USE OF VEGF INHIBITOR IN PREPARATION OF MEDICAMENT FOR TREATING HYPOXIA-RELATED DISEASES

Abstract

A VEGF inhibitor is used in preparation of a medicament for treating hypoxia-related diseases. The VEGF inhibitor can significantly inhibit VEGF stress expression caused by hypoxia by acting on a binding pathway of VEGF and a VEGF receptor, is used for treating hypoxia and other related diseases, can significantly improve the oxygenation index of a patient, and can alleviate the hypoxic state of lung and other organ tissues, having good therapeutic effects.

Claims

1. A method for treating a hypoxia-related disease, comprising administering a VEGF (vascular endothelial growth factor) inhibitor to a subject in need thereof.

2. The method according to claim 1, wherein the hypoxia-related disease comprises a pulmonary injury or symptom causing hypoxia or insufficient oxygen intake in lungs of a subject's body, or a lesion or injury due to insufficient oxygen supply to cells, tissues or organs of the subject; for example, the hypoxia-related disease comprises a pulmonary disease caused by hypoxia.

3. The method according to claim 1, wherein the hypoxia-related disease is at least one selected from respiratory distress syndrome, pneumonia, pulmonary edema, acute lung injury, ventilator-induced lung injury, smoking-induced lung injury, lung cancer, pathological apnea and asphyxia.

4. The method according to claim 1, wherein the hypoxia-related disease is at least one selected from ischemic heart disease, acute myocardial infarction (AMI), ischemic encephalopathy, ischemic stroke, ocular ischemic disease, ischemic optic neuropathy, inflammation, septicemia, renal failure, tissue fibrosis, bronchial dysplasia, fetal distress, postsurgical hypoxia, anemia, hypovolemia, rheumatoid arthritis, poisoning (e.g., carbon monoxide poisoning, heavy metal poisoning), ischemia reperfusion injury (e.g., limb, bowel and kidney ischemia) and vascular embolism.

5. The method according to claim 1, wherein the hypoxia-related disease is respiratory distress syndrome or a complication thereof caused by respiratory tract infection, acute lung injury, trauma or poisoning.

6. The method according to claim 5, wherein the complication comprises at least one selected from pulmonary edema, inflammatory response or inflammatory factor storm, sepsis and organ failure.

7. The method according to claim 5, wherein the respiratory tract infection comprises at least one selected from viral pneumonia, bacterial pneumonia and pulmonary fungal infection.

8. The method according to claim 7, wherein the viral pneumonia is severe or critical pneumonia caused by infection with any one or more of coronavirus SARS-CoV-2, SARS-Cov or MERS-Cov.

9. The method according to claim 1, wherein the VEGF inhibitor is a substance capable of inhibiting VEGF expression or a pathway thereof; preferably, the VEGF inhibitor is a substance targeting the interaction between VEGF and VEGFr (vascular endothelial growth factor receptor); preferably, the VEGF inhibitor is an mTOR inhibitor, such as a macromolecular drug, a gene therapy drug or a micromolecular compound of the mTOR signaling pathway; for example, the mTOR inhibitor is selected from at least one selected from rapamycin and everolimus; preferably, the VEGF inhibitor is an HIF-1α inhibitor; for example, the HIF-1α inhibitor is at least one selected from temsirolimus, topotecan and camptothecin.

10. The method according to claim 1, wherein the VEGF inhibitor is an anti-VEGF antibody, an antibody derivative or an anti-VEGF peptide; for example, the VEGF inhibitor is bevacizumab or ranibizumab.

11. The method according to claim 1, wherein the VEGF inhibitor is a gene-based drug; for example, the VEGF inhibitor is a microbial cloning vector expressing a VEGF antibody or a gene-based drug inhibiting VEGF expression.

12. The method according to claim 1, wherein the VEGF inhibitor is a micromolecular VEGF receptor inhibitor compound; for example, the VEGF inhibitor is any one selected from lapatinib, sunitinib, sorafenib, axitinib and pazopanib.

13. The method according to claim 1, wherein the hypoxia comprises chronic hypoxia or acute hypoxia.

14. The method according to claim 1, wherein a subject with hypoxia-related disease has an oxygenation index (PaO.sub.2/FiO.sub.2, in mmHg)≤300 mmHg and/or a fingertip pulse oxygen saturation in resting state without oxygen therapy ≤96%, for example ≤90%, for another example ≤85%, for still another example ≤80%.

