PHARMACEUTICAL COMPOSITION AND METHOD FOR TREATMENT OF ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) IN CORONAVIRUS DISEASE (COVID-19)

Abstract

A pharmaceutical composition for treating acute respiratory distress syndrome (ARDS), multiple end organ failure and survival in serious and life-threatening condition in patients with coronavirus disease 2019 (COVID-19) including (a) centhaquine; (b) antiviral therapies for SARS-CoV-2 infection (remdesivir, ivermectin, chloroquine, hydroxychloroquine, azythromicyn, tenofovir, emtricitabine, ritonavir, lopinavir, ASC09, favipiravir, danoprevir, angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), recombinant human angotensin-converting enzyme 2 (rhACE2), xiyanping, alpha-interferon, fludase (DAS181), eicosapentaenoic acid free fatty acid (EPA-FFA), nitric oxide, PUL-042, Pam2CSK4 acetate, agonists of TLR2 TLR6, and TLR9), convalescent plasma, stem cells or their exosomes, immunomodulation and cytokine-targeted therapies (itolizumab, tocilizumab, sarilumab, acalabrutinib, piclidenoson, tradipitant, CD24Fc, emapalumab, anakinra, TJ003234, BLD-2660, blood purification systems, Spectra Optia Apheresis System, corticosteroids) oxygen concentrator and generator, T89, dantonic, plasminogen supplementation, plasminogen activators, alteplase; (c) budesonide, supportive therapies to reduce fever (like acetaminophen or ibuprofen), steroids (dexamethasone, prednisolone), anticoagulants (aspirin, heparin, non-heparin anticoagulants such as argatroban, bivalirudin, danaparoid, fondaparinux or a direct oral anti-coagulant (DOAC), (d) inhaled synthetic surfactant, antibody to endotoxin, interferon-beta-1a, IV prostaglandin E1, neutrophil elastase inhibitors, nitric oxide and (e) an excipient. A method for preparing the composition for treating acute respiratory distress syndrome, multiple end organ failure and shock symptoms caused by coronaviruses infection, in particular SARS-CoV-2, MERS-CoV and SARS-CoV, using centhaquine and its analogues compound by mechanism of reduction of edema in the lungs, improvement in ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2 or SpO2/FiO2), blood oxygen saturation (SpO2), normalization in respiratory rate, reduction in lung infiltration, improvement in ARDS score, MODS, Ordinal Scale of COVID-19, and better blood flow and oxygenation of tissues.

Claims

1. A pharmaceutical composition for treating acute respiratory distress syndrome, comprising: (a) centhaquine or its analogues in a predefined amount; (b) antiviral therapies for SARS-CoV-2 infection (remdesivir, ivermectin, chloroquine, hydroxychloroquine, azythromicyn, tenofovir, emtricitabine, ritonavir, lopinavir, ASC09, favipiravir, danoprevir, angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), recombinant human angotensin-converting enzyme 2 (rhACE2), xiyanping, alpha-interferon, fludase (DAS181), eicosapentaenoic acid free fatty acid (EPA-FFA), nitric oxide, PUL-042, Pam2CSK4 acetate, agonists of TLR2 TLR6, and TLR9), convalescent plasma, stem cells or their exosomes, immunomodulation and cytokine-targeted therapies (itolizumab, tocilizumab, sarilumab, acalabrutinib, piclidenoson, tradipitant, CD24Fc, emapalumab, anakinra, TJ003234, BLD-2660, blood purification systems, Spectra Optia Apheresis System, corticosteroids) oxygen concentrator and generator, T89, dantonic, plasminogen supplementation, plasminogen activators, and alteplase; (c) budesonide, supportive therapies to reduce fever (like acetaminophen or ibuprofen), steroids (dexamethasone, prednisolone); (d) anticoagulants (aspirin, heparin, non-heparin anticoagulants such as argatroban, bivalirudin, danaparoid, fondaparinux or a direct oral anti-coagulant (DOAC); (e) inhaled synthetic surfactant, antibody to endotoxin, interferon-beta-1a, IV prostaglandin E1, neutrophil elastase inhibitors, nitric oxide; and (f) an excipient.

2. A method for reduction of edema in the lungs, improvement in ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2 or SpO2/FiO2), blood oxygen saturation (SpO2), normalization in respiratory rate, reduction in lung infiltration, improvement in ARDS score, MODS and better blood flow and oxygenation of tissues using centhaquine or its analogues.

3. The method of claim 2, wherein centhaquine and/or its analogues are delivered intravenