WO2022199049A1 - Use of ulinastatin in preparation of drug for treating novel coronavirus pneumonia - Google Patents
Use of ulinastatin in preparation of drug for treating novel coronavirus pneumonia Download PDFInfo
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- WO2022199049A1 WO2022199049A1 PCT/CN2021/130408 CN2021130408W WO2022199049A1 WO 2022199049 A1 WO2022199049 A1 WO 2022199049A1 CN 2021130408 W CN2021130408 W CN 2021130408W WO 2022199049 A1 WO2022199049 A1 WO 2022199049A1
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- ulinastatin
- treatment
- carrier
- novel coronavirus
- preparation
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- 229950008558 ulinastatin Drugs 0.000 title claims abstract description 43
- ODVKSTFPQDVPJZ-UHFFFAOYSA-N urinastatin Chemical compound C1C=CCCC11COC(C=2OC=CC=2)OC1 ODVKSTFPQDVPJZ-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 108010088854 urinastatin Proteins 0.000 title claims abstract description 43
- 241000711573 Coronaviridae Species 0.000 title claims abstract description 36
- 239000003814 drug Substances 0.000 title claims abstract description 29
- 206010035664 Pneumonia Diseases 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 229940079593 drug Drugs 0.000 title abstract description 10
- YWXYYJSYQOXTPL-SLPGGIOYSA-N isosorbide mononitrate Chemical compound [O-][N+](=O)O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-SLPGGIOYSA-N 0.000 claims abstract description 12
- 229960003827 isosorbide mononitrate Drugs 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims description 29
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 15
- 229930195725 Mannitol Natural products 0.000 claims description 15
- 239000000594 mannitol Substances 0.000 claims description 15
- 235000010355 mannitol Nutrition 0.000 claims description 15
- 238000003113 dilution method Methods 0.000 claims description 11
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- IBFYXTRXDNAPMM-BVTMAQQCSA-N Geniposide Chemical compound O([C@@H]1OC=C([C@@H]2[C@H]1C(=CC2)CO)C(=O)OC)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O IBFYXTRXDNAPMM-BVTMAQQCSA-N 0.000 claims description 9
- IBFYXTRXDNAPMM-FZEIBHLUSA-N Geniposide Natural products COC(=O)C1=CO[C@@H](O[C@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2O)[C@H]2[C@@H]1CC=C2CO IBFYXTRXDNAPMM-FZEIBHLUSA-N 0.000 claims description 9
- VGLLGNISLBPZNL-RBUKDIBWSA-N arborescoside Natural products O=C(OC)C=1[C@@H]2C([C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O3)OC=1)=C(CO)CC2 VGLLGNISLBPZNL-RBUKDIBWSA-N 0.000 claims description 9
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- 235000018417 cysteine Nutrition 0.000 claims description 8
- 238000004108 freeze drying Methods 0.000 claims description 8
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 8
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 8
- 241001678559 COVID-19 virus Species 0.000 claims description 7
- 230000000750 progressive effect Effects 0.000 claims description 7
- 239000008215 water for injection Substances 0.000 claims description 6
- AZKVWQKMDGGDSV-BCMRRPTOSA-N Genipin Chemical compound COC(=O)C1=CO[C@@H](O)[C@@H]2C(CO)=CC[C@H]12 AZKVWQKMDGGDSV-BCMRRPTOSA-N 0.000 claims description 4
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 4
- 229960002433 cysteine Drugs 0.000 claims description 4
- AZKVWQKMDGGDSV-UHFFFAOYSA-N genipin Natural products COC(=O)C1=COC(O)C2C(CO)=CCC12 AZKVWQKMDGGDSV-UHFFFAOYSA-N 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 238000011146 sterile filtration Methods 0.000 claims description 2
- 230000003680 myocardial damage Effects 0.000 abstract description 6
- 230000001225 therapeutic effect Effects 0.000 abstract description 6
- ZJDOESGVOWAULF-OGJQONSISA-N Geniposidic acid Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@@H]2C(CO)=CC[C@@H]2C(C(O)=O)=CO1 ZJDOESGVOWAULF-OGJQONSISA-N 0.000 abstract 1
- VYAALAFRWREWLA-BVTMAQQCSA-N Geniposidic acid Natural products CCC1=CC[C@H]2[C@@H]1[C@H](O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)OC=C2C(=O)O VYAALAFRWREWLA-BVTMAQQCSA-N 0.000 abstract 1
- ZJDOESGVOWAULF-UHFFFAOYSA-N Geniposidinsaeure Natural products OC1C(O)C(O)C(CO)OC1OC1C2C(CO)=CCC2C(C(O)=O)=CO1 ZJDOESGVOWAULF-UHFFFAOYSA-N 0.000 abstract 1
- BZPMXJKRKXDRID-UOIKKKDVSA-N Scandoside Natural products OC[C@H]1O[C@@H](O[C@H]2CC=C([C@@H]3[C@@H](O)C=C(CO)[C@H]23)C(=O)O)[C@H](O)[C@@H](O)[C@@H]1O BZPMXJKRKXDRID-UOIKKKDVSA-N 0.000 abstract 1
- 230000003319 supportive effect Effects 0.000 description 12
- 230000000840 anti-viral effect Effects 0.000 description 11
- 229940124599 anti-inflammatory drug Drugs 0.000 description 10
- 239000003623 enhancer Substances 0.000 description 10
- 208000037891 myocardial injury Diseases 0.000 description 10
- 239000002671 adjuvant Substances 0.000 description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- 206010061218 Inflammation Diseases 0.000 description 6
- 230000004054 inflammatory process Effects 0.000 description 6
- 150000007523 nucleic acids Chemical class 0.000 description 6
- 102000039446 nucleic acids Human genes 0.000 description 6
- 108020004707 nucleic acids Proteins 0.000 description 6
- 208000025721 COVID-19 Diseases 0.000 description 5
- 230000036387 respiratory rate Effects 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000008354 sodium chloride injection Substances 0.000 description 4
- 208000001528 Coronaviridae Infections Diseases 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 208000037892 acute myocardial injury Diseases 0.000 description 2
- 230000002924 anti-infective effect Effects 0.000 description 2
- -1 aseptic filtration Substances 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
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- 238000002474 experimental method Methods 0.000 description 2
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- 230000028709 inflammatory response Effects 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000011272 standard treatment Methods 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 208000003322 Coinfection Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 241000711467 Human coronavirus 229E Species 0.000 description 1
- 241001109669 Human coronavirus HKU1 Species 0.000 description 1
- 241000482741 Human coronavirus NL63 Species 0.000 description 1
- 241001428935 Human coronavirus OC43 Species 0.000 description 1
- OFFWOVJBSQMVPI-RMLGOCCBSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O.N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 OFFWOVJBSQMVPI-RMLGOCCBSA-N 0.000 description 1
- 208000025370 Middle East respiratory syndrome Diseases 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- 206010035737 Pneumonia viral Diseases 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 241000315672 SARS coronavirus Species 0.000 description 1
- 229940122618 Trypsin inhibitor Drugs 0.000 description 1
- 101710162629 Trypsin inhibitor Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000003683 cardiac damage Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229940094089 isosorbide mononitrate 20 mg Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229940113983 lopinavir / ritonavir Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- RWWYLEGWBNMMLJ-MEUHYHILSA-N remdesivir Drugs C([C@@H]1[C@H]([C@@H](O)[C@@](C#N)(O1)C=1N2N=CN=C(N)C2=CC=1)O)OP(=O)(N[C@@H](C)C(=O)OCC(CC)CC)OC1=CC=CC=C1 RWWYLEGWBNMMLJ-MEUHYHILSA-N 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
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- 239000000243 solution Substances 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
- A61K38/57—Protease inhibitors from animals; from humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Definitions
- the invention belongs to the technical field of medicine, and particularly relates to the use of ulinastatin in preparing a medicine for treating novel coronavirus pneumonia.
