CN113209087B - Pharmaceutical composition for inhibiting coronavirus and application thereof - Google Patents
Pharmaceutical composition for inhibiting coronavirus and application thereof Download PDFInfo
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- CN113209087B CN113209087B CN202110160730.8A CN202110160730A CN113209087B CN 113209087 B CN113209087 B CN 113209087B CN 202110160730 A CN202110160730 A CN 202110160730A CN 113209087 B CN113209087 B CN 113209087B
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
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- A—HUMAN NECESSITIES
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- 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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention provides a pharmaceutical composition for inhibiting coronavirus and application thereof. The pharmaceutical composition can remarkably inhibit coronaviruses, in particular 2019 novel coronaviruses, thereby providing effective clinical medicines for preventing and/or treating respiratory tract, gastrointestinal tract, liver and/or central nervous system infectious diseases caused by the coronaviruses, in particular 2019 novel coronaviruses.
Description
Technical Field
The invention belongs to the field of pharmacy, relates to a pharmaceutical composition containing darunary Wei Heli tolnafvir for inhibiting coronavirus and application thereof, and in particular relates to a pharmaceutical composition containing darunary Wei Heli tolnafvir for inhibiting 2019 novel coronavirus and application thereof.
Background
Coronaviruses (covs) are important pathogens in humans and vertebrates that can infect the respiratory, gastrointestinal, hepatic and central nervous systems of humans, livestock, poultry, bats, mice and many other wild animals. Since the outbreak of Severe Acute Respiratory Syndrome (SARS) in 2003 and the outbreak of Middle East Respiratory Syndrome (MERS) in 2012, the possibility of CoV transmission from animals to humans has been demonstrated.
The world health organization temporarily named the new virus 2019 new coronavirus (2019-nCoV) on 1 month 12 of 2020. The formal name of the virus will be given by the international committee for virology (ICTV) according to the virus naming guidelines. Intermittent emergence and outbreaks of new coronaviruses alert us that coronaviruses remain a serious global health threat. With the changing climate and ecological environment and increasing human-animal interaction, new coronavirus outbreaks appear to be unavoidable in the future, and effective anti-coronavirus therapies and vaccines must be developed as soon as possible.
Current methods of treatment for coronaviruses are very limited, including:
(1) Aerosol inhalation of interferon alpha
An open study in 2003 on SARS patients showed that INF-a 1 in combination with a large dose of methylprednisolone improved oxygen saturation and pulmonary imaging in patients more rapidly. There are small-scale clinical studies in China, which show that in children suffering from acute bronchiolitis (respiratory syncytial virus), viral pneumonia (including influenza virus and coronavirus), hand-foot-and-mouth disease (enterovirus) and the like, atomized INFα1b or INFα2b can be effective for improving clinical symptoms and shortening the course of disease, and safety and tolerance are good.
(2) Remdesivir (also known as GS-5734) is an experimental RNA polymerase inhibitor that was initiated by Gilradic in order to cope with the start of the West Africa Ebola virus epidemic in 2013, developed by the Cooperation of Gilradi with the United states centers for disease control and prevention (CDC) and the United states army infectious disease medical institute in 2014.
(3) Compound preparation of lopinavir and ritonavir
Lopinavir (lopinavir) is a protease inhibitor that binds to the catalytic site of HIV protease, interfering with the viral assembly process, and is therefore used as an antiviral agent.
Ritonavir (ritonavir) is also an HIV protease inhibitor, and low doses of ritonavir can also increase lopinavir blood levels by inhibiting liver metabolism. For this reason lopinavir is commonly used in combination with small doses of ritonavir to treat HIV infection.
The literature reports that 41 patients with hong Kong "SARS" received three weeks of "lopinavir/ritonavir tablets" + ribavirin treatment during the SARS outbreak period in 2003, with a patient mortality rate of 2.4%. Mortality in 111 atypical patients treated with ribavirin Lin Changgui was 28.8% in the hong Kong Hospital where the control investigator was located. However, since the above clinical treatments did not strictly set the test and control groups, the treatment was irregular and did not result in optimal doses, and since the SARS was near disappeared, there was no further trial (Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings, thorax 2004,59:252-256.Doi:10.1136/thorax.2003.012658; treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study, hong Kong Med J, vol 9,No 6,December 2003,399). Clinical trials have also been developed internationally to investigate whether "lopinavir/ritonavir tablets" in combination with beta interferon could be used to treat the Middle East Respiratory Syndrome (MERS) (Treatment of Middle East respiratory syndrome with a combination of lopinavir/ritonavir and interferon-. Beta.1 1b (MIRACLE trial): statistical analysis plan for a recursive two-stage group sequential randomized controlled trial, trials.2020,21 (1), 8.doi:10.1186/s 13063-019-3846-x.). It is because of this that "lopinavir/ritonavir 2 particles at a time, twice a day" can be used for antiviral treatment as also mentioned in "new pneumonic diagnosis and treatment of coronavirus infection (trial third edition)" issued by the national institute of Committee Wei Jian to the respective Wei Jian Committee.
