical syndrome which can be caused by various causes and mainly shows progressive dyspnea and refractory hypoxia, has high incidence rate and large harm, and is a major difficult problem to be solved in clinical treatment. The etiology of acute respiratory distress syndrome is numerous and can be divided into intrapulmonary causes: bacterial or viral pneumonia (including coronavirus pneumonia), aspiration of gastric contents, lung bruise, toxic aspiration, drowning, etc., and extrapulmonary causes: sepsis, pancreatitis, severe trauma, massive blood transfusion, burns, etc., but the common pathological basis is diffuse alveolar injury, and clinical manifestations are mainly characterized by progressive respiratory distress and refractory hypoxia. Pathological studies of acute respiratory distress syndrome have long found that there are a large number of proteins and a variety of inflammatory cells in the oedema fluid that accumulate in the alveoli and pulmonary interstitium, with neutrophils being the dominant factor.
In some embodiments of the application, the acute respiratory distress syndrome is an infectious or non-infectious acute respiratory distress syndrome; such infections include, but are not limited to, viral, bacterial, fungal, mycoplasma or chlamydia infections. Such bacteria include, but are not limited to, streptococcus pneumoniae, staphylococcus or Klebsiella pneumoniae. Such viruses include, but are not limited to, influenza virus, parainfluenza virus, or coronavirus (e.g., 2019-nCoV). Such fungi include, but are not limited to, actinomycetes.
In some embodiments, the application further provides a method of treating acute respiratory distress syndrome comprising administering to a patient a therapeutically effective amount of a polyanionic cellobiose compound of formula II. Preferably, intravenous continuous infusion is used, the infusion rate may be 15 to 120mg/hr, preferably 20 to 90mg/hr, for example: 25mg/hr, 30mg/hr, 35mg/hr, 40mg/hr, 45mg/hr, 50mg/hr, 55mg/hr, 58.3mg/hr, 60mg/hr, 65mg/hr, 70mg/hr, 75mg/hr, 80mg/hr, 87.5mg/hr or 90mg/hr; infusion times may be 1-120hr, for example: 2hr, 4hr, 6hr, 8hr, 10hr, 12hr, 24hr, 36hr, 48hr, 60hr, 72hr, 84hr, 96hr, 108hr, etc. The numerical values include intermediate values of all point values.
The term "C 1-6 Alkyl "denotes straight-chain or branched alkyl having the specifically indicated number of carbon atoms (for example one, two, three, four, five or six carbon atoms), for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2,3-dimethylbutyl, 1, 3-dimethylbutyl or 1, 2-dimethylbutyl.
The term "therapeutically effective amount" refers to an amount of a compound administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted as appropriate by one skilled in the art.
The term "treatment" refers to any of the following conditions: (1) alleviating one or more biological manifestations of a disease; (2) Interfere with one or more points in the biological cascade that trigger the disease; (3) Slowing the progression of one or more biological manifestations of the disease.
The term "patient" refers to any animal, preferably a mammal, most preferably a human, that has been or is about to be treated. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present application can be obtained.
The reagents and materials used in the present application are commercially available.
The application has the positive progress effects that: the compound of the formula II is safe, can obviously improve related diseases or symptoms caused by 2019-nCoV infection, and can achieve treatment effect on acute respiratory distress syndrome caused by other reasons.
FIG. 1 is a graph showing the effect of a compound of formula II on the extent of inflammatory lesions in lung tissue in rats in a model of acute respiratory distress syndrome.
The present application will be described in further detail with reference to examples, but should not be construed as being limited thereto. The reagents or equipment used below are all commercial varieties, and are operated according to the specification unless otherwise specified, and are not described herein.
Example 1 evaluation of the Effect of Compounds of formula II on treatment of acute respiratory distress syndrome
Animal species: male Sprague-Dawley rats (SD rats)
Animal grade: SPF stage
Age at the beginning of modeling: 6-8 weeks old.
Body weight at the beginning of molding: 195-270 g.
1.1 grouping and modeling of animals:
grouping animals: randomly dividing 56 qualified male animals into a normal control group, a model control group, a low-dose group of the test sample, a medium-dose group of the test sample and a high-dose group of the test sample according to the weight measured before grouping; the normal control group had 8, and the remaining groups were 12/group.
Test batch: the test was performed in two batches. Batch 1 was the first half of the animals per group and batch 2 was the second half of the animals per group. Model construction, drug administration, index detection and the like of animals in each batch are uniform.