- Coronaviruses are a large class of viruses that exist widely in nature. Before 2019, a total of 6 coronaviruses that can infect humans were found, namely HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV and MERS. -CoV, and the coronavirus that caused the outbreak was named the new coronavirus (SARS-CoV-2) after isolation and confirmation. According to existing studies, the common symptoms of patients with novel coronavirus infection are fever, cough and myalgia or fatigue; all patients suffered from pneumonia and abnormal chest CT examination findings; complications include acute respiratory distress syndrome , myocardial injury and secondary infection.
- the treatment of myocardial damage caused by the new coronavirus includes antiviral therapy.
- antiviral drugs such as remdesivir, chloroquine, lopinavir/ritonavir and abidol has a better treatment of the new coronavirus
- the role of viral pneumonia but it has also been found to cause heart damage.
- it also includes myocarditis and heart failure treatment and traditional Chinese medicine treatment.
- Ulinastatin is a trypsin inhibitor.
- the Shanghai Expert Consensus on Comprehensive Treatment of COVID-19 has recommended the use of high-dose broad-spectrum protease inhibitors, such as ulinastatin, to reduce pulmonary interstitial inflammation and pulmonary lesions. Ding, but whether ulinastatin can play a positive role in the treatment of new coronavirus pneumonia needs further research.
- the present invention aims to provide the use of ulinastatin in the preparation of medicines for treating novel coronavirus pneumonia.
- ulinastatin in preparing a medicine for treating novel coronavirus pneumonia, the single administration dosage of ulinastatin is 10-10 million units.
- the single dosage of ulinastatin is 300,000 to 5,000,000 units.
- the novel coronavirus pneumonia is a disease caused by the novel coronavirus SARS-CoV-2.
- the drug includes ulinastatin and geniposide.
- the medicament includes ulinastatin, geniposide and isosorbide mononitrate.
- the drug is a freeze-dried powder for injection, an injection, a spray formulation or an atomized formulation.
- the medicament includes the following components:
- the carrier is lactose or/and mannitol.
- the preparation method of the medicine comprises the following steps:
- step S3 Mix the mixture A and the mixture B of step S1 and step S2 fully, and pass through a 60-mesh sieve.
- the incremental dilution method is as follows: the carrier is added sequentially according to 5%, 15%, 25% and 55% of the prescription amount.
- Ulinastatin is a drug that has been successfully industrialized. Ulinastatin has a therapeutic effect on the new coronavirus SARS-CoV-2.
- the new coronavirus SARS-CoV-2 can cause myocardial damage, especially in the elderly, although ulinastatin can play a role in the myocardial damage caused by the new coronavirus. It has a certain therapeutic effect. However, it was unexpectedly found through clinical trials that when ulinastatin is combined with geniposide and isosorbide mononitrate, it can play a significant role in the treatment of myocardial damage caused by the new coronavirus.
- ulinastatin is a broad-spectrum protease inhibitor, which can interfere with the synthesis of RNA polymerase in SARS-CoV-2 virus, thereby inhibiting the replication of SARS-CoV-2 virus and achieving anti-SARS-CoV-2 The purpose of COVID-19 caused by viral infection.
- ulinastatin can also inhibit various enzymes involved in the inflammatory response to reduce the degree of organ inflammatory response and relieve the symptoms of myocardial injury. Ding this effect.
- the present invention has the following beneficial effects:
- the present invention finds through clinical trials that ulinastatin can be used to treat novel coronavirus pneumonia, and can treat myocardial injury caused by novel coronavirus.
- the present invention combines ulinastatin with geniposide and isosorbide mononitrate. It is found through clinical trials that after the combination, the therapeutic effect of treatment group B is better than that of treatment group A, treatment group C and Group D was treated, indicating that it can enhance the therapeutic effect of ulinastatin on myocardial injury caused by the new coronavirus after the combination.
- Embodiment 1 the medicine containing ulinastatin
- Embodiment 2 the medicine containing ulinastatin
- Embodiment 3 the medicine containing ulinastatin
- the medicine is an atomized preparation, including the following components:
- the preparation method of the medicine comprises the following steps:
- the incremental dilution method is: adding mannitol in sequence according to 5%, 15%, 25% and 55% of the prescription amount.
- Embodiment 4 the medicine containing ulinastatin
- the medicine is an atomized preparation, including the following components:
- the preparation method of the medicine comprises the following steps:
- step S3 Mix the mixture A and the mixture B of step S1 and step S2 fully, and pass through a 60-mesh sieve.
- the incremental dilution method is: adding mannitol sequentially according to 5%, 15%, 25% and 55% of the prescribed amount.
- Example 3 Compared with Example 3, the difference is that geniposide is not added.