However, the efficacy of the above therapies on coronaviruses has not been demonstrated, and particularly for the prevention and/or treatment of 2019 novel coronaviruses, there is a lack of effective treatments and prevention means. In view of the severe situation of epidemic situation, there is an urgent need for a truly effective treatment.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition containing darunavir Wei Heli tolnafvir for inhibiting coronavirus and application thereof, which can effectively inhibit coronavirus, in particular 2019 novel coronavirus, so as to provide effective clinical medicines for preventing and/or treating infectious diseases of respiratory tract, gastrointestinal tract, liver and/or central nervous system caused by coronavirus, in particular 2019 novel coronavirus.
In one aspect, the invention provides a pharmaceutical composition for inhibiting coronavirus comprising a compound of formula I and a compound of formula II:
wherein the weight ratio of the compound shown in the formula I to the compound shown in the formula II can be (0.5-3): 1, preferably 1:1. optionally, the compound of formula I and the compound of formula II are placed separately.
Preferably, the pharmaceutical composition further comprises an interferon, such as interferon- α.
Wherein the weight ratio of the compound of formula I, the compound of formula II and the interferon may be (50-300) mg: 100 mg: (250 to 1000 tens of thousands of units), preferably 100 mg: 100 mg: 500 ten thousand units; optionally, the compound of formula I, the compound of formula II and the interferon are placed separately.
Preferably, the pharmaceutical composition may further comprise a compound of formula III:
wherein the weight ratio of the compound shown in the formula I, the compound shown in the formula II and the compound shown in the formula III can be (0.5-3): 1: (1-10), preferably 1:1:5. optionally, the compound of formula I, the compound of formula II and the compound of formula III are placed separately.
Preferably, the pharmaceutical composition may further comprise pharmaceutically acceptable carriers, excipients and/or diluents. More preferably, the compound of formula I, the compound of formula II and/or the compound of formula III is an oral formulation, such as a tablet or capsule, and the interferon is an aerosol.
In another aspect, the invention also provides the use of the pharmaceutical composition in the preparation of a medicament for preventing and/or treating infectious diseases of the respiratory tract, the gastrointestinal tract, the liver and/or the central nervous system caused by coronaviruses. Wherein the infectious diseases of the respiratory tract, gastrointestinal tract, liver and/or central nervous system caused by coronavirus may be selected from one or more of viral pneumonia, autoimmune diseases, organ failure, acute respiratory distress syndrome, septic shock, uncorrectable metabolic acidosis or coagulation dysfunction; preferably, the respiratory, gastrointestinal, hepatic and/or central nervous system infectious disease caused by coronavirus is a respiratory, gastrointestinal, hepatic and/or central nervous system infectious disease caused by 2019 novel coronavirus, such as viral pneumonia, autoimmune diseases, organ failure, acute respiratory distress syndrome, septic shock, metabolic acidosis or clotting dysfunction that is difficult to correct.
In yet another aspect, the invention also provides the use of the above pharmaceutical composition in the preparation of an anti-coronavirus drug, in particular a drug against 2019 novel coronavirus.
In yet another aspect, the present invention also provides a method for preventing and/or treating infectious diseases of the respiratory tract, gastrointestinal tract, liver and/or central nervous system caused by coronaviruses, in particular 2019 novel coronaviruses, comprising administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of the above pharmaceutical composition.
Accordingly, the present invention also provides a method of combating coronaviruses, particularly novel 2019 coronaviruses, comprising administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of the above pharmaceutical composition.
The compound shown in the formula I has the general name of darunavir (Danoprevir, DVR, RG7227, ITMN-191, gorboom and CAS# 850876-88-9), has strong virus protease inhibition function, and can effectively inhibit the activity (molecular activity IC) of HCV NS3/4A serine protease 50 =290 pM, cell activity 1.8 nM), has been approved for the treatment of hepatitis c. The result of the phase III clinical test completed in the continental China shows that after 12 weeks of treatment, the cure rate (SVR 12) in the patients with the hepatitis C of the genotype 1 non-liver cirrhosis reaches 97 percent, and the cure rate in the patients with the genotype 4 non-liver cirrhosis reaches100％。
The compounds of formula II employed in the present invention are known by the generic name Ritonavir (Ritonavir, CAS# 155213-67-5) and are orally potent inhibitors of human immunodeficiency virus-1 (HIV-1) and human immunodeficiency virus-2 (HIV-2) aspartic proteases. Ritonavir is not only a protease inhibitor, but also a powerful CYP3A4 inhibitor, and small dosage of ritonavir can be used as a pharmacokinetics synergist to inhibit metabolism of the CYP3A mediated protease inhibitor, so that the blood concentration of other protease inhibitors is improved, and the curative effect of antiviral drugs is enhanced.