Model construction:
the animals of group D0 were given lipopolysaccharide (0.8 mg/kg, 400. Mu.L/kg) by intraperitoneal injection by extracting a molding agent (lipopolysaccharide, LPS) according to their body weights.
D1: after 16h (+ -30 min) intraperitoneal injection, isoflurane was inhaled for anaesthesia and lipopolysaccharide (5 mg/kg, 1000. Mu.L/kg) was given intratracheal nebulization to each group of animals.
Intraperitoneal injection of Lipopolysaccharide (LPS): according to the recently weighed animal body weight, the amount of lipopolysaccharide administered to each animal was withdrawn using a disposable microinjector, and lipopolysaccharide was administered by intraperitoneal injection. The lipopolysaccharide volume is held to an integer position and is aspirated according to the upper graduation value when the lipopolysaccharide volume is between the two graduation capacity lines.
Nebulized Lipopolysaccharide (LPS) in the airways: the animal isoflurane is inhaled for anesthesia, then the animal isoflurane is fixed on a rat fixer placed at 45 degrees, a small animal anesthesia pharyngoscope is used for pressing the root of an animal tongue, a glottis is exposed, a lung micro liquid atomizer needle head (blunt) for extracting quantitative Lipopolysaccharide (LPS) solution is gently inserted into a trachea, then a piston is quickly pushed, the LPS solution is atomized into lungs, the needle head is quickly pulled out, the animal is taken down from the fixer, and the head is rotated upwards and leftwards and rightwards, so that the LPS is uniformly distributed on each lung lobe as much as possible. The lipopolysaccharide volume is held to the 1-position after the decimal, and is sucked according to the upper graduation value when the lipopolysaccharide volume is between the two graduation capacity lines.
1.2 sample dosage and method
After animal model construction, the test and control substances were administered according to the following table. The details are given in the following table:
the test sample was a compound of formula II (1-O-methyl 2,2', 3',4', 6' -hepta-O-sulfonyl-beta-cellobioside heptasodium salt), the compound of formula II was prepared as a stock solution of 70mg/mL (the solvent was phosphate buffer solution of pH 7.5), and before administration, 70mg/mL of the stock solution was diluted to a test sample solution of 1mg/mL, 5mg/mL, 20mg/mL using sodium chloride injection.
The normal control group and the model control group were given sodium chloride injection by intravenous injection.
TABLE 1 dosing amounts
Route of administration: group 1 to group 5: tail vein injection.
Frequency and time of administration: group 1 to group 5: d1, D2: 9:00-10:30 am, 13:00-14:30, 16:00-17:30; d3 (dosing 2 times): 8:30-10:00 am, 11:00-12:30 am.
1.3 test observations and data collection
1.3.1 general clinical observations
Animals were observed 2 times daily during quarantine and dosing (1 each of morning and afternoon). The content is observed: mental state, behavioral activity, death, respiration, secretion, fecal behavior, and other abnormalities.
1.3.2 body weight
Weighing animals on the day of modeling and on the day of administration of the test sample before receiving and grouping; animals were also weighed when death or euthanasia was found.
1.3.3 survival
After planned euthanasia, the ratio of the number of animals surviving each group to the total number of animals in each group during the test period was calculated.
Survival (%) = number of animals surviving group/total number of animals group x 100%.
1.3.4 blood gas detection
Detection time: d3 after the end of the last 1 dose for about 2 hours
Sample collection: anesthesia is carried out by injecting chloral hydrate (350 mg/kg,100 mg/mL) into the abdominal cavity, the abdominal midline is longitudinally cut, the abdominal aorta is separated, about 0.5mL of arterial blood is collected by adopting an arterial hemostix, the hemostix is rubbed by the syringe in the palm and turned upside down for 5 seconds respectively, and the hemostix cannot be pulled back to carry out uniform blood mixing treatment.
The detection method comprises the following steps: after arterial blood collection, the needle is gently inserted into the blood injection opening of the test card, blood is slowly pushed in, the sample filling pipe is filled up, when the blood reaches the sample filling position, sample filling is stopped, the cover is buckled, the blood automatically enters the test tube, the test card is inserted into the blood gas analyzer, and the test result is waited.
Detecting the index: PO2 (mmHg), PCO2 (mmHg), pH, sO2%.