- the distinguishing feature is that no isosorbide mononitrate was added.
- Treatment methods 100 patients diagnosed with novel coronavirus pneumonia were randomly divided into treatment group A, treatment group B and control group with 25 cases in each group. After admission, the patients in both groups were given basic treatment such as anti-infection, symptomatic and supportive treatment, and received treatment. Oxygen inhalation or non-invasive ventilator treatment was given according to the patient's condition.
- the patients in the control group were treated with standard treatment (conventional antiviral and anti-inflammatory drugs, adjuvant immune enhancers and supportive treatment) for 5 days;
- the treatment group A was combined with 800,000 units of ulinastatin and 100ml of 0.9% sodium chloride injection by intravenous drip on the basis of the control group (conventional antiviral, anti-inflammatory drugs, adjuvant immune enhancers and supportive treatment). Every 8 hours. Continuous treatment for 5 days;
- treatment group B on the basis of the control group (conventional antiviral and anti-inflammatory drugs, auxiliary immune enhancers and supportive treatment), 100 ml of 0.9% sodium chloride injection was added intravenously in Example 3. Every 8 hours. Treatment was continued for 5 days.
- control group conventional antiviral and anti-inflammatory drugs, auxiliary immune enhancers and supportive treatment
- treatment group D on the basis of control group (conventional antiviral, anti-inflammatory drugs, adjuvant immune enhancer and supportive treatment), 100ml of 0.9% sodium chloride injection was added intravenously in Comparative Example 2. Every 8 hours. Treatment was continued for 5 days.
- the patient's respiratory rate RR is 21-28 times/min, the oxygen saturation is >95%, the CDC throat swab is negative for new coronavirus nucleic acid, and chest CT shows that the inflammation is mostly absorbed than before;
- treatment group A As can be seen from Table 2 and Table 3, after treatment group A, treatment group B, treatment group C and treatment D were treated with ulinastatin for 5 days on the basis of the treatment of the control group, the body temperature, respiratory rate and oxygen saturation were significantly improved. Improvement, the patient's coronavirus nucleic acid all turned negative. Compared with the control group, treatment group B was better than treatment group A, treatment group C and treatment group D.
- Treatment methods 100 patients diagnosed with novel coronavirus pneumonia and myocardial injury caused by novel coronavirus infection were randomly divided into treatment group A, treatment group B, treatment group C and control group, 25 cases in each. All were given basic treatment such as anti-infection, symptomatic and supportive treatment, and given oxygen inhalation or non-invasive ventilator treatment according to the patient's condition.
- the patients in the control group were treated with standard treatment (conventional antiviral and anti-inflammatory drugs, adjuvant immune enhancers and supportive treatment) for 5 days;
- the treatment group A was combined with 800,000 units of ulinastatin on the basis of the control group (conventional antiviral and anti-inflammatory drugs, adjuvant immune enhancers and supportive treatment). Every 8 hours. Continuous treatment for 5 days;
- the treatment group B was treated in Example 3 on the basis of the control group (conventional antiviral and anti-inflammatory drugs, auxiliary immune enhancers and supportive treatment). Every 8 hours. Treatment was continued for 5 days.
- Treatment group C was treated on the basis of control group (conventional antiviral, anti-inflammatory drugs, adjuvant immune enhancers and supportive treatment) on the basis of control group 1. Every 8 hours. Treatment was continued for 5 days.
- the treatment group D was treated on the basis of the control group (conventional antiviral, anti-inflammatory drugs, adjuvant immune enhancers and supportive treatment) on the basis of the control group 2. Every 8 hours. Treatment was continued for 5 days.
- Chest CT showed that the inflammation was absorbed earlier than before.
- Chest CT showed that the inflammation was not absorbed or slightly absorbed than before.
- treatment group B has a good therapeutic effect on patients with novel coronavirus pneumonia and myocardial injury caused by novel coronavirus infection.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Virology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Molecular Biology (AREA)
- Zoology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A use of ulinastatin in the preparation of a drug for treating novel coronavirus pneumonia, the drug comprising components such as ulinastatin, geniposidic acid, isosorbide mononitrate, and the drug has a therapeutic effect on novel coronavirus pneumonia and on myocardial damage caused by novel coronavirus.
Description
本发明属于医药技术领域，具体涉及乌司他丁在制备治疗新型冠状病毒肺炎药物中的用途。The invention belongs to the technical field of medicine, and particularly relates to the use of ulinastatin in preparing a medicine for treating novel coronavirus pneumonia.
冠状病毒是自然界广泛存在的一大类病毒，在2019年之前，共发现6种可感染人类的冠状病毒，为HCoV-229E、HCoV-OC43、HCoV-NL63、HCoV-HKU1、SARS-CoV以及MERS-CoV，而此次引起疫情的冠状病毒，经分离确认后被命名新型冠状病毒(SARS-CoV-2)。根据已有的研究来看，新型冠状病毒感染的患者发病时的常见症状为发烧，咳嗽和肌痛或疲劳；全部患者均患有肺炎，胸部CT检查发现异常；并发症包括急性呼吸窘迫综合征，心肌损伤和继发感染。Huang等对截至2020年1月2日确诊的41例COVID-19患者统计中，发现病毒所致的急性心肌损伤有5例(12％)。武汉大学中南医院统计的138例COVID-19患者中，7.2％患者出现了肌钙蛋白升高，即出现心肌损伤表现。Coronaviruses are a large class of viruses that exist widely in nature. Before 2019, a total of 6 coronaviruses that can infect humans were found, namely HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV and MERS. -CoV, and the coronavirus that caused the outbreak was named the new coronavirus (SARS-CoV-2) after isolation and confirmation. According to existing studies, the common symptoms of patients with novel coronavirus infection are fever, cough and myalgia or fatigue; all patients suffered from pneumonia and abnormal chest CT examination findings; complications include acute respiratory distress syndrome , myocardial injury and secondary infection. Among the 41 COVID-19 patients diagnosed as of January 2, 2020, Huang et al found that 5 cases (12%) of acute myocardial injury caused by the virus were found. Among the 138 COVID-19 patients counted by Zhongnan Hospital of Wuhan University, 7.2% of the patients had elevated troponin, that is, myocardial damage.