The general name of the compound shown in the formula III adopted by the invention is ribavirin, which is a broad-spectrum strong antiviral drug, belongs to a synthetic nucleoside drug and has inhibition effect on a plurality of DNA and RNA viruses. The ribavirin Lin Weian spectrum antiviral agent can inhibit inosinic acid-5-phosphate dehydrogenase, block inosinic acid from being converted into guanylic acid, inhibit RNA and DNA synthesis of viruses, and inhibit replication of DNA viruses and RNA viruses.
The inventor surprisingly discovers that the compound shown in the formula I and the compound shown in the formula II contained in the pharmaceutical composition have obvious synergistic effect in activity, and can obviously inhibit coronaviruses, especially 2019 novel coronaviruses, so that the pharmaceutical composition is provided with novel application for preventing and/or treating respiratory tract, gastrointestinal tract, liver and/or central nervous system infectious diseases caused by coronaviruses, especially 2019 novel coronaviruses. Furthermore, the above-mentioned activity can be enhanced by further adding a compound represented by formula III. The invention can obviously reduce the infection rate of viruses to cells by combining different mechanism medicaments (cocktail therapy) and inhibiting the replication of the viruses at different stages.
Drawings
Embodiments of the present invention are described in detail below with reference to the attached drawing figures, wherein:
figure 1 illustrates the potential coronavirus drug therapeutic mechanism.
FIG. 2 shows the schedule of reverse transcription polymerase chain reaction detection, computer tomography and antiviral treatment for 11 admitted patients in example 1.
Figure 3 shows CT images of the lungs of patient 1 before and after treatment with ritonavir potentiation, in example 1.
Figure 4 shows CT images of the lungs of patient 6 of example 1 before and after treatment with ritonavir potentiation.
Figure 5 shows CT images of the lungs of patient 8 of example 1 before and after treatment with ritonavir potentiation.
Detailed Description
The following are specific examples of the present invention, which further describe the technical aspects of the present invention, but the scope of the present invention is not limited to these examples. All changes and equivalents that do not depart from the gist of the invention are intended to be within the scope of the invention.
EXAMPLE 1 darunary Wei Liange ritonavir treatment (naive/naive) plain COVID-19 patient
Darunavir tablets: (provided by Song Gift pharmaceutical Co., ltd., the manufacturer is Song Gift pharmaceutical Co., ltd., zhejiang)
Ritonavir tablets: (offered by Song Gift pharmaceutical Co., ltd., manufacturer AbbVie Deutschland GmbH & Co.)
Alpha-interferon: (recombinant human interferon alpha 2b injection 0.5ml,500 ten thousand units, added with injection water 2 ml)
Study design: after the removal of severe or critical cases of established pneumonia of new coronavirus infection in 2019, patients who combine multiple underlying diseases, or patients with related contraindications in darunavir, ritonavir specifications, 11 persons of established cases of established pneumonia of new coronavirus infection in 2019 (common type, diagnosis criteria reference "new coronavirus infection pneumonia diagnosis protocol").
Treatment protocol: orally administered darunavir tablets, 100mg each time, 2 times daily for 14 days; ritonavir tablets, 100mg each time, 2 times daily for 14 days; inhaled interferon-alpha, 500 ten thousand units/time, twice daily, for 14 days, with or without nebulization.
Discharge standard: according to the national standard of China, the following four conditions must be met before discharge: (1) the body temperature is recovered to be normal for more than 3 days; (2) a marked improvement in respiratory symptoms; (3) Pulmonary imaging shows a significant improvement in acute exudative lesions; (4) Two consecutive respiratory tract sample nucleic acid tests were negative (sampling times at least 1 day apart).
Experimental results:
baseline demographics and clinical features
A total of 11 common covd-19 patients were enrolled, including 2 primary and 9 treated patients. Table 1 illustrates baseline demographics for all patients in the group. Patients range in age from 18 to 66 years old with 4 men out of a total of 11 patients. Two treated patients (patient 6 and patient 8) had a history of hypertension. Symptoms reported at onset are mainly fever, cough and shortness of breath. Two primary patients were hospitalized for 9 days and 7 days, respectively, and the median hospitalization time for the treated patients was 20 days.