1.3.5 plasma histone concentration assay
D3, about 1mL each of abdominal aortic blood and venous blood was collected separately and loaded into a sampling tube for anticoagulation of sodium citrate. After blood sample collection, wet ice is temporarily stored, centrifugation is carried out at 3000rpm at 4 ℃ within 2 hours, separated blood plasma is respectively filled in a freezing tube marked with arterial blood plasma and venous blood plasma, freezing is carried out at-70 ℃, and after the test, plasma histone concentration is detected according to the steps required by the kit.
1.3.6 blood cell counts
D3 collecting main abdominal venous blood 1mL, and loading it into EDTA-K containing solution 2 Sampling tubes for anticoagulant. By usingBlood counts were performed with a 2120 series hematology analyzer. The detection parameter indexes are as follows:
blood cell count
1.3.7 Lung lavage fluid (BALF) detection
Sample collection: after euthanasia of the animals, the neck and chest skin and tissue is cut to expose the trachea, bronchi and lungs, the right lung bronchi are isolated and ligated. The suture line is penetrated under the trachea, a 1/2 incision is made between the tracheal cartilage rings at a proper position under the thyroid cartilage, the tracheal cannula is slowly inserted into the left bronchus along the incision to the airway, and the cannula and the trachea are tightly fixed at a proper position in the incision centripetal direction by the penetrated suture line. 3mL of PBS buffer is sucked by a syringe and slowly injected, alveolar lavage is carried out, the lavage is repeatedly carried out for 3 times, each time of rinsing stays for about 10s, and the lavage liquid is collected in a centrifuge tube with proper capacity (not less than 2.1mL and finally based on the actual collection amount).
BALF processing: the collected lavage fluid was kept 2mL (excess treated as medical waste) per animal and centrifuged at about 2000rpm at 4℃for 10min. The supernatant was dispensed into 2 tubes and kept at below-70℃until use (after the test was completed, the consignor was sent or otherwise treated). The pellet was resuspended in 1mL PBS buffer for total white blood cell count and differential count.
And (3) detecting the concentration of the lavage fluid histone: and (3) after the test is finished, carrying out the detection of the histone concentration of the lung lavage fluid according to the steps required by the kit on the supernatant of the lung lavage fluid.
Leukocyte classification detection: the resuspended lung lavage fluid was subjected to white blood cell count and classification using a fully automatic blood cell analyzer.
1.3.8 euthanasia of animals
All animals were anesthetized by intraperitoneal injection of chloral hydrate (350 mg/kg,100 mg/mL) and euthanized by abdominal aortic exsanguination according to AVMA Guidelines for the Euthanasia of Animals:2013 Edition (the American Veterinary Medical Association, 2013). After the moribund animals were anesthetized with isoflurane, the abdominal aorta was exsanguinated to effect euthanasia.
1.3.9 histopathological examination
General observations: all animals in each group (including dead, moribund euthanized animals) were dissected and tissues were preserved. The animals were found to die in a dead time, stored in a refrigerator at 2-8℃, and dissected as soon as possible within 24 hours. After dissecting and leaving the tissue, the animal carcasses are treated according to medical waste.
During necropsy, animals were observed for abnormalities in the lungs, trachea and bronchi. The right lung middle leaf was cut and used to calculate the wet/dry weight ratio. The remaining right lung tissue and bronchi were fixed in 10% neutral buffered formalin solution, paraffin embedded, sectioned, pelleted, HE stained for pathological morphological observation of lung tissue, and the lung tissue was pathologically examined using standard terminology for diagnosis and classification according to 4-grade method (mild, moderate, severe).
1.3.10 Lung wet to Dry weight ratio
The surface of the tissue of the right lung is wiped clean with paper towel, and the foreign matters such as blood, tissue fluid and the like are weighed, then the tissue of the right lung is placed in a 60 ℃ oven for 72 hours for weighing again, and the wet/dry weight ratio is calculated.
Lung wet dry weight ratio = leaf wet weight/dry weight in right lung
1.3.11 data acquisition and statistical analysis
And (3) data acquisition: the data is collected by adopting a system generation and manual recording mode.
Data analysis: the data were processed using statistical software SPSS 13.0 and or GraphPad Prism 5. All statistical analyses were performed using a two-tailed analysis, with the statistical level set at P.ltoreq.0.05. Each index is expressed as "mean ± standard deviation" and analyzed as follows: firstly, carrying out uniformity Test on data by using a level's Test, and if the data are uniform (P > 0.05), carrying out one-way analysis of variance (ANOVA); if the analysis of variance is significant (P.ltoreq.0.05), dunnett's multiple comparisons are made of the differences between the model control group and the other groups. If the result of the level's Test is significant (P.ltoreq.0.05), a Kruskal-wallis nonparametric Test is performed. If the Kruskal-wallis nonparametric test results are significant (P.ltoreq.0.05), the Mann-Whitney U test is further used for pairwise comparison.
1.4 experimental results
And (3) molding: microscopic observation shows pathological changes such as alveolar space, blood vessel, alveolar wall inflammatory cell infiltration/alveolar wall interval thickening, intra-alveolar hemorrhage (with or without hemoglobin crystallization) and the like of the animal in the model control group; in the lung lavage of the model control group animals, WBC, neut and histone are respectively increased from 0.32+/-0.22, 0.04+/-0.02 and 0.039+/-0.012 of the normal control group to 9.41+/-2.01, 5.17+/-1.90 and 0.835+/-0.380; the wet-dry ratio of the lung is increased from 1.17+/-0.09 of the normal control group to 2.26+/-0.51; PO2 and sO2% are respectively reduced from 103.3+/-5.9 and 98.4+/-0.5 to 77.5+/-11.4 and 95.3+/-2.5 of the normal control group; and the indexes all have statistical differences. In summary, under the present test conditions, intraperitoneal injection in combination with intra-airway nebulization of the modeling agent Lipopolysaccharide (LPS) was considered successful in constructing an acute respiratory distress syndrome model.
Survival rate: no animal death was observed during the test, and the survival rate of each group of animals was 100%. Data details see the attached table: table 6.
Lung lavage fluid detection: the total number of white blood cells and the average value of classification indexes in the lung lavage fluid of the low, medium and high dose groups of animals of the test sample are respectively reduced to (2.88+/-1.50), (0.91+/-0.45) and (0.59+/-0.49) compared with the average value (9.41+/-2.01) of the WBC indexes of the model control group; compared with the mean value (5.17+/-1.90) of the Neut index of the model control group, the Neut index is respectively reduced to (1.45+/-1.13), (0.50+/-0.43) and (0.30+/-0.26); the Lymph and Mono index mean value is also obviously lower; and all have statistical differences. Data details see the attached table: table 2.
And (3) blood gas analysis and detection: the mean values of the blood gas analysis indexes of the animals in the low, medium and high dose groups of the test sample are respectively increased to (88.4+/-8.6), (90.3+/-6.4) and (92.3+/-9.2) compared with the mean value of the PO2 index of the model control group (77.5+/-11.4), respectively increased to (97.2+/-1.1), (97.4+/-0.8) and (97.3+/-1.2) compared with the mean value of the sO2 index of the model control group (95.3+/-2.5), and have statistical differences; no statistical difference was seen between PCO2 and pH index. Data details see the attached table: table 3.
And (3) histone detection: comparing the histone index mean value of the low, medium and high dose animals of the test sample with the histone index mean value (0.835+/-0.380) of the lung lavage fluid of the model control group, respectively reducing the mean value to (0.686+/-0.452), (0.415+/-0.445) and (0.449+/-0.606), wherein the medium and high dose animals of the test sample have statistical differences; compared with the mean value (0.164+/-0.093) of the arterial plasma histone index of the model control group, the mean value is respectively reduced to (0.126+/-0.039), (0.117+/-0.062) and (0.091+/-0.035), and the high-dose group of the test sample has statistical difference; compared with the mean value (0.074+/-0.019) of the model control group intravenous plasma histone index, the mean value is respectively reduced to (0.073+/-0.046), (0.057+/-0.008) and (0.049+/-0.009), and the statistical difference exists between the medium-dose group and the high-dose group of the test sample. Data details see the attached table: table 4.
Lung wet-dry ratio detection: compared with a model control group (2.26+/-0.51), the mean value of lung wet-dry ratio indexes of the animals in the low, medium and high dose groups of the test sample is respectively reduced to (1.97+/-0.33), (1.85+/-0.20) and (1.61+/-0.43), and the average value of lung wet-dry ratio indexes of the animals in the low, medium and high dose groups of the test sample has statistical differences. Data details see the attached table: table 5.
