CN115944632A - Application of Felodipine in preparation of medicine for treating cytokine storm caused by COVID-19 - Google Patents
Application of Felodipine in preparation of medicine for treating cytokine storm caused by COVID-19 Download PDFInfo
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- CN115944632A CN115944632A CN202210823464.7A CN202210823464A CN115944632A CN 115944632 A CN115944632 A CN 115944632A CN 202210823464 A CN202210823464 A CN 202210823464A CN 115944632 A CN115944632 A CN 115944632A
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Abstract
The invention discloses an application of Felodipine in preparing a medicament for treating cytokine storm caused by COVID-19. The Felodipine of the invention can have protective action and anti-inflammatory action on SARS-CoV-2 infection in vivo.
Description
Technical Field
The invention belongs to the technical field of coronavirus treatment medicines, and particularly relates to application of Felodipine in preparation of a medicine for treating cytokine storm caused by COVID-19.
Background
Human coronaviruses are a class of envelope-carrying positive-sense RNA viruses that cause highly pathogenic human diseases with clinical symptoms ranging from mild common cold to acute respiratory distress syndrome and death. Three highly pathogenic human coronaviruses that have exploded over the last two decades: severe acute respiratory syndrome coronavirus (SARS-CoV), middle east respiratory syndrome coronavirus (MERS), and SARS-CoV-2, demonstrate the pandemic potential of human coronavirus. SARS-CoV-2 is a novel coronavirus that appeared in 2019, which subsequently caused a pandemic of a novel coronary pneumonia (COVID-19) on a global scale. Currently, there are over 4 million diagnosed cases and over 500 million deaths worldwide, and there is no specific prevention or treatment. SARS-CoV-2 can cause upper and lower respiratory tract infections often with fever, cough and loss of smell and taste, while some patients develop more severe symptoms including systemic inflammation, tissue damage, acute respiratory distress syndrome, thromboembolic complications, heart damage and/or cytokine storms, and even death.
Among these, cytokine storm is one of the key pathological features observed in SARS-CoV-infected patients, and is common in severe human coronavirus (CoV) (e.g., SARS and MERS) infections. CoVID-19 presents high levels of cytokines in critically ill patients. Among them, TNFa, IL6 and IL 1. Beta. Are mainly released by innate immune cells and may be one of the major drivers of cytokine release syndrome and severe systemic inflammatory response in patients with advanced SARS-CoV-2 infection. And the increase of chemokines and cytokines such as CCL2/3/5, CXCL8/9/10, IFN beta, IFN-gamma, TNFa, IL1 beta, IL1RA, IL6, IL7, IL8, IL12, IL33, granulocyte/granulocyte-macrophage colony stimulating factor (G-CSF and GM-CSF), vascular Endothelial Growth Factor A (VEGFA) and platelet-derived growth factor subunit B (PDGFB) further causes severe Acute Respiratory Distress Syndrome (ARDS) and tissue injury. Cytokine storms are mainly produced by the over-activation of a variety of immune cells, mainly macrophages, neutrophils, dendritic cells, NK cells, B cells and T cells. While SARS-CoV-2 specific T cells, activated by dendritic cells and macrophages through antigen presentation, may mediate antiviral responses early, the immune escape capacity of SARS-CoV-2 may make it difficult for T cells to mount an effective antiviral response, and importantly, T cell-mediated inflammation and sustained activation of innate immune cells may be factors leading to secondary complications that occur in lung pathology and in severe cases. Simultaneous studies have shown that patients with poor T or B cell activation are less sick, while CD4 + T cells and CD8 + Patients with over-activation of T cells are more severely ill, also suggesting a role for T cells in mediating the inflammatory response in patients with COVID-19. These evidences suggest that COVID-19 may be an immune-related disease, becomingThe first strong evidence supports severe acute infections using immunotherapy, and therefore treatment via immunomodulation will have important effects in reducing inflammatory responses, improving patient survival, and reducing mortality.