Table 111 baseline demographics, primary medical status, and clinical profile of patients receiving ritonavir-fortified darunavir treatment
| Primary treatment (N=2) | Warp therapy (N=9) | |
| Middle position age (age) | 44，18 | 44(18-66) # |
| Hospitalization for middle position (day) | 9，7 | 20(7-22) # |
| Male men | 1 | 3 |
| Basic drug condition | None, none | 2 $ |
| Symptoms reported at the time of onset | ||
| Fever with fever | None, none | 4 |
| Cough with cough | There is no one or more | 3 |
| Shortness of breath | There is no one or more | 6 |
The number # is indicated as the median, with maximum and minimum values in brackets.
Two patients treated, patient 6 and patient 8, had a history of hypertension.
Table 2 gives the key parameters for 11 patients and fig. 2 illustrates them. In general, 9 patients receiving combined interferon nebulization therapy with lopinavir/ritonavir and modified darunavir/ritonavir therapy were enrolled, including 4 patients with combined interferon nebulization after modification and 5 patients without combined interferon nebulization. Two untreated patients received darunavir/ritonavir combined interferon aerosol inhalation treatment. After starting the treatment with darunavir/ritonavir, the first RT-PCR assay negative occurred at median 2 days (1 to 8 days) and significant absorption in CT scan occurred at median 3 days (2 to 4 days).
Table 2 11 critical parameters for patients receiving ritonavir-fortified darunavir treatment
NA: is not suitable for
* The first negative detection was confirmed by a second RT-PCR detection at least 1 day apart.
The lung image of patient 10 showed no apparent lesions at the time of admission and during hospitalization.
Primary treatment patients receiving darunavir/ritonavir combined interferon aerosol inhalation treatment
Two untreated patients received darunavir/ritonavir combined interferon aerosol inhalation treatment at hospitalization. The medical history, treatment and various examinations of one of the two patients (patient 1) are described in detail below.
In year 2020, month 2 and 19, a 40-year-old female was in intimate contact with a patient with covd-19, and positive for SARS-COV-2 on the nasal swab was detected by RT-PCR, thus admitted. The patient's vital signs showed a Body Temperature (BT) of 36.4 ℃, oxygen saturation (SPO 2 ) 99%. The initial breath sounds are normal. Until then she had no other underlying disease.
She was treated with the first ritonavir-fortified danorel Wei Binglian in interferon aerosol inhalation 2 months and 20 am.
For 2 months and 20 days, according to chest CT scan (fig. 3A), both lower lungs showed multiple diffuse plaque areas and ground glass shadows (GGO), especially in the lower left lung. Laboratory results showed lymphopenia (0.62×10) 9 /L) and platelet elevation (322X 1)0 9 L) (Table 3).
After 2 months and 22 days, the patient did not develop abnormal symptoms or vital signs after 3 days of ritonavir-fortified darunavir treatment. The GGO and plaque areas of the bilateral lower lung lobes were reduced compared to the previous image for day 2 and 20, indicating partial absorption (fig. 3B). The RT-PCR result of the nasal swab was negative. These results indicate that patients respond rapidly to ritonavir-fortified danorel Wei Binglian interferon aerosol inhalation therapy.
After 2 months 24 days, 5 days following ritonavir-fortified danorevir treatment, both the density and scale of GGO and plaque areas in the double lung were significantly reduced compared to the previous image of day 2 months 22 (fig. 3C). RT-PCR nasal swab results were negative at both 24 days of 2 months and 26 days of 2 months.
Patient #1 received the last dose of ritonavir-fortified danorel Wei Binglian co-interferon aerosol inhalation treatment on day 28 of 2 months. Since she meets all four discharge criteria described in the section "discharge criteria", the patient is discharged from the hospital on the same day.
Treated patients receiving lopinavir/ritonavir + interferon aerosol inhalation therapy, with or without dry therapy
Darunavir/ritonavir under the condition of aerosol inhalation of interferon
9 patients with treatment history received lopinavir/ritonavir combined interferon aerosol inhalation treatment for 2 to 13 days. 4 patients received lopinavir/ritonavir combined interferon nebulization for 2 to 5 days, CT scan was worsened, and darunavir/ritonavir combined interferon nebulization was used instead. The medical history, treatment and various examinations of one of the patients (patient 6) are described in detail below.