Blood cell count: compared with corresponding indexes of animals in a model control group, the average value of the indexes of WBC, lymph, PLT and the like of the animals in low, medium and high dose groups of the test sample is increased, the average value of the indexes of Neut, mono, LUC and the like is reduced, and the statistical difference exists. Data details see the attached table: table 7.
And (3) pathology detection: in this test, pulmonary inflammation was observed in model animals, and the inflammation was mainly expressed as: neutrophil-dominated inflammatory cells (alveolar space, blood vessels, alveolar walls), thickening of alveolar wall spaces, intra-alveolar hemorrhage (with or without hemoglobin crystallization). The animal of the administration group has the inflammation degree obviously lower than that of the model control group, which indicates that the test sample reduces the inflammation degree, the animal of each administration group has the dose relation, and the pathological change degree of the inflammation gradually reduces along with the increase of the dose. See the drawings for details: FIG. 1 (1, normal control animals showed no pathological changes in the histopathological examination of the lung, and therefore, not shown in the figure; 2, the number of lung lobes for pathological examination per group = the number of animals per group (12) ×the number of lung lobes for pathological examination per animal (3 lobes: upper right lobe, lower right lobe, and minor lobes), each group was 36 lobes).
TABLE 2 total and score of white blood cells in lung lavage fluid (BALF) from rats model for acute respiratory distress syndromeInfluence of classn=8/12)
Note that: 1. number of animals: 8 normal control groups and 12 other groups; 2. compared with the model control group, "x" indicates that p is less than or equal to 0.05; 3. the level's Test WBC, neut, lymph, mono index was non-uniform and was statistically analyzed using the Kruskal-wallis nonparametric Test.
TABLE 3 influence on blood gas analysis in rats model of acute respiratory distress syndromen=8/12)
Group of | PH | PCO2(mmHg) | PO2(mmHg) | sO 2 % |
Normal control group | 7.477±0.054 | 34.33±3.02 | 103.3±5.9* | 98.4±0.5* |
Model control group | 7.437±0.033 | 37.14±4.31 | 77.5±11.4 | 95.3±2.5 |
Test article low dose group | 7.463±0.052 | 36.26±4.86 | 88.4±8.6* | 97.2±1.1* |
Dose group in test article | 7.450±0.035 | 36.23±4.09 | 90.3±6.4* | 97.4±0.8* |
High dose group of test articles | 7.437±0.045 | 37.20±3.70 | 92.3±9.2* | 97.3±1.2* |
Note that: 1. number of animals: 8 normal control groups and 12 other groups; 2. compared with the model control group, "x" indicates that p is less than or equal to 0.05; 3. levene's Test for sO 2 % index inhomogeneities were statistically analyzed using the Kruskal-wallis nonparametric test.
TABLE 4 influence of rat histone on acute respiratory distress syndrome modeln=8/12;Median)
Note that: 1. number of animals: 8 normal control groups and 12 other groups; 2. compared with the model control group, "x" indicates that p is less than or equal to 0.05; 3. the Levene's Test examined non-uniform lung lavage histone and venous plasma histone index, and the Kruskal-wallis nonparametric Test was used for statistical analysis.
TABLE 5 influence on the lung wet to dry ratio of rats in the model of acute respiratory distress syndromen=8/12)
Group of | Wet to dry ratio |
Normal control group | 1.17±0.09* |
Model control group | 2.26±0.51 |
Test article low dose group | 1.97±0.33 |
Dose group in test article | 1.85±0.20* |
High dose group of test articles | 1.61±0.43* |
Note that: 1. number of animals: 8 normal control groups and 12 other groups; 2. compared with the model control group, "x" indicates that p is less than or equal to 0.05; 3. the Levene's Test tests that the lung wet to dry ratio index was not uniform, and the Kruskal-wallis nonparametric Test was used for statistical analysis.
TABLE 6 effect on survival of rats in acute respiratory distress syndrome model
Group of | Modeling animal number (only) | Group memory number of living animals (only) | Survival (%) |
Normal control group | 8 | 8 | 100.0 |
Model control group | 12 | 12 | 100.0 |
Test article low dose group | 12 | 12 | 100.0 |
Dose group in test article | 12 | 12 | 100.0 |
High dose group of test articles | 12 | 12 | 100.0 |
Remarks: 1. survival (%) = number of animals surviving group/total number of animals group x 100%.