Facing the global pandemic situation of the new coronavirus, scientists have been looking for the development of vaccines and effective drugs for the prevention and treatment of SARS-CoV-2 infection, but no specific effective treatment methods exist at present. In addition to vaccine development, the main therapeutic drugs include antiviral drugs and immunomodulatory drugs. Antiviral drugs are directed against mediators of viral infection into cells, including the Receptor Binding Domain (RBD)/angiotensin converting enzyme 2 (ACE 2), the transmembrane protease serine 2 (TMPRSS 2), the 3C-like protease (M) pro ) RNA-dependent RNA polymerase (RdRp), etc., are generally used in early stages of disease. Immunomodulatory drugs are commonly used in the advanced stages of the disease to balance the immune response and relieve symptoms such as inflammatory responses, cytokine storms and secondary tissue damage and acute respiratory distress syndrome. The development of therapeutic approaches aimed at reducing the severity of the disease is also the most important priority worldwide. Currently used immunomodulatory drugs mainly include three classes. The first group is the dexamethasone-based corticosteroid, which has been shown in several studies to reduce patient mortality, particularly in patients with exacerbations during treatment. It is noteworthy, however, that corticosteroids may have deleterious effects on patients early in the treatment due to broad, non-specific immunosuppressive effects. The second class is kinase inhibitors, such as the JAK inhibitor baricitinib (baricitinib). Studies have shown that patients in the baracitinib-treated group recovered in shorter time compared to placebo and that baracitinib treatment was able to reduce patient mortality, with greater efficacy in subgroups requiring high flow of oxygen or non-invasive ventilation. The FDA recently approved baracitinib for use in the emergency treatment of COVID-19. In addition, imatinib (imatinib), a cytoplasmic polytyrosine kinase inhibitor, was also found to be effective in a clinical trial in the Netherlands on 400 COVID-19 hospitalized patients, but these findings required follow-up trials to verify and determine which patients might benefit from imatinib treatment. Other kinase inhibitors under investigation include Bruton's tyrosine kinase inhibitors (e.g., ibrutinib, acalabutinib, zanubutriniib), phosphatidylinositol-3 kinase (PI 3K)/rapamycin (mTOR) inhibitors (e.g., duvelisib, temsirolimus), and JAK inhibitors (e.g., ruxolitinib, tofacitinib). In addition to the beneficial effects exhibited by some tyrosine kinase inhibitors, previous studies have shown the pleiotropic properties of tyrosine kinases (which can block cytokine signaling pathways and many immune effector pathways), as well as the well-known clinical safety of most tyrosine kinase inhibitors, suggesting that tyrosine kinase inhibitors are a potential COVID-19 therapeutic approach. The third class is cytokine-targeting drugs, which are currently dominated by anti-IL 1 and IL 6. Both IL1 and IL6 can cause local effects such as macrophage activation, endothelial leakage and fluid extravasation, as well as systemic effects. However, two studies have found that treatment with the IL1 inhibitor anakinra does not produce significant effects. However, the subsequent further research shows that the analkinra is effective for the patients with plasma high soluble urokinase plasminogen receptor (suPAR), so the application of the analkinra needs to be carried out under the guidance of the suPAR content. In addition, the IL1 β blocker canakinumab also produced no significant effect in the assay. In contrast, blocking therapy of IL6 appears to be more effective. Wherein both tocilizumab (tocilizumab) and salilumab show the effects of reducing mortality and improving patient survival in clinical trials. In addition to pro-inflammatory cytokines on the IL1-IL6 axis, other pro-inflammatory cytokines are involved in COVID-19 mediated inflammation. Clinical trials have shown that the anti-GM-CSF antibody, otilimab, has a significant effect on elderly people over 70 years of age, but it is noted that this age dependence suggests possible side effects in younger patients. In addition, anti-TNF therapies are currently in clinical trials (NCT 04705844). Cytokine-targeted therapeutic strategies against covi-19 appear to be an attractive approach, but given the complexity of covi-19 mediated inflammatory responses, and the relatively single effect of cytokine-specific targeted therapies, random control assays that accurately detect biomarkers may be required to help further determine which patients are likely to benefit the most. In addition to the above three classes of immunomodulatory drugs, other immune regulation strategies include anti-complementSomatic therapy (e.g., anti-C5 a antibody vilobelimab), interferons that stimulate antiviral defenses (e.g., IFN β, IFN γ), and the like.