A40-year old man was sent to the hospital for a nasal swab SARS-CoV-2RT-PCR nucleic acid detection positive on day 14, 2, 2020. His family was diagnosed with COVID-19 on day 11 of 2 months. From the chest CT scan, the lower right lung subpleural area displays GGO (fig. 4A). At admission, the patient reported a 3 day history of chest discomfort and fatigue. He showed no signs of fever, shortness of breath, nausea and diarrhea. He had a history of hypertension.
At night, 14 months, he received a first dose of kalelta (lopinavir (200 mg)/ritonavir (50 mg), 2 tablets each, twice daily, in combination with interferon aerosol inhalation.
For 2 months 15 days, the patient reported that he still had chest distress, still reported that the stool was thin and occasionally coughed and white sputum appeared. The patient continued to receive lopinavir/ritonavir treatment and received rehydration support treatment.
After 3 days of lopinavir/ritonavir treatment, following day 17 of 2 months, the lower lung showed further consolidation according to CT scan, with GGO and plaque areas (fig. 4B). Thus, at night of 17 months, the patient was discontinued from lopinavir/ritonavir treatment and ritonavir-fortified danorel Wei Binglian co-interferon aerosol inhalation treatment was used instead. The RT-PCR detection result of the viral RNA in the nasal swab of the patient was weak positive after 18 days of 2 months.
For 2 months and 20 days, the lower right lung showed a reduced plaque area and a reduced GGO density 4 days after ritonavir-fortified danorevir treatment (fig. 4C). On the same day, the RT-PCR test results of the nasal swabs became negative, and the RT-PCR test results remained negative the next day.
The patient received the last ritonavir-fortified darunavir treatment at 23 am 2 months. Since he meets all four discharge criteria as described in the "discharge criteria" section, the patient is discharged from the hospital on the same day.
Five patients failed to be treated with lopinavir/ritonavir plus interferon nebulization and were instead treated with darunavir/ritonavir, without interferon nebulization. The medical history, treatment and various examinations of one of the patients (patient 8) are described in detail below.
On day 2 and 9, a 40-year-old female (she is a permanent resident of the Wuhan market) was hospitalized positively for maximum BT 38℃and nasal swab SARS-COV-2RT-PCR nucleic acid detection. She occasionally cough with white sputum. Patient vital signs in ambient air showed BT of 37.4 ℃, SPO 2 99%. The patient had a history of half an year hypertension. The patient was given the first lopinavir dose at night of 2 months 9Ritonavir, 2 tablets each, twice daily, in combination with interferon nebulization.
On day 2 and 10, both the subpleural region of the lower lung and the lingual segment of the left lung showed GGO and plaque-like areas according to CT scan (fig. 5A). From day 2, 10 to day 2, 13, the patient had slightly fluctuating BT (highest 37.3 ℃ to lowest 36.4 ℃), cough with white sputum, anorexia and diarrhea, and the stool was yellow thin. Laboratory results showed leukopenia (3.40×10 9 L) and lymphopenia (0.7X10) 9 L) (Table 3).
On day 2 and 13, after 4 days of lopinavir/ritonavir treatment, the density of GGO and plaque areas was slightly increased compared to the previous CT image on day 2 and 10 (fig. 5B).
After 8 days of lopinavir/ritonavir treatment, the patient reported an improvement in appetite, but cough with white sputum while sleeping, on day 17. CT scan showed no significant change from the previous CT image of day 13 of 2 months and the opacity of the tongue segment increased (fig. 5C).
The patient received the final dose of lopinavir/ritonavir and interferon nebulization inhalation treatment for 2 months and 19 days. The treatment time of lopinavir/ritonavir and interferon aerosol inhalation is more than recommended by Chinese national standards. Thus, both lopinavir/ritonavir and interferon aerosol inhalation cease.
For 2 months and 20 days, she had changed to ritonavir-fortified darunavir without combined interferon aerosol inhalation.
2 months 22 days, after 3 days of darunavir/ritonavir treatment, both nasal swabs and sputum swabs were negative for RT-PCR detection.
On day 23 of 2 months, the patient showed improved white blood cell count (4.31×10 on day 4 after the ritonavir boost was changed 9 /L). CT scans showed a decrease in the density of GGO and plaque areas compared to the previous CT images of day 17 of 2 months, indicating absorption in both lungs (fig. 5D).
The patient received the last ritonavir-fortified darunavir dose for 25 days of 2 months.
For 26 days of 2 months, CT scan showed that lesions of the tongue section of the lung had been completely absorbed. The shadow density of the double lower lung is reduced compared to the previous CT image (fig. 5E).
RT-PCR tests of nasal swabs and sputum swabs were negative for both day 26 and day 27 of 2 months.
On day 2 and 29, the patient has met all four discharge criteria as described in the discharge criteria section and has therefore been discharged.