TABLE 7 influence on the blood cell count of rats in the model of acute respiratory distress syndromen=8/12)
Note that: 1. number of animals: 8 normal control groups and 12 other groups; 2. compared with the model control group, "x" indicates that p is less than or equal to 0.05; 3. the level's Test Neut, mono, LUC, HCT, PLT index was non-uniform and was statistically analyzed using the Kruskal-wallis nonparametric Test.
EXAMPLE 2 clinical study of Compounds of formula II
The present study is a randomized, open-label, multicenter clinical study aimed at evaluating the safety and efficacy of continuous infusion of compounds of formula II in patients with severe 2019 coronavirus Pneumonia (sever covd-19 Pneumonia). The subjects will be randomized into three cohorts at a 2:2:1 ratio, receiving continuous infusion of the compound of formula II, at 58.3mg/hr or 87.5mg/hr for 3 days (72 hours), or receiving appropriate standard of care (placebo as 0.9% sodium chloride injection). All subjects in the compound of formula II treatment group will also receive standard of care as background treatment.
The compound of formula II was prepared as a sterile concentrated solution (70 mg/mL, phosphate buffer pH 7.5 in a solvent) and placed in a 10mL glass bottle equipped with a rubber stopper and a sealing cap, and stored under refrigeration at 2℃to 8 ℃. Immediately before use, the preparation is diluted by normal saline for injection and is prepared according to a clinical scheme for intravenous infusion administration.
The placebo for this study was 0.9% sodium chloride injection provided in the form of individual glass penicillin bottles with the same label, 10mL each, and stored under the same conditions as the study medication, refrigerated at 2-8 ℃. Placebo must be administered following the same procedure and instructions as the compound of formula II.
The present study explored: 1) Occurrence rate of adverse events and serious adverse events; 2) Adverse events lead to treatment termination rates; 3) An electrocardiographic abnormality; 4) Laboratory checking for anomalies; 5) Vital signs and physical examination abnormalities various adverse event occurrences, including symptoms or abnormal signs and laboratory examination abnormalities. Changes in PaO2/FiO2 after 1) administration compared to baseline; 2) Changes in biological indicators such as c-reactive protein (CRP), alanine Aminotransferase (ALT), lactate Dehydrogenase (LDH), etc. after administration as compared to baseline; 3) Changes in SOFA score after dosing compared to baseline; 4) A time of life within 30 days; 5) Survival time after off-line within 30 days; 6) Hospitalization time within 30 days; 7) ICU hospital stay within 30 days; 8) Invasive mechanical ventilation time was within 30 days.
The above-mentioned index detection is conventional in the art, and those skilled in the art know how to obtain the detection index.
Few adverse events or severe adverse reactions associated with the test agents were found in the clinical study. After administration of the compound of formula II, the patient has improved clinical symptoms, including an improvement in one or more of the biological or clinical indicators shown below: biological indicators such as C-reactive protein (CRP), alanine Aminotransferase (ALT), lactate Dehydrogenase (LDH) or PaO2/FiO2 are improved (or restored to normal levels), sequential organ failure assessment Score (SOFA) is reduced (e.g., to 1 or 0), use of mechanical ventilation and reduced time to use, reduced hospitalization time or ICU hospitalization time, and reduced mortality, etc.
The improvement or restoration of PaO2/FiO2 to normal levels may reflect some improvement or alleviation of the patient's respiratory condition (e.g., symptoms such as respiratory distress, hypoxia, acute respiratory distress syndrome, etc.). Improvement of C-reactive protein (CRP), improvement of Lactate Dehydrogenase (LDH) may reflect improvement of the patient's degree of infection (e.g., symptoms such as sepsis, septic shock, etc.), and decrease of SOFA score may reflect improvement of the patient's organ injury or failure to some extent. Improvement in alanine Aminotransferase (ALT) may reflect to some extent improvement in liver injury. The reduction of hospital stays, reduction of ICU hospital stays, reduction of use time of mechanical ventilation, prolongation of ventilator free survival, and the like, may reflect, to some extent, overall improvement or therapeutic effects of the patient on the associated diseases or conditions caused by 2019-nCoV infection (including pneumonia, organ damage, respiratory distress, hypoxia, thrombosis and embolism, microcirculation disorders, acute respiratory distress syndrome, sepsis, septic shock, multiple organ failure, and the like).
The clinical research results show that the compound of the formula II has good safety and has therapeutic effect on related diseases or symptoms caused by 2019-nCoV infection.