Although the anti-inflammatory treatment of COVID-19 has been developed to a great extent, one major dilemma faced at present is that despite the use of immunotherapeutic drugs such as dexamethasone and IL6 blocking antibodies, some patients with COVID-19 have no improvement in treatment and still have a severe inflammatory response, and there are not enough randomized controlled trials to guide dosing. In addition, the host-pathogen response and the resulting immune environment are heterogeneous, dynamic, suggesting that not every patient may benefit from the same immunomodulatory treatment strategy. There is therefore a need to increase the potential treatment options to deal with the failure of patients to respond and to further alleviate symptoms in severe cases. It is also noted that some of the currently used antibody therapies or combination therapies face the problem of being expensive and difficult to ensure that all patients receive an equal chance of treatment. Therefore, in addition to increasing replacement therapy and improving efficacy, cheaper alternative drugs are found to better complete the therapeutic strategy of COVID-19.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides the application of Felodipine in preparing a medicament for treating cytokine storm caused by COVID-19.
Another object of the present invention is to provide the use of Felodipine as a broad-spectrum inhibitor of COVID-19-induced inflammatory factors.
The technical scheme of the invention is as follows:
application of Felodipine in preparing medicine for treating cytokine storm caused by COVID-19.
In a preferred embodiment of the invention, the inflammatory factor in the cytokine storm comprises at least CCL3, CCL4, CCL5, CKC12, IL1 β, IL2, IL4, IL5, IL6, IL8, IP10, IL13, IL18, GM-CSF, IFN β, IFN γ, TNF α, TNF β, CXCL12, LTA, IL22 and IL21.
Further preferably, the inflammatory factor in the cytokine storm consists of CCL3, CCL4, CCL5, CKC12, IL1 β, IL2, IL4, IL5, IL6, IL8, IP10, IL13, IL18, GM-CSF, IFN β, IFN γ, TNF α, TNF β, CXCL12, LTA, IL22 and IL21.
The application of Felodipine as a broad-spectrum inhibitor of inflammatory factors induced by COVID-19.
In a preferred embodiment of the invention, the inflammatory factor comprises at least CCL3, CCL4, CCL5, CKC12, IL1 β, IL2, IL4, IL5, IL6, IL8, IP10, IL13, IL18, GM-CSF, IFN β, IFN γ, TNFa, TNF β, CXCL12, LTA, IL22 and IL21.
Further preferably, the inflammatory factor consists of CCL3, CCL4, CCL5, CKC12, IL1 β, IL2, IL4, IL5, IL6, IL8, IP10, IL13, IL18, GM-CSF, IFN β, IFN γ, TNF α, TNF β, CXCL12, LTA, IL22 and IL21.
Drawings
FIG. 1 is a heat map showing the amounts of secretion of 34 cytokines and chemokines in cell supernatants detected by adding 4 selection drugs (# 1 Felodipine, #2 Fasciil, #3 Imatinib, #4 Caspofungi) to the cells under co-culture of S-293T, SARS-CoV-2S CAR-T and THP-1 in example 1 of the present invention.
FIG. 2 is a schematic diagram of the experimental strategy for evaluating the in vivo effect of Felodipine, imatinib, caspofungi and Fasudil by SARS-CoV-2 virus challenge and drug therapy using golden hamster in example 2 of the present invention.
Fig. 3 is a graph showing the body weight change of golden mice in the control group, and the Felodipine, imatinib, caspofungi, and fadauil-treated groups in example 2 of the present invention, and a table showing the significance of the golden mice at each time point.
FIG. 4 is a graph showing the survival rate of golden mice in the control group and Felodipine, imatinib, caspofungi, fasudil-treated groups in example 2 of the present invention.
FIG. 5 is a photograph of lung tissues of golden hamsters in the control group and Felodipine, imatinib, caspofungi and Fasudi1 treatment groups at the end point (day 7) in example 2 of the present invention.
FIG. 6 is a graph showing the results of HE staining of lung tissue sections of golden mice in the control group and Felodipine, imatinib, caspofungi, and Fasudil-treated groups in example 2 of the present invention (lung tissue of non-detoxified golden mice was used as a negative control).