目前，新型冠状病毒所引起心肌损伤的治疗包括抗病毒治疗，使用瑞德西韦、氯喹、洛匹那韦/利托那韦和阿比多尔等抗病毒药物虽然具有较好的治疗新型冠状病毒肺炎的作用，但是其也有发现其会带来心脏损伤。同时，还包括心肌炎及心力衰竭治疗和中医治疗等方法。At present, the treatment of myocardial damage caused by the new coronavirus includes antiviral therapy. Although the use of antiviral drugs such as remdesivir, chloroquine, lopinavir/ritonavir and abidol has a better treatment of the new coronavirus The role of viral pneumonia, but it has also been found to cause heart damage. At the same time, it also includes myocarditis and heart failure treatment and traditional Chinese medicine treatment.
乌司他丁是一种胰蛋白酶抑制剂，上海市2019冠状病毒病综合救治专家共识中曾建议在减轻肺间质炎症和肺部病灶中采用大剂量的广谱蛋白酶抑制剂，如乌司他丁，但是乌司他丁对新型冠状病毒肺炎的治疗能否起到一定的积极作用需进一步研究。Ulinastatin is a trypsin inhibitor. The Shanghai Expert Consensus on Comprehensive Treatment of COVID-19 has recommended the use of high-dose broad-spectrum protease inhibitors, such as ulinastatin, to reduce pulmonary interstitial inflammation and pulmonary lesions. Ding, but whether ulinastatin can play a positive role in the treatment of new coronavirus pneumonia needs further research.
而原有基础心血管疾病的存在加大了新型冠状病毒肺炎患者的救治难度，已公布的新冠肺炎患者病例表明，新冠肺炎患者的重症或死亡病例多为患有心血管疾病等慢性基础疾病的老年人，说明新型冠状病毒引发的心肌损伤进一步 加速了病情进展，因此，对于乌司他丁在治疗新型冠状病毒肺炎的同时是否能治疗由其引发的心肌损伤应进行着重研究。The existence of the original basic cardiovascular disease has made the treatment of patients with new coronary pneumonia more difficult. The published cases of new coronary pneumonia patients show that most severe or dead cases of new coronary pneumonia patients are elderly people with chronic basic diseases such as cardiovascular disease. , indicating that the myocardial injury caused by the new coronavirus further accelerates the progression of the disease. Therefore, it is necessary to focus on whether ulinastatin can treat the myocardial injury caused by it while treating the new coronavirus pneumonia.
发明内容SUMMARY OF THE INVENTION
本发明旨在提供乌司他丁在制备治疗新型冠状病毒肺炎药物中的用途。The present invention aims to provide the use of ulinastatin in the preparation of medicines for treating novel coronavirus pneumonia.
为了达到上述目的，本发明采用以下技术方案：In order to achieve the above object, the present invention adopts the following technical solutions:
乌司他丁在制备治疗新型冠状病毒肺炎药物中的用途，所述乌司他丁的单次给药用量为10～1000万单位。The use of ulinastatin in preparing a medicine for treating novel coronavirus pneumonia, the single administration dosage of ulinastatin is 10-10 million units.
优选地，所述乌司他丁的单次给药用量为30～500万单位。Preferably, the single dosage of ulinastatin is 300,000 to 5,000,000 units.
优选地，所述新型冠状病毒肺炎由新型冠状病毒SARS-CoV-2引发的疾病。Preferably, the novel coronavirus pneumonia is a disease caused by the novel coronavirus SARS-CoV-2.
优选地，所述药物包括乌司他丁和京尼平苷酸。Preferably, the drug includes ulinastatin and geniposide.
优选地，所述药物包括乌司他丁、京尼平苷酸和单硝酸异山梨酯。Preferably, the medicament includes ulinastatin, geniposide and isosorbide mononitrate.
优选地，所述药物为冻干粉针剂、注射液、喷雾制剂或雾化制剂。Preferably, the drug is a freeze-dried powder for injection, an injection, a spray formulation or an atomized formulation.
优选地，所述药物包括以下组分：Preferably, the medicament includes the following components:
乌司他丁10～1000万单位；Ulinastatin 10-10 million units;
京尼平苷酸0.5～1.5g；Genipin 0.5～1.5g;
单硝酸异山梨酯15～30mg；Isosorbide mononitrate 15～30mg;
半胱氨酸2～5g；Cysteine 2～5g;
透明质酸钠3～8g；Sodium hyaluronate 3～8g;
载体10～30g；Carrier 10～30g;
优选地，所述载体为乳糖或/和甘露醇。Preferably, the carrier is lactose or/and mannitol.
优选地，所述药物的制备方法包括以下步骤：Preferably, the preparation method of the medicine comprises the following steps:
S1)取乌司他丁、半胱氨酸、透明质酸钠和1/4处方量的载体用注射用水溶解，调节pH为6.8～7.2，无菌过滤，喷雾冷冻干燥，按照递加稀释法与1/4处方量的载体充分混合，过60目筛，得到混合物A；S1) get the carrier of ulinastatin, cysteine, sodium hyaluronate and 1/4 recipe quantity to dissolve with water for injection, adjust pH to be 6.8～7.2, sterile filter, spray freeze-drying, according to progressive dilution method Mix fully with the carrier of 1/4 recipe quantity, pass through 60 mesh sieve, obtain mixture A;
S2)取京尼平苷酸、单硝酸异山梨酯和1/4处方量的载体用注射用水溶解，无菌过滤，喷雾冷冻干燥，按照递加稀释法与1/4处方量的载体充分混合，过 60目筛，得到混合物B；S2) get the carrier of geniposide, isosorbide mononitrate and 1/4 recipe quantity to dissolve with water for injection, sterile filtration, spray freeze-drying, fully mix with the carrier of 1/4 recipe quantity according to progressive dilution method , passed through a 60-mesh sieve to obtain mixture B;
S3)将步骤S1和步骤S2的混合物A和混合物B充分混合，过60目筛，即得。S3) Mix the mixture A and the mixture B of step S1 and step S2 fully, and pass through a 60-mesh sieve.
优选地，所述递加稀释法为：将载体按照处方量的5％、15％、25％和55％依次加入。Preferably, the incremental dilution method is as follows: the carrier is added sequentially according to 5%, 15%, 25% and 55% of the prescription amount.