15. The method according to claim 1, wherein administration of the VEGF inhibitor results in an oxygenation index (PaO.sub.2/FiO.sub.2, in mmHg)≥300 mmHg, for example ≥330 mmHg, for another example ≥360 mmHg, in a subject.

16. The method according to claim 1, wherein administration of the VEGF inhibitor results in a fingertip pulse oxygen saturation in resting state without oxygen therapy ≥96%, for example ≥98%, for another example ≥99%, for still another example 100%, in a subject.

17-27. (canceled)

28. A pharmaceutical composition comprising the VEGF inhibitor of claim 1.

29. The pharmaceutical composition according to claim 28, wherein the VEGF inhibitor is bevacizumab.

30. The pharmaceutical composition according to claim 28, wherein the pharmaceutical composition further comprises at least one therapeutic agent selected from an antifungal agent, an antibacterial agent, an antiviral agent, an antithrombotic agent, an immunomodulatory agent, an eye drop, a urologic agent, a hormonal agent, an anti-infective agent and an anti-inflammatory agent.

31. The method according to claim 1, wherein the hypoxia-related disease is caused by COVID-19.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0047] FIG. 1 illustrates a curve and a histogram showing oxygenation index changes in subjects in the treatment group before bevacizumab treatment, 1 day after bevacizumab treatment and 7 days after bevacizumab treatment;

[0048] FIG. 2 illustrates the lung CT imaging performance comparison of different subjects before and after treatment;

[0049] FIG. 3 illustrates a curve and a histogram showing lymphocyte count changes in subjects in the treatment group before bevacizumab treatment and 3 days after the treatment;

[0050] FIG. 4 illustrates curves showing hs-CRP and CRP changes in subjects in the treatment group before bevacizumab treatment and 3 days after the treatment; and

[0051] FIG. 5 illustrates a curve and a histogram showing lactate dehydrogenase changes in subjects in the treatment group before bevacizumab treatment and 3 days after the treatment.

DETAILED DESCRIPTION

[0052] The present disclosure will be further illustrated with reference to the following examples, but the present disclosure is not limited thereto. The methods are conventional methods unless otherwise stated. The materials are available from published sources unless otherwise indicated.

[0053] Bevacizumab used in the examples of the present disclosure is an approved product Avastin.

Protocol:

[0054] The study was conducted by Qilu Hospital of Shandong University after repeated verifications, ethical review and regulatory registration (NCT04275414).

[0055] Subject (P): Patients with severe or critical COVID-19 and radiologically confirmed exudative lesions; Intervention (I): bevacizumab 500 mg in 0.9% sodium chloride solution 100 mL, administered through a single intravenous drip within not less than 90 min combined with conventional treatment; Comparison (C): comparison between before and after bevacizumab treatment, and comparison with reference; Primary endpoint (O): oxygenation index, quantitative pulmonary lesion value (calculated by imaging software).

[0056] Subjects with possible COVID-19 should be subjected to nasopharyngeal swab RT-PCR COVID-19 viral nucleic acid test, combined with specific IgM antibody and IgG antibody serum test and pulmonary CT imaging for diagnosis. Patients were classified into severe and critical cases according to diagnosis criteria for severe and critical types in the “Diagnosis and Treatment Protocol for COVID-19” (trial version 5, revised version) issued by the National Health Committee, PRC:

(I) Severe Case

[0057] The subject should meet any of the following: [0058] 1. Respiratory distress with a respiratory rate (RR)≥30 times/min; [0059] 2. Fingertip pulse oxygen saturation in resting state without oxygen therapy ≤93%; [0060] 3. Partial arterial pressure of oxygen (PaO.sub.2)/fraction of inspired oxygen (FiO.sub.2)≤300 mmHg; [0061] 4. Those conforming to any one of the above are managed as severe cases; alternatively, the following cases that does not conform to the diagnosis criteria described above may also be managed as severe cases: radiologically confirmed significant progression in lungs >50% within 24-48 hours; aged >60 years with severe chronic diseases including hypertension, diabetes, coronary heart disease, malignancy, structural lung disease, pulmonary heart disease, immunosuppression or the like.

(II) Critical Case

[0062] The subject should meet any of the following: [0063] 1. Respiratory failure requiring mechanical ventilation; [0064] 2. Occurrence of shock; [0065] 3. Having other organ failure and requiring admission to ICU.

[0066] The total number of subjects in the treatment group was 11. The demographics and baseline characteristics of the patients in the treatment and control groups are shown in Table 1.

TABLE-US-00001 TABLE 1 Baseline characteristics of patients in the treatment and control groups Treatment Control group group (n = 11) (n =22) P Age (years) 60.1 ± 9.3 61.9 ± 9.9 0.615 Highest body temperature (° C.) 38.9 ± 0.8 38.5 ± 0.7 0.182 Days from onset to admission 10.5 ± 4.1 11.8 ± 5.2 0.467 Gender Female 3 (27.3%) 6 (27.3%) 1.000 Male 8 (72.7%) 16 (72.7%) Medical History Heart disease 0 (0.0%) 3 (13.6%) 0.534 Hypertension 2 (18.2%) 9 (40.9%) 0.258 Diabetes 0 (0.0%) 4 (18.2%) 0.276 Chronic obstructive 0 (0.0%) 0 (0.0%) 1.000 pulmonary disease Symptoms Fever 11 (100.0%) 19 (86.4%) 0.534 Asthenia 8 (72.7%) 11 (50.0%) 0.278 Dry cough 7 (63.6%) 12 (54.5%) 0.719 Polypnea 6 (54.5%) 5 (22.7%) 0.117 Productive cough 4 (36.4%) 5 (22.7%) 0.438 Tightness in chest 4 (36.4%) 6 (27.3%) 0.437 Chills 3 (27.3%) 4 (18.2%) 0.661 Head pain 3 (27.3%) 1 (4.5%) 0.097

(1) Oxygenation Index

[0067] The oxygenation status of the tissues in the subjects was significantly improved on Days 1 and 7 after bevacizumab treatment (results are shown in Table 2 and FIG. 1), and the oxygenation index (PaO.sub.2/FiO.sub.2) was significantly increased (P<0.001) as compared to that before treatment.

TABLE-US-00002 TABLE 2 Changes in respiratory indexes in treatment group before and after bevacizumab treatment Before 1 day after 7 days after intervention intervention intervention (n = 11) (n = 11) (n = 10) P Oxygenation index 225.0 ± 333.2 ± 362.6 ± <0.001 (PaO.sub.2/FiO.sub.2, mmHg) 74.3 124.5 104.7 Oxygen saturation 96.2 ± 96.8 ± 96.9 ± 0.505 (SpO.sub.2, %) 5.3 3.2 2.4 Partial pressure 125.4 ± 108.1 ± 103.1 ± 0.467 of oxygen 58.5 39.3 36.6 (PaO.sub.2, mmHg)

(2) Lung CT Quantitative Analysis and Radiological Representation

[0068] Taking pre-dose CT images as the initial point, the CT images 7 days after the bevacizumab treatment were compared and analyzed. Quantitative lung CT analysis showed that bevacizumab treatment significantly promoted absorption of lung lesions within 7 days. After bevacizumab treatment, the number of patchy opacifications decreased significantly (P=0.024) and some shifted to milder ground glass opacifications after absorption (P=0.007); the total lesion volume decreased significantly (P=0.028), and proportion of lesions in the left (right) lung decreased (Table 3). The changes reflected by the above quantitative analysis can be visually observed through the lung images, suggesting significant efficacy (FIG. 2).

TABLE-US-00003 TABLE 3 Lung CT quantitative analysis in treatment group before and after bevacizumab treatment Initial point 7 d (n = 10) (n = 10) P Number of patchy opacifications 2.5 (0, 8) 0 (0, 6) 0.024 Number of ground glass opacifications 3 (0, 9) 7 (2, 18) 0.007 Total volume of lesion (cm.sup.3) 785.9 (362.3, 1554.4) 568.9 (374.4, 1372.0) 0.028 Proportion of lesions in right lung (%) 27.2 (7.9, 65.2) 14.0 (6.3, 76.1) 0.074 Proportion of lesions in left lung (%) 31.4 (7.3, 60.0) 14.6 (6.2, 41.7) 0.093

(3) Immunity

[0069] Lymphocyte in the subjects were significantly increased 3 days after bevacizumab treatment (P=0.013), suggesting that the immune status was improved (results are shown in Table 4 and FIG. 3).

TABLE-US-00004 TABLE 4 Comparison of complete blood counts in treatment group before and after bevacizumab treatment Before 3 days after intervention intervention (n = 11) (n = 11) P White blood cell count (×10.sup.9/L) 6.6 (3.6, 19.2) 7.3 (3.1, 15.8) 0.722 Neutrophil count (×10.sup.9/L) 4.3 (1.5, 18.2) 4.3 (1.4, 13.2) 0.722 Lymphocyte count (×10.sup.9/L)  1.0 ± 0.4 1.5 ± 0.9 0.013 Platelet count (×10.sup.9/L) 243.3 ± 92.1 231.3 ± 100.1 0.589 Red blood cell count (×10.sup.12/L)  4.1 ± 0.7 4.0 ± 0.7 0.120 Hemoglobin (g/L) 122.0 ± 17.9 117.3 ± 20.4  0.055

(4) Inflammatory Factors

[0070] hs-CRP level decreased significantly as compared to the baseline 3 days after bevacizumab treatment (P=0.036); CRP also exhibited a descending trend (results are shown in Table 5 and FIG. 4).

TABLE-US-00005 TABLE 5 Changes in hs-CRP and CRP in treatment group before and after bevacizumab treatment Before 3 days after intervention intervention (n = 11) (n = 11) P hs-CRP (mg/L) 5.0 (0.5, 5.0)  1.1 (0.5, 5.0)  0.036 CRP (mg/L) 9.2 (5.0, 169.5) 5.0 (5.0, 128.2) 0.401

(5) Lactate Dehydrogenase (LDH)

[0071] LDH decreased significantly (P=0.032) 3 days after bevacizumab treatment as compared to the baseline, suggesting a recovery trend of tissue injury (results are shown in Table 6 and FIG. 5).

TABLE-US-00006 TABLE 6 Changes in LDH in treatment group before and after bevacizumab treatment Before 3 days after intervention intervention (n = 11) (n = 11) P LDH lactate 358.1 ± 131.9 268.3 ± 105.4 0.032 dehydrogenase (U/L)

[0072] The results showed that: for patients with severe and critical COVID-19, after bevacizumab treatment, the oxygenation index was significantly improved; lung CT quantitative analysis showed significantly reduced volume of lesions, significantly reduced proportion of lesions and shift from patchy opacifications to milder ground glass opacifications; lymphocyte count (L) was increased, indicating improvement of immunity; a plurality of important indexes including high-sensitivity C-reactive protein (hs-CRP) and lactate dehydrogenase (LDH) were significantly improved; adverse events such as allergy, hemoptysis, gastrointestinal hemorrhage, neutropenia and the like were not found in any patients during the treatment.

(6) Matching Analysis of Treatment and Control Groups

[0073] The treatment group and the control group showed no statistical significance (P>0.05) in the aspects of age, highest body temperature, days from onset to admission, gender, heart disease history, hypertension history, diabetes history, chronic obstructive pulmonary disease history and symptoms such as fever, asthenia, dry cough and the like. The two groups were comparable in the aspect of baseline data (shown in Table 1). In the important indexes, the proportion of significantly improved oxygenation indexes (increased by 100 mmHg) in the treatment group receiving bevacizumab and the improvements in hs-CRP and lymphocyte count were higher than those in the control group, and other indexes demonstrated no significant difference (Table 7).

TABLE-US-00007 TABLE 7 Comparison of improvement in important indexes of treatment and control groups Treatment Control group group (n = 11) (n = 22) P Ratio of significant improvements in 55% 25% 0.183 oxygenation index Median difference in lymphocyte count 0.42 0.14 0.132 Median difference in hs-CRP −1.8 0.0 0.180 Median difference in CRP −4.0 0.0 0.432 Median difference in LDH −47.0 −42.0 0.890

[0074] The results showed that compared with the control group, bevacizumab significantly improved the oxygenation index and alleviated respiratory failure symptoms in patients with severe and critical COVID-19 in the treatment group.

[0075] The exemplary embodiments of the present disclosure have been described above. However, the scope of the present disclosure is not limited to the above embodiments. Any modifications, equivalents, improvements and the like made by those skilled in the art without departing from the spirit and principle of the present disclosure shall fall within the protection scope of the present disclosure.