FIG. 7 is a histogram of HE staining pathology scores of lung tissue sections of golden mice in the control group and Felodipine, imatinib, caspofungi, fasudil-treated groups of example 2 of the present invention (lung tissue of non-detoxified golden mice was used as a negative control).
FIG. 8 is a thermogram of inflammatory factor gene expression in lung tissue of golden hamster of control group and Felodipine, imatinib, caspofungi, fasudil treatment group detected by RT-qPCR in example 2 of the present invention (lung tissue of non-challenged golden hamster was used as negative control, and CXCL15 in golden hamster corresponds to IL 8).
FIG. 9 is a graph showing the expression of a representative inflammatory factor in lung tissues of golden mice in the control group and Felodipine, imatinib, caspofungi, and Fasudil-treated groups, which were tested by ELISA in example 2 of the present invention (lung tissues of non-challenged golden mice were used as negative controls).
FIG. 10 is a graph showing the results of cytokine screening in the model for Felodipine and dipine-like drugs in example 2 of the present invention.
Detailed Description
The technical solution of the present invention is further illustrated and described by the following detailed description in conjunction with the accompanying drawings.
Example 1
This example evaluates the anti-inflammatory effects of 4 drugs (Felodipine, imatinib, caspofungi, fasudil) screened in a cytokine storm model.
Cloning the S gene of the new corona strain into a pCAG-eGFP vector to construct an S gene expression vector pCAG-S-eGFP. 24h before transfection, 293T was applied at 1X 10 6 Each hole is paved in a six-hole plate. 5 μ L of transfection reagent Lipofectamine was used at the time of transfection TM 3000 (manufactured by Thermo Fisher Co., ltd.) was added to 125. Mu.L of basic medium RMPI 1640 to dilute it; in addition, 2.5. Mu.g of pCAG-S-eGFP plasmid and 5. Mu.L of P3000 were added TM The reagent (manufactured by Thermo Fisher Co., ltd.) was added to 125. Mu.L of the basal medium RPMI 1640 to dilute it, followed by dilution of the plasmid/P3000 TM Reagent addition to diluted Lipofectamine TM 3000 mixing in the reagentIncubated at room temperature for 10-15min and added to 293T cells. 24h after transfection, cells were digested and subjected to subsequent experiments.
S-293T cells prepared as above were cultured at 2X 10 4 Inoculating into 96-well plate, 37 deg.C, 5% CO 2 After adherence in the incubator, the ratio of 10:1 (the structure of the CAR used is Fc-SARS-CoV-2CAR, the amino acid sequence of which is shown in SEQ ID No.01, and the nucleotide sequence of which is shown in SEQ ID No. 02), and the ratio of SARS-CoV-2S CAR-T (the CAR used is Fc-SARS-CoV-2 CAR) to S-293T cells was measured at a ratio of 10:1, adding THP-1 cells, simultaneously adding Felodipine, imatinib, caspofungi and Fasudil in a distributed manner to ensure that the working concentration is 10 mu M, and co-culturing for 72 h; cell supernatants were collected, and the amounts of 34 cytokines and chemokines secreted were measured by ProcartaPlex Hu Cytokine/Chemokine Panel (Invitrogen).
As shown in FIG. 1, the drugs Felodipine, imatinib, caspofungi and Fasudil screened in this example, in addition to inhibiting the secretion of IL8 and IFN γ, also produced broad-spectrum inhibitory effect on other cytokines.
Example 2
This example demonstrates the effect of Felodipine, imatinib, caspofungi and Fasudil on SARS-CoV-2 infection and the resulting inflammatory response in vivo.