乌司他丁属于已成功产业化的药品，乌司他丁对新型冠状病毒SARS-CoV-2具有治疗作用。Ulinastatin is a drug that has been successfully industrialized. Ulinastatin has a therapeutic effect on the new coronavirus SARS-CoV-2.
而根据COVID-19患者治疗过程的临床表现，新型冠状病毒SARS-CoV-2会引起心肌损伤，特别是老年人的心肌损伤，虽然乌司他丁能够对因新型冠状病毒引起的心肌损伤起到一定的治疗作用，然而通过临床试验意外地发现当将乌司他丁与京尼平苷酸、单硝酸异山梨酯联合用药后，能够对因新型冠状病毒引起的心肌损伤起到显著的治疗作用，这可能是因为乌司他丁属于广谱蛋白酶抑制剂，其可干扰SARS-CoV-2病毒中RNA聚合酶的合成，从而抑制SARS-CoV-2病毒的复制，达到抗SARS-CoV-2病毒感染引发的新冠肺炎的目的。同时乌司他丁还能抑制参与炎症反应的各种酶以减轻器官炎症反应程度，减轻心肌损伤的症状，而与京尼平苷酸、单硝酸异山梨酯联合用药后，增强了乌司他丁这个效果。According to the clinical manifestations of the treatment process of COVID-19 patients, the new coronavirus SARS-CoV-2 can cause myocardial damage, especially in the elderly, although ulinastatin can play a role in the myocardial damage caused by the new coronavirus. It has a certain therapeutic effect. However, it was unexpectedly found through clinical trials that when ulinastatin is combined with geniposide and isosorbide mononitrate, it can play a significant role in the treatment of myocardial damage caused by the new coronavirus. , this may be because ulinastatin is a broad-spectrum protease inhibitor, which can interfere with the synthesis of RNA polymerase in SARS-CoV-2 virus, thereby inhibiting the replication of SARS-CoV-2 virus and achieving anti-SARS-CoV-2 The purpose of COVID-19 caused by viral infection. At the same time, ulinastatin can also inhibit various enzymes involved in the inflammatory response to reduce the degree of organ inflammatory response and relieve the symptoms of myocardial injury. Ding this effect.
与现有技术相比，本发明具有以下有益效果：Compared with the prior art, the present invention has the following beneficial effects:
(1)本发明通过临床试验发现，乌司他丁能够用于治疗新型冠状病毒肺炎，且能够治疗由新型冠状病毒引起的心肌损伤。(1) The present invention finds through clinical trials that ulinastatin can be used to treat novel coronavirus pneumonia, and can treat myocardial injury caused by novel coronavirus.
(2)本发明将乌司他丁与京尼平苷酸、单硝酸异山梨酯联合用药，经临床试验发现，联合用药后，治疗B组的治疗效果优于治疗A组、治疗C组和治疗D组，说明联合用药后其能够增强乌司他丁对由新型冠状病毒引起心肌损伤的治疗效果。(2) The present invention combines ulinastatin with geniposide and isosorbide mononitrate. It is found through clinical trials that after the combination, the therapeutic effect of treatment group B is better than that of treatment group A, treatment group C and Group D was treated, indicating that it can enhance the therapeutic effect of ulinastatin on myocardial injury caused by the new coronavirus after the combination.
以下通过实施例形式的具体实施方式，对本发明的上述内容作进一步的详 细说明。但不应将此理解为本发明上述主题的范围仅限于以下实施例。The above-mentioned content of the present invention will be described in further detail below through the specific implementation in the form of examples. However, it should not be understood that the scope of the above-mentioned subject matter of the present invention is limited to the following examples.
实施例1、含有乌司他丁的药物Embodiment 1, the medicine containing ulinastatin
取过滤灭菌后的乌司他丁10000万单位，加20g甘露醇和10g氯化钠溶解，调节pH到6.8，用注射用水补足体积至1500mL，无菌过滤，分装于1000个西林瓶中，即得。Take 100 million units of ulinastatin after filter sterilization, add 20g mannitol and 10g sodium chloride to dissolve, adjust the pH to 6.8, make up the volume to 1500mL with water for injection, sterile filter, and divide into 1000 vials. That's it.
实施例2、含有乌司他丁的药物Embodiment 2, the medicine containing ulinastatin
取过滤灭菌后的乌司他丁10000万单位，加20g葡萄糖和5g氯化钠溶解，调节pH到7.1，用注射用水补足体积至1500mL，无菌过滤，分装于1000个西林瓶中，即得。Take 100 million units of ulinastatin after filter sterilization, add 20g glucose and 5g sodium chloride to dissolve, adjust the pH to 7.1, make up the volume to 1500mL with water for injection, sterile filter, and divide into 1000 vials. That's it.
实施例3、含有乌司他丁的药物Embodiment 3, the medicine containing ulinastatin
所述药物为雾化制剂，包括以下组分：The medicine is an atomized preparation, including the following components:
乌司他丁80万单位；Ulinastatin 800,000 units;
京尼平苷酸0.5g；Genipin 0.5g;
单硝酸异山梨酯20mg；Isosorbide mononitrate 20mg;
半胱氨酸3g；Cysteine 3g;
透明质酸钠5g；Sodium Hyaluronate 5g;
甘露醇20g；Mannitol 20g;
所述药物的制备方法包括以下步骤：The preparation method of the medicine comprises the following steps:
S1)取乌司他丁、半胱氨酸、透明质酸钠和1/4处方量的甘露醇用注射用水溶解，调节pH为6.8，无菌过滤，喷雾冷冻干燥，按照递加稀释法与1/4处方量的甘露醇充分混合，过60目筛，得到混合物A；S1) get the mannitol of ulinastatin, cysteine, sodium hyaluronate and 1/4 recipe quantity and dissolve with water for injection, adjust pH to be 6.8, sterile filter, spray freeze-drying, according to progressive dilution method and 1/4 of the mannitol of the recipe quantity is fully mixed, and passed through a 60-mesh sieve to obtain mixture A;
S2)取京尼平苷酸、单硝酸异山梨酯和1/4处方量的甘露醇用注射用水溶解，无菌过滤，喷雾冷冻干燥，按照递加稀释法与1/4处方量的甘露醇充分混合，过60目筛，得到混合物B；S2) get the mannitol of geniposide, isosorbide mononitrate and 1/4 recipe quantity to dissolve with water for injection, aseptic filtration, spray freeze-drying, according to progressive dilution method and the mannitol of 1/4 recipe quantity Mix well, pass through a 60-mesh sieve to obtain mixture B;
S3)将步骤S1和步骤S2的混合物A和混合物B充分混合，过60目筛， 即得。S3) Mix mixture A and mixture B of step S1 and step S2 fully, and pass through a 60-mesh sieve.