While embodiments of the present application have been shown and described, it will be understood that the above embodiments are illustrative and not to be construed as limiting the application, and that variations, modifications, alternatives, and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the application. The scope of the application is defined by the appended claims.
Claims (15)
- Use of a compound of formula II in the manufacture of a medicament for the treatment of a disease or condition associated with 2019-nCoV infection;
- the use of claim 1, wherein the 2019-nCoV infection causes related diseases or conditions including, but not limited to: pneumonia, organ damage, respiratory distress, hypoxia, thrombosis and embolism, microcirculation disturbance, acute respiratory distress syndrome, acute respiratory failure, sepsis, septic shock, multiple organ failure, fever, respiratory tract and other symptoms, dyspnea, somnolence and convulsion.
- The application of claim 2, wherein the application satisfies one or both of the following conditions:a) The pneumonia is COVID-19; preferably, the COVID-19 is a heavy or critical COVID-19;b) The acute respiratory distress syndrome may be lipopolysaccharide-initiated acute respiratory distress syndrome.
- Use of a pharmaceutical composition in the manufacture of a medicament;the pharmaceutical composition comprises a compound of a formula II and pharmaceutically acceptable auxiliary materials;the medicine is used for treating 2019-nCoV infection-induced related diseases or symptoms.
- The use according to claim 4, wherein the pharmaceutical composition is a pharmaceutical composition for injection; preferably, the pharmaceutical composition for injection is in the form of a powder or a concentrated solution.
- The use according to claim 5, wherein the pH of the concentrated solution is 7.0 to 8.0, preferably 7.4 to 7.6, further 7.5.
- The use according to claim 6, wherein the concentrated solution is pH adjusted by adding a buffer selected from the group consisting of phosphate buffer, citrate buffer and acetate buffer.
- The use of claim 4, wherein the 2019-nCoV infection causes related diseases or conditions including, but not limited to: pneumonia, organ damage, respiratory distress, hypoxia, thrombosis and embolism, microcirculation disturbance, acute respiratory distress syndrome, acute respiratory failure, sepsis, septic shock, multiple organ failure, fever, respiratory tract and other symptoms, dyspnea, somnolence and convulsion.
- The application of claim 8, wherein the application satisfies one or both of the following conditions:c) The pneumonia is COVID-19; preferably, the COVID-19 is a heavy or critical COVID-19;d) The acute respiratory distress syndrome may be lipopolysaccharide-initiated acute respiratory distress syndrome.
- The use according to any one of claims 5 to 9, wherein the concentration of the compound of formula II in the concentrated solution is 50-500mg/mL, further 60-100mg/mL, preferably 65-85mg/mL, more preferably 68-80mg/mL.
- The use according to claim 10, wherein the injectable pharmaceutical composition is administered by intravenous continuous infusion at a rate of 15 to 120mg/hr for a period of 1 to 120hr.
- Use of a compound of formula II in the manufacture of a medicament for the treatment of acute respiratory distress syndrome or acute respiratory failure;the acute respiratory distress syndrome can be acute respiratory distress syndrome caused by infection or acute respiratory distress syndrome caused by lipopolysaccharide, and can also be acute respiratory distress syndrome caused by 2019-nCoV infection.
- A method of treating a 2019-nCoV infection-associated disease or disorder comprising administering to a patient a therapeutically effective amount of a compound of formula II;wherein the 2019-nCoV infection causes related diseases or conditions including but not limited to: pneumonia, organ damage, respiratory distress, hypoxia, thrombosis and embolism, microcirculation disturbance, acute respiratory distress syndrome, acute respiratory failure, sepsis, septic shock, multiple organ failure, fever, respiratory tract and other symptoms, dyspnea, somnolence and convulsion.
- The method of claim 13, wherein the application satisfies one or both of the following conditions:e) The pneumonia is COVID-19; preferably, the COVID-19 is a heavy or critical COVID-19;f) The acute respiratory distress syndrome may be lipopolysaccharide-initiated acute respiratory distress syndrome.
- A method of treating acute respiratory distress syndrome or acute respiratory failure comprising administering to a patient a therapeutically effective amount of a compound of formula II;the acute respiratory distress syndrome can be acute respiratory distress syndrome caused by infection or acute respiratory distress syndrome caused by lipopolysaccharide, and can also be acute respiratory distress syndrome caused by 2019-nCoV infection.
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