Table 3 three representative patients were examined in laboratory and underlying disease before and after ritonavir-fortified darunavir treatment
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ALT: alanine aminotransferase; AST: aspartate aminotransferase; ALP: alkaline phosphatase; LDH: lactate dehydrogenase; INR: international normalized ratio; PT: prothrombin time.
And ∈ indicates that the value is below the minimum reference value.
∈ indicates that the value is above the maximum reference value.
The present study was first successful in treating 11 patients with covd-19 using anti-HCV protease inhibitors. Nucleic acid detection results indicate that darunary Wei Liange ritonavir regimen treatment for 4-12 days effectively inhibits viral replication, and chest CT shows that lung-in-grind glass-like shadows (GGO) and diffuse plaque area can be effectively reduced. Viral nucleic acid in nasopharyngeal swabs turned negative at 2 days after initiation of darunary Wei Liange ritonavir treatment and absorbed at 3 days at GGO. Especially for common type COVID-19 patients, the efficacy of the darunary Wei Liange ritonavir regimen in treating primary and treated patients with antiviral treatment was demonstrated.
EXAMPLE 2 darunary Wei Liange ritonavir treatment of patients with long-term nucleic acid detection positive (55-66 days) treated (antiviral treatment) with covd-19
Case 1
A 50 year old man with positive SARS-CoV-2 was sent to the Wuhan fire Shenshan Hospital 47 days after cough and fever, 3 months and 10 days 2020. The result of the nucleic acid detection of SARS-CoV-2 was positive after 15 days of 2 months. Previous treatments included arbidol (0.2 g, three times per day) and Lianhua qingwen granule (6 g, three times per day). At admission, the ambient oxygen saturation in the ambient air was 96% and the respiratory rate was 18 breaths/min. The immunoglobulin M (IgM) and immunoglobulin G (IgG) levels of SARS-CoV-2 were 53.12G/L and 173.69G/L, respectively (normal ranges of both: <10G/L; shenzhen YHLO biotechnology Co., ltd., shenzhen, china). Computed Tomography (CT) has been found to show bilateral, diffuse, high density shadows, and fibrous and streak shadows. Recovery plasma from covd-19 patients (200 mL,3 months 17 and 18 days), recombinant human interferon (0.3 mL, nebulized inhaled once a day), even flower antipyretic particles (6 g, three times a day) and arbidol (2 tablets, three times a day) were treated from 3 months 10 to 22 days; for 3 months and 23 days, chloroquine phosphate (2 tablets twice daily) was administered instead of arbidol. The SARS-COV-2RT-PCR nucleic acid detection was positive for 23 days 3 months. CT scan shows clear improvement of lesions without clear lung lesions for 24 days of 3 months. He received ritonavir-fortified darunavir (DNVr) treatment alone (100/100 mg, twice daily, one at a time). The nucleic acid detection results of SARS-CoV-2 were negative from 3 days to 5 days of 4 months. SARS-CoV-2IgM and IgG levels were significantly reduced (5.38 g/L and 108.68g/L, respectively). For 7 days 4 months, he was discharged from hospital after three consecutive SARS-COV-2RT-PCR nucleic acid tests were negative. The duration from detection of positive by SARS-COV-2RT-PCR nucleic acid to three consecutive negative results was 55 days.
Case 2
On 12 days 3 and 2020, an 81 year old man diagnosed with covd-19 was sent to the fire mountain hospital after 50 days of intermittent fever, chest pain and shortness of breath for 40 days. The patient also suffers from type 2 diabetes, hypertension and aortic dissection related diseases. The result of nucleic acid detection of SARS-CoV-2 was positive after 2 months and 1 day. During the previous hospitalization, gastrointestinal bleeding was observed with black stool; CT scan showed bilateral plaque shadows, small pleural effusions in right lung and aortic dissection. At admission, SARS-CoV-2IgM and IgG levels were 20.89g/L and 187.92g/L, respectively. Treatment included 3 months 15 to 26 days chloroquine phosphate (2 tablets twice daily) and/or convalescent plasma (400 ml) from the covd-19 patient. And the detection result of the nucleic acid swab is positive after 3 months and 23 days. The SARS-COV-2RT-PCR nucleic acid detection in the patient's feces was positive for 25 days of 3 months. The CT scan showed significant improvement and significant reduction of lung lesions for 24 days of 3 months. For 3 months and 27 days, he received DNVr alone (100/100 mg, twice daily, one at a time). After 3 consecutive negative nucleic acid detection results, he was discharged from hospital and transferred to another hospital for further treatment of co-morbidities on day 4 and 5. The duration from detection of the SARS-COV-2RT-PCR nucleic acid positive to the consecutive three negative results was 65 days.