其中，递加稀释法为：将甘露醇按照处方量的5％、15％、25％和55％依次加入。Wherein, the incremental dilution method is: adding mannitol in sequence according to 5%, 15%, 25% and 55% of the prescription amount.
实施例4、含有乌司他丁的药物Embodiment 4, the medicine containing ulinastatin
所述药物为雾化制剂，包括以下组分：The medicine is an atomized preparation, including the following components:
乌司他丁500万单位；Ulinastatin 5 million units;
京尼平苷酸0.7g；Genipin 0.7g;
单硝酸异山梨酯22mg；Isosorbide mononitrate 22mg;
半胱氨酸3.g；Cysteine 3.g;
透明质酸钠5g；Sodium Hyaluronate 5g;
甘露醇25g；Mannitol 25g;
所述药物的制备方法包括以下步骤：The preparation method of the medicine comprises the following steps:
S1)取乌司他丁、半胱氨酸、透明质酸钠和1/4处方量的甘露醇用注射用水溶解，调节pH为7.1，无菌过滤，喷雾冷冻干燥，按照递加稀释法与1/4处方量的甘露醇充分混合，过60目筛，得到混合物A；S1) Dissolve ulinastatin, cysteine, sodium hyaluronate and 1/4 recipe amount of mannitol with water for injection, adjust pH to 7.1, sterile filter, spray freeze-drying, and mix with 1/4 of the mannitol of the recipe quantity is fully mixed, and passed through a 60-mesh sieve to obtain mixture A;
S2)取京尼平苷酸、单硝酸异山梨酯和1/4处方量的甘露醇用注射用水溶解，无菌过滤，喷雾冷冻干燥，按照递加稀释法与1/4处方量的甘露醇充分混合，过60目筛，得到混合物B；S2) get the mannitol of geniposide, isosorbide mononitrate and 1/4 recipe quantity to dissolve with water for injection, aseptic filtration, spray freeze-drying, according to progressive dilution method and the mannitol of 1/4 recipe quantity Mix well, pass through a 60-mesh sieve to obtain mixture B;
S3)将步骤S1和步骤S2的混合物A和混合物B充分混合，过60目筛，即得。S3) Mix the mixture A and the mixture B of step S1 and step S2 fully, and pass through a 60-mesh sieve.
优选地，所述递加稀释法为：将甘露醇按照处方量的5％、15％、25％和55％依次加入。Preferably, the incremental dilution method is: adding mannitol sequentially according to 5%, 15%, 25% and 55% of the prescribed amount.
对比例1、含有乌司他丁的药物Comparative Example 1. Drugs containing ulinastatin
与实施例3相比，区别特征在于，未加入京尼平苷酸。Compared with Example 3, the difference is that geniposide is not added.
对比例2、含有乌司他丁的药物Comparative example 2. Drugs containing ulinastatin
与实施例3相比，区别特征在于，未加入单硝酸异山梨酯。Compared to Example 3, the distinguishing feature is that no isosorbide mononitrate was added.
实验一、新型冠状病毒肺炎的临床试验Experiment 1. Clinical trials of novel coronavirus pneumonia
1.1治疗方法：100例确诊了新型冠状病毒肺炎的患者，随机分为治疗A组、治疗B组和对照组各25例，两组患者入院后均给予抗感染、对症支持治疗等基础治疗，并根据患者病情给予吸氧或无创呼吸机治疗。1.1 Treatment methods: 100 patients diagnosed with novel coronavirus pneumonia were randomly divided into treatment group A, treatment group B and control group with 25 cases in each group. After admission, the patients in both groups were given basic treatment such as anti-infection, symptomatic and supportive treatment, and received treatment. Oxygen inhalation or non-invasive ventilator treatment was given according to the patient's condition.
对照组患者采用标准治疗方案(常规抗病毒、抗炎药物，辅助免疫增强剂及支持治疗)，持续治疗5天；The patients in the control group were treated with standard treatment (conventional antiviral and anti-inflammatory drugs, adjuvant immune enhancers and supportive treatment) for 5 days;
治疗A组在对照组(常规抗病毒、抗炎药物，辅助免疫增强剂及支持治疗)基础上联合乌司他丁80万单位加入0.9％氯化钠注射液100ml静脉滴注。8小时一次。持续治疗5天；The treatment group A was combined with 800,000 units of ulinastatin and 100ml of 0.9% sodium chloride injection by intravenous drip on the basis of the control group (conventional antiviral, anti-inflammatory drugs, adjuvant immune enhancers and supportive treatment). Every 8 hours. Continuous treatment for 5 days;
治疗B组在对照组(常规抗病毒、抗炎药物，辅助免疫增强剂及支持治疗)基础上实施例3加入0.9％氯化钠注射液100ml静脉滴注。8小时一次。持续治疗5天。In the treatment group B, on the basis of the control group (conventional antiviral and anti-inflammatory drugs, auxiliary immune enhancers and supportive treatment), 100 ml of 0.9% sodium chloride injection was added intravenously in Example 3. Every 8 hours. Treatment was continued for 5 days.
治疗C组在对照组(常规抗病毒、抗炎药物，辅助免疫增强剂及支持治疗)基础上对比例1加入0.9％氯化钠注射液100ml静脉滴注。8小时一次。持续治疗5天。In the treatment group C, 100ml of 0.9% sodium chloride injection was added intravenously in the control group (conventional antiviral, anti-inflammatory drugs, adjuvant immune enhancer and supportive treatment) based on Comparative Example 1. Every 8 hours. Treatment was continued for 5 days.
治疗D组在对照组(常规抗病毒、抗炎药物，辅助免疫增强剂及支持治疗)基础上对比例2加入0.9％氯化钠注射液100ml静脉滴注。8小时一次。持续治疗5天。In treatment group D, on the basis of control group (conventional antiviral, anti-inflammatory drugs, adjuvant immune enhancer and supportive treatment), 100ml of 0.9% sodium chloride injection was added intravenously in Comparative Example 2. Every 8 hours. Treatment was continued for 5 days.