Using 8-14 weeks old golden hamster, narcotize with isoflurane, then inject 100 μ L PBS diluted 1X 10 4 SARS-CoV-2 virus at pDU dose; dividing golden hamster into 5 groups of 6 control groups (untreated), felodipine group, imatinib group, fasudil group and Caspofungin group; treatment with 15mg/kg dose of drug on days 1, 2, 3 and 4 respectively, wherein Felodipine, fasudil and Caspofungin are administered intraperitoneally and Imatinib is administered by intragastric gavage; it was observed that the golden hamster of the control group died (day 7), and the body weight of the golden hamster was measured daily by an electronic balance (experimental strategy shown in fig. 2). Killing golden hamster on 7 days, obtaining lung tissue, observing lung pathological changes, taking pictures, fixing with methanol, dehydrating, embedding paraffin, and slicing to obtain lung tissue slice for HE staining to detect pathological changes, and treating lung diseases according to pulmonary alveolus on each lung lobe with increased thickness, consolidation, hemorrhage, exudation, and exudation,Performing comprehensive pathological scoring on the condition of lung edema, mucus and inflammatory cell chemotaxis and infiltration; in addition, lung tissue was subjected to Extraction of Total RNA using Eastep Super Total RNA Extraction Kit (manufactured by Promega corporation), followed by detection of cytokine genes by RT-qPCR and ELISA.
The results are shown in FIGS. 3 to 9. Figures 3 and 4 show that golden hamster continued to lose body weight on the 1 to 6 scale after infection, eventually by more than 20%, and died altogether within 7 days; while the weight loss was significantly reduced by treatment with Felodipine, imatinib, fasuil and Caspofungin, the average weight loss was 5.2%, 2.5%, 2.1% and 11% on day 7, respectively, and all golden mice of 4 treatment groups survived. Fig. 5 shows photographs of lung tissues of the groups on day 7, and severe lung lesions (including solid, multifocal and diffuse congestion) were observed in the control golden hamster, whereas no severe lung lesions were observed after Felodipine, imatinib and Faudil treatment, and the lung lesions were also improved by Caspofungin treatment. Correspondingly, fig. 6 and 7 show HE staining results and overall pathology scores for lung tissues, and also demonstrate that Felodipine, imatinib, and faudinil significantly reduced lung lesions, with slightly less effective Caspofungin. The RT-qPCR of fig. 8 and ELISA results of fig. 9 showed that the expression of inflammatory factor genes detected in lung tissues of Felodipine, imatinib, faudil and Caspofungin treated groups was significantly down-regulated compared to the control group.
This example shows that Felodipine, imatinib, fasudil and Caspofungin have protective and anti-inflammatory effects on SARS-CoV-2 infection in vivo.
It will be appreciated by those skilled in the art that Felodipine (Felodipine) is a potent vasoselective calcium channel antagonist and has been approved by the FDA for the treatment of essential hypertension, the most significant benefit of its antihypertensive effect being the reduction in the incidence of stroke. Other non-FDA approved applications also include the treatment of angina, congestive heart failure, renovascular hypertension and pulmonary hypertension. In addition, felodipine has been shown to be more selective for vascular tissue than other commonly used dihydropyridine calcium channel antagonists, such as amlodipine and nifedipine. Recent studies have reported the role of CCB in combating SARS-CoV-2 invasion and infectionThe application is. Based on the similarity between SARS-CoV virus and SARS-CoV-2 virus in the report by Marco et al, it was hypothesized that SARS-CoV-2 also has Ca required for entry into the host cell 2+ Ion characteristics, the effect of various FDA-approved CCB drugs on the resistance of SARS-CoV-2 infection was evaluated, and felodipine (Amlodipine) and Nifedipine (Nifedipine) were found to produce the strongest effect of inhibiting SARS-CoV-2 infection in vitro. Zhang and the like similarly evaluate a plurality of CCB medicines, and find that Benidipine hydrochloride (Benidipine) and Amlodipine besylate (Amlodipine) can generate remarkable antiviral infection effect in vitro, but the effect is stronger than that of Felodipine. However, the anti-inflammatory effect of CCB drugs in COVID-19 has not been reported. Felodipine has shown potential anti-inflammatory effects in some previous studies. Researchers found that rats induced by fructose feeding increased serum, cardiac IL18 mRNA levels and resultant coronary perivascular fibrosis can be inhibited by Felodipine, which also reduces ICAM-1 and VCAM-1 expression and reduces macrophages in the aortic wall by inhibiting NF- κ B, thereby reducing vascular wall inflammatory response. Tanaka et al found that Felodipine can inhibit collagen production under the action of TGF-beta 1 and improve bleomycin-induced pulmonary fibrosis, and notably found that other dihydropyridines Ca2 + Channel blockers (such as Nifedipine and Benidipine) can also produce similar effects.