Case 3
A42 year old male infected with COVID-19 was sent to the Huoshen mountain hospital for 1 month cough, debilitation and 10 days fever on day 13 of 2020. Previous medical history included chronic hepatitis c that successfully healed in 2015, a persistent negative result on Hepatitis C Virus (HCV) RNA. The result of nucleic acid detection of SARS-CoV-2 was positive after 14 days of 2 months. Previous treatments included Lianhua qingwen granule (6 g, three times per day) and ribavirin (900-1200 mg, three times per day). At admission, CT results showed bilateral, multiple, scattered and flaky high density shadows and ground glass shadows. 3. And the nucleic acid detection result is positive on 27 days of the month. The CT scan showed significant improvement and significant reduction of lung lesions on day 31 of 3 months. For 4 months and 3 days, he received treatment with DNVr (100/100 mg, twice daily, one at a time). On day 4 and 14, he was discharged from his hospital after two consecutive SARS-CoV-2 assays were negative. The duration from detection of the SARS-COV-2RT-PCR nucleic acid positive to the consecutive two negative results was 58 days.
Case 4
A 33 year old male with covd-19 was admitted to the fire mountain hospital for cough, chest pain, shortness of breath and back pain for 7 days on day 29, 3 in 2020. The CT results showed bilateral ground glass-like shadows on day 31 of 1 month. The result of nucleic acid detection of SARS-CoV-2 was positive after 2 months and 6 days. The CT results showed bilateral small flocculent shadows, ground glass-like shadows, isolated lung nodules of the middle lobe of the right lung for 30 months. Previous treatments included Lianhua qingfebrile granule (6 g, three times per day), arbidol (0.2 g, three times per day) and ritonavir-fortified lopinavir (2 tablets, once every 12 hours). And 4 months and 2 days, the result of the nucleic acid detection is positive. 4 months and 4 days, he received treatment with DNVr (100/100 mg, twice daily, one at a time). On day 4 and 14, he was discharged from his hospital after two consecutive SARS-CoV-2 assays were negative. The duration from detection of the SARS-COV-2RT-PCR nucleic acid positive to the consecutive two negative results was 66 days.
All of the above cases received various antiviral treatments such as interferon aerosol inhalation, arbidol, chloroquine, plasma from patients in convalescence to new coronaries, and Lianhua qingwen granules. After long-term use of these antiviral drugs, nasopharyngeal swab test results showed that SARS-COV-2RT-PCR nucleic acid detection was still positive. Following treatment with the darunary Wei Liange ritonavir regimen, a shift in the results of the nucleic acid detection was observed. Thus the darunary Wei Liange ritonavir regimen may be a potential therapeutic for patients with long-term positive nucleic acid for new coronaries.
Claims (1)
1. Use of a pharmaceutical composition in the manufacture of a medicament against 2019 novel coronavirus, wherein the pharmaceutical composition consists of, by weight: 1 and a compound shown in a formula II:
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Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011057148A1 (en) * | 2009-11-05 | 2011-05-12 | Irm Llc | Compounds and compositions as tlr-7 activity modulators |
| CN104010631A (en) * | 2011-12-29 | 2014-08-27 | 艾伯维公司 | Solid compositions comprising an HCV inhibitor |
| CN104379145A (en) * | 2012-06-27 | 2015-02-25 | 艾伯维公司 | Combination treatment of abt-450 and ritonavir and e.g. abt-072 and/or abt-333|for use in treating hcv |
| WO2015135652A1 (en) * | 2014-03-12 | 2015-09-17 | Technische Universität München | Antagonists of acid lipase for preventing virus infection |
| CN109475562A (en) * | 2016-07-19 | 2019-03-15 | 诺华股份有限公司 | Oxazines derivative for the Alzheimer disease in anticipating risk patient |
| CN110123810A (en) * | 2018-02-02 | 2019-08-16 | 歌礼生物科技（杭州）有限公司 | For treating the pharmaceutical composition of viral hepatitis type C |