1.2观察指标1.2 Observation indicators
(1)比较五组患者治疗前后的体温、呼吸频率RR和静息状态下的氧饱和度。(1) The body temperature, respiratory rate RR and resting oxygen saturation of the five groups of patients before and after treatment were compared.
(2)比较五组患者临床疗效。(2) The clinical efficacy of the five groups of patients was compared.
治愈：治疗后患者呼吸平稳，呼吸频率RR为10～20次/min，氧饱和度>95％，CDC咽拭子新型冠状病毒核酸呈阴性，胸部CT示炎症较前吸收；Cure: After treatment, the patient's breathing is stable, the respiratory rate RR is 10-20 times/min, the oxygen saturation is >95%, the CDC throat swab is negative for the nucleic acid of the new coronavirus, and the chest CT shows that the inflammation is absorbed earlier;
有效：治疗后患者呼吸频率RR为21～28次/min，氧饱和度>95％，CDC咽拭子新型冠状病毒核酸呈阴性，胸部CT示炎症较前大部分吸收；Effective: After treatment, the patient's respiratory rate RR is 21-28 times/min, the oxygen saturation is >95%, the CDC throat swab is negative for new coronavirus nucleic acid, and chest CT shows that the inflammation is mostly absorbed than before;
无效：治疗后患者出现气促，呼吸频率RR>28次/min，氧饱和度<95％，CDC咽拭子新型冠状病毒核酸呈阳性，胸部CT示炎症较前未吸收或略吸收。Ineffective: After treatment, the patient developed shortness of breath, respiratory rate RR>28 times/min, oxygen saturation <95%, CDC throat swab was positive for novel coronavirus nucleic acid, and chest CT showed that the inflammation was not absorbed or slightly absorbed.
(3)出院标准按照《新型冠状病毒肺炎诊疗方案(试行第七版)》执行。(3) The discharge standard is implemented in accordance with the "New Coronavirus Pneumonia Diagnosis and Treatment Program (Trial Version 7)".
1.3观察结果1.3 Observations
表1 患者的性别与年龄分析指标比较Table 1 Comparison of gender and age analysis indicators of patients
从表1可以看出，治疗A组、治疗B组、治疗C组、治疗D组分别和对照组相比的差异无统计学意义，具有可比性。As can be seen from Table 1, there was no statistically significant difference between treatment group A, treatment group B, treatment group C, and treatment group D compared with the control group, and they were comparable.
表2 治疗组与对照组治疗前的分析指标比较Table 2 Comparison of analysis indicators between the treatment group and the control group before treatment
表3 治疗A组与对照组治疗后的分析指标比较Table 3 Comparison of analysis indexes between treatment group A and control group after treatment
从表2和表3可以看出，治疗A组、治疗B组、治疗C组和治疗D在对照组的治疗基础上联合乌司他丁进行治疗5天后，体温、呼吸频率和氧饱和度明显改善，患者冠状病毒核酸全部转阴。与对照组相比，治疗B组较优于治疗A组、治疗C组和治疗D组。As can be seen from Table 2 and Table 3, after treatment group A, treatment group B, treatment group C and treatment D were treated with ulinastatin for 5 days on the basis of the treatment of the control group, the body temperature, respiratory rate and oxygen saturation were significantly improved. Improvement, the patient's coronavirus nucleic acid all turned negative. Compared with the control group, treatment group B was better than treatment group A, treatment group C and treatment group D.
实验二、新型冠状病毒引发心肌损伤的临床试验Experiment 2. Clinical trial of myocardial injury caused by novel coronavirus
治疗方法：100例确诊了新型冠状病毒肺炎、且因新型冠状病毒感染引起心肌损伤的患者，随机分为治疗A组、治疗B组、治疗C组和对照组各25例，两组患者入院后均给予抗感染、对症支持治疗等基础治疗，并根据患者病情给予吸氧或无创呼吸机治疗。Treatment methods: 100 patients diagnosed with novel coronavirus pneumonia and myocardial injury caused by novel coronavirus infection were randomly divided into treatment group A, treatment group B, treatment group C and control group, 25 cases in each. All were given basic treatment such as anti-infection, symptomatic and supportive treatment, and given oxygen inhalation or non-invasive ventilator treatment according to the patient's condition.
对照组患者采用标准治疗方案(常规抗病毒、抗炎药物，辅助免疫增强剂及支持治疗)，持续治疗5天；The patients in the control group were treated with standard treatment (conventional antiviral and anti-inflammatory drugs, adjuvant immune enhancers and supportive treatment) for 5 days;
治疗A组在对照组(常规抗病毒、抗炎药物，辅助免疫增强剂及支持治疗)基础上联合乌司他丁80万单位进行治疗。8小时一次。持续治疗5天；The treatment group A was combined with 800,000 units of ulinastatin on the basis of the control group (conventional antiviral and anti-inflammatory drugs, adjuvant immune enhancers and supportive treatment). Every 8 hours. Continuous treatment for 5 days;
治疗B组在对照组(常规抗病毒、抗炎药物，辅助免疫增强剂及支持治疗)基础上实施例3进行治疗。8小时一次。持续治疗5天。The treatment group B was treated in Example 3 on the basis of the control group (conventional antiviral and anti-inflammatory drugs, auxiliary immune enhancers and supportive treatment). Every 8 hours. Treatment was continued for 5 days.
治疗C组在对照组(常规抗病毒、抗炎药物，辅助免疫增强剂及支持治疗)基础上对比例1进行治疗。8小时一次。持续治疗5天。Treatment group C was treated on the basis of control group (conventional antiviral, anti-inflammatory drugs, adjuvant immune enhancers and supportive treatment) on the basis of control group 1. Every 8 hours. Treatment was continued for 5 days.
治疗D组在对照组(常规抗病毒、抗炎药物，辅助免疫增强剂及支持治疗)基础上对比例2进行治疗。8小时一次。持续治疗5天。The treatment group D was treated on the basis of the control group (conventional antiviral, anti-inflammatory drugs, adjuvant immune enhancers and supportive treatment) on the basis of the control group 2. Every 8 hours. Treatment was continued for 5 days.