Yet another CCB drug, amlodipine, is more complex in its role in affecting inflammatory responses. Early reports that CCB drug Amlodipine can activate NF-IL6 and NF-kB, thereby increasing the expression and secretion of IL6 on human vascular smooth muscle cells; additional studies found that Amlodipine can modulate LPS-induced inflammatory factors in the spontaneously hypertensive rat model, including lowering TNF α levels, elevating IL6 levels, but not affecting IL1 levels; it is also found that Amlodipine has anti-arthritis effect, and the modulation of inflammatory factors shows that the gene expression of TNF alpha, IL6 and IL1 beta is reduced, and the gene expression of IL4 and IL10 is increased.
Overall, the anti-inflammatory action and mechanism of CCB agents are currently unknown, and there is no evidence that either CCB agents produce anti-inflammatory effects or are used in covi-19 therapy. In addition, the research on the anti-inflammatory effect of Felodipine only detects the secretion of individual inflammatory factors, and cannot show that Felodipine has broad-spectrum inhibition effect on the inflammatory factors to support the effective application of Felodipine in COVID-19. The calcium channel antagonist Amlodipine is exemplified as follows: in one study, amlodipine is found to have an anti-arthritis effect, and the modulation of inflammatory factors is shown to reduce the gene expression of TNF alpha, IL6 and IL1 beta, but increase the gene expression of other cytokines IL4 and IL 10; in additional studies, amlodipine may modulate LPS-induced inflammatory factors in a spontaneous hypertensive rat model, including reducing TNF α levels, increasing IL6 levels, but not affecting IL1 levels; it is stated that the inhibitory effect of a certain drug on a portion of cytokines is not necessarily applicable to other cytokines and that there may be differences in different diseases.
Fig. 10 is a graph of the results of cytokine screening in models with Felodipine and dipine-like drugs, where only Felodipine exhibited strong IL8 inhibitory potency and all other drugs were eliminated.
SEQ ID NO.01：
SEQ ID NO.02：
The above description is only a preferred embodiment of the present invention, and therefore should not be taken as limiting the scope of the invention, and all equivalent variations and modifications made within the scope of the present invention and the content of the description should be included in the scope of the present invention.
Claims (6)
- Application of Felodipine in preparation of medicine for treating cytokine storm caused by COVID-19.
- 2. The use of claim 1, wherein: the inflammatory factor in the cytokine storm comprises at least CCL3, CCL4, CCL5, CKC12, IL1 beta, IL2, IL4, IL5, IL6, IL8, IP10, IL13, IL18, GM-CSF, IFN beta, IFN gamma, TNF alpha, TNF beta, CXCL12, LTA, IL22 and IL21.
- 3. Use according to claim 2, characterized in that: the inflammatory factors in the cytokine storm consist of CCL3, CCL4, CCL5, CKC12, IL1 beta, IL2, IL4, IL5, IL6, IL8, IP10, IL13, IL18, GM-CSF, IFN beta, IFN gamma, TNF alpha, TNF beta, CXCL12, LTA, IL22 and IL21.
- Use of felodipine as a broad-spectrum inhibitor of inflammatory factors induced by COVID-19.
- 5. The use of claim 4, wherein: the inflammatory factors include at least CCL3, CCL4, CCL5, CKC12, IL1 beta, IL2, IL4, IL5, IL6, IL8, IP10, IL13, IL18, GM-CSF, IFN beta, IFN gamma, TNF alpha, TNF beta, CXCL12, LTA, IL22 and IL21.
- 6. The use of claim 5, wherein: the inflammatory factor consists of CCL3, CCIA, CCL5, CKC12, IL1 beta, IL2, IL4, IL5, IL6, IL8, IP10, IL13, IL18, GM-CSF, IFN beta, IFN gamma, TNF alpha, TNF beta, CXCL12, LTA, IL22 and IL21.
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