| CN111346219A (en) * | 2020-02-21 | 2020-06-30 | 上海甘翼生物医药科技有限公司 | Use of interferon in preparing medicine for preventing coronavirus infection or preventing diseases caused by coronavirus infection |
| WO2021209563A1 (en) * | 2020-04-16 | 2021-10-21 | Som Innovation Biotech, S.A. | Compounds for use in the treatment of viral infections by respiratory syndrome-related coronavirus |
| CN113786478A (en) * | 2021-10-09 | 2021-12-14 | 成都市公共卫生临床医疗中心 | Antiviral treatment method for systemic novel coronavirus pneumonia |
| WO2022115654A1 (en) * | 2020-11-30 | 2022-06-02 | Academia Sinica | Methods for treating sars-cov-2 infection |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070161611A1 (en) * | 2005-12-01 | 2007-07-12 | Dominique Dugourd | Polycyclic phenolic compounds and use in treating viral infections |
| CA2832818A1 (en) * | 2011-04-06 | 2012-10-11 | The Trustees Of Princeton University | Anti-viral combination therapy |
| US8492386B2 (en) * | 2011-10-21 | 2013-07-23 | Abbvie Inc. | Methods for treating HCV |
| US9034832B2 (en) * | 2011-12-29 | 2015-05-19 | Abbvie Inc. | Solid compositions |
| US20160333404A1 (en) * | 2012-10-09 | 2016-11-17 | Abbvie Inc. | Methods for treating hcv |
| CA3218643A1 (en) * | 2021-05-11 | 2022-11-17 | Anil Gulati | Pharmaceutical composition and method for treatment of acute respiratory distress syndrome (ards) in corona virus disease (covid-19) |
-
2021
- 2021-02-05 CN CN202110160730.8A patent/CN113209087B/en active Active
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011057148A1 (en) * | 2009-11-05 | 2011-05-12 | Irm Llc | Compounds and compositions as tlr-7 activity modulators |
| CN104010631A (en) * | 2011-12-29 | 2014-08-27 | 艾伯维公司 | Solid compositions comprising an HCV inhibitor |
| CN104379145A (en) * | 2012-06-27 | 2015-02-25 | 艾伯维公司 | Combination treatment of abt-450 and ritonavir and e.g. abt-072 and/or abt-333|for use in treating hcv |
| WO2015135652A1 (en) * | 2014-03-12 | 2015-09-17 | Technische Universität München | Antagonists of acid lipase for preventing virus infection |
| CN109475562A (en) * | 2016-07-19 | 2019-03-15 | 诺华股份有限公司 | Oxazines derivative for the Alzheimer disease in anticipating risk patient |
| CN110123810A (en) * | 2018-02-02 | 2019-08-16 | 歌礼生物科技（杭州）有限公司 | For treating the pharmaceutical composition of viral hepatitis type C |
| CN111346219A (en) * | 2020-02-21 | 2020-06-30 | 上海甘翼生物医药科技有限公司 | Use of interferon in preparing medicine for preventing coronavirus infection or preventing diseases caused by coronavirus infection |
| WO2021209563A1 (en) * | 2020-04-16 | 2021-10-21 | Som Innovation Biotech, S.A. | Compounds for use in the treatment of viral infections by respiratory syndrome-related coronavirus |
| WO2022115654A1 (en) * | 2020-11-30 | 2022-06-02 | Academia Sinica | Methods for treating sars-cov-2 infection |
| CN113786478A (en) * | 2021-10-09 | 2021-12-14 | 成都市公共卫生临床医疗中心 | Antiviral treatment method for systemic novel coronavirus pneumonia |
Non-Patent Citations (7)
| Title |
|---|
| Danoprevir/ritonavir联合聚乙二醇化干扰素a-2a/利巴韦林治疗丙型肝炎的疗效、安全性、药代动力学研究;赵红，等;肝脏;第17卷(第07期);第527页 * |
| First clinical study using HCV protease inhibitor danoprevir to treat COVID-19 patients;Hongyi Chen，等;Medicine (Baltimore);第99卷(第48期);第2页"2.2. Study design, patients, treatments, and discharge"项下内容、第4页的表2 * |
| Hongyi Chen，等.First clinical study using HCV protease inhibitor danoprevir to treat COVID-19 patients.Medicine (Baltimore).2020,第99卷(第48期),第2页"2.2. Study design, patients, treatments, and discharge"项下内容、第4页的表2. * |
| Identification of potential inhibitors of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) main protease from non-natural and natural sources: a molecular docking study;Osvaldo A. Santos-Filho;Journal of the Brazilian Chemical Society;第31卷(第12期);第2638-2643页 * |
| NS3/4A蛋白酶抑制剂danoprevir的临床研究进展;石催催，等;世界临床药物;第38卷(第11期);第785-789页 * |
| 新型冠状病毒肺炎抗病毒药物的治疗药物监测及药代动力学研究进展;张露，等;中国临床药理学与治疗学;第25卷(第5期);第566页的正文第1段、第569页的"1.2.1 利巴韦林" * |
| 用于COVID-19潜在治疗的小分子药物及专利研究;黄璐，等;中国医药工业杂志;第51卷(第04期);第467-475页 * |
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