1.2观察指标：1.2 Observation indicators:
比较五组患者临床疗效：The clinical efficacy of the five groups of patients was compared:
有效：efficient:
(1)心肌损伤标志物：hs-cTnI<28pg/mg，肌钙蛋白>6.125pg/ml；(1) Markers of myocardial injury: hs-cTnI<28pg/mg, troponin>6.125pg/ml;
(2)CDC咽拭子新型冠状病毒核酸呈阴性；(2) CDC throat swabs were negative for novel coronavirus nucleic acid;
(3)胸部CT示炎症较前吸收。(3) Chest CT showed that the inflammation was absorbed earlier than before.
无效：invalid:
(1)心肌损伤标志物：hs-cTnI>28pg/mg，肌钙蛋白<6.125pg/ml；(1) Markers of myocardial injury: hs-cTnI>28pg/mg, troponin<6.125pg/ml;
(2)CDC咽拭子新型冠状病毒核酸呈阳性；(2) CDC throat swabs were positive for novel coronavirus nucleic acid;
(3)胸部CT示炎症较前未吸收或略吸收。(3) Chest CT showed that the inflammation was not absorbed or slightly absorbed than before.
表4 观察结果Table 4 Observations
从表4可以看出，治疗B组对新型冠状病毒肺炎、且因新型冠状病毒感染引起心肌损伤的患者具有较好的治疗效果。As can be seen from Table 4, treatment group B has a good therapeutic effect on patients with novel coronavirus pneumonia and myocardial injury caused by novel coronavirus infection.
上述实施例仅例示性说明本发明的原理及其功效，而非用于限制本发明。任何熟悉此技术的人士皆可在不违背本发明的精神及范畴下，对上述实施例进行修饰或改变。因此，举凡所属技术领域中具有通常知识者在未脱离本发明所揭示的精神与技术思想下所完成的一切等效修饰或改变，仍应由本发明的权利要求所涵盖。The above-mentioned embodiments merely illustrate the principles and effects of the present invention, but are not intended to limit the present invention. Anyone skilled in the art can modify or change the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or changes made by those with ordinary knowledge in the technical field without departing from the spirit and technical idea disclosed in the present invention should still be covered by the claims of the present invention.
Claims (6)
- 乌司他丁在制备治疗新型冠状病毒肺炎药物中的用途，其特征在于，所述药物包括以下组分：The use of ulinastatin in the preparation of a medicine for the treatment of novel coronavirus pneumonia, characterized in that the medicine comprises the following components:乌司他丁10～1000万单位；Ulinastatin 10-10 million units;京尼平苷酸0.5～1.5g；Genipin 0.5～1.5g;单硝酸异山梨酯15～30mg；Isosorbide mononitrate 15～30mg;半胱氨酸2～5g；Cysteine 2～5g;透明质酸钠3～8g；Sodium hyaluronate 3～8g;载体10～30g。Carrier 10～30g.
- 根据权利要求1所述的用途，其特征在于，所述新型冠状病毒肺炎由新型冠状病毒SARS-CoV-2引发。The use according to claim 1, wherein the novel coronavirus pneumonia is caused by the novel coronavirus SARS-CoV-2.
- 根据权利要求1所述的用途，其特征在于，所述药物为冻干粉针剂、注射液、喷雾制剂或雾化制剂。The use according to claim 1, wherein the medicine is a freeze-dried powder injection, an injection, a spray preparation or an atomized preparation.
- 根据权利要求1所述的用途，其特征在于，所述载体为乳糖或/和甘露醇。The use according to claim 1, wherein the carrier is lactose or/and mannitol.
- 根据权利要求1所述的用途，其特征在于，所述药物的制备方法包括以下步骤：purposes according to claim 1, is characterized in that, the preparation method of described medicine comprises the following steps:S1)取乌司他丁、半胱氨酸、透明质酸钠和1/4处方量的载体用注射用水溶解，调节pH为6.8～7.2，无菌过滤，喷雾冷冻干燥，按照递加稀释法与1/4处方量的载体充分混合，过60目筛，得到混合物A；S1) get the carrier of ulinastatin, cysteine, sodium hyaluronate and 1/4 recipe quantity to dissolve with water for injection, adjust pH to be 6.8～7.2, sterile filter, spray freeze-drying, according to progressive dilution method Mix fully with the carrier of 1/4 recipe quantity, pass through 60 mesh sieve, obtain mixture A;S2)取京尼平苷酸、单硝酸异山梨酯和1/4处方量的载体用注射用水溶解，无菌过滤，喷雾冷冻干燥，按照递加稀释法与1/4处方量的载体充分混合，过60目筛，得到混合物B；S2) get the carrier of geniposide, isosorbide mononitrate and 1/4 recipe quantity to dissolve with water for injection, sterile filtration, spray freeze-drying, fully mix with the carrier of 1/4 recipe quantity according to progressive dilution method , passed through a 60-mesh sieve to obtain mixture B;S3)将步骤S1和步骤S2的混合物A和混合物B充分混合，过60目筛，即得。S3) Mix the mixture A and the mixture B of step S1 and step S2 fully, and pass through a 60-mesh sieve.
- 根据权利要求5所述的用途，其特征在于，所述递加稀释法为：将载体按照处方量的5％、15％、25％和55％依次加入。The use according to claim 5, characterized in that, the stepwise dilution method is: adding the carrier sequentially according to 5%, 15%, 25% and 55% of the prescription amount.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| CN111329999A (en) * | 2020-03-27 | 2020-06-26 | 广东天普生化医药股份有限公司 | Application of ulinastatin in preparing medicine for treating novel coronavirus pneumonia |
| CN113144180A (en) * | 2020-03-27 | 2021-07-23 | 广东天普生化医药股份有限公司 | Application of ulinastatin in preparing medicine for treating novel coronavirus pneumonia |
| CN112063708A (en) * | 2020-09-11 | 2020-12-11 | 成都中医药大学 | Method for screening active compound from traditional Chinese medicine and agent |
Non-Patent Citations (1)
| Title |
|---|
| MIR JAN MOHAMMAD, MAURYA RAM CHARITRA: "Nitric oxide boosters as defensive agents against COVID-19 infection: an opinion", JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, ADENINE PRESS, NEW YORK, NY, US, vol. 40, no. 9, 13 June 2022 (2022-06-13), US , pages 4285 - 4291, XP055971236, ISSN: 0739-1102, DOI: 10.1080/07391102.2020.1852969 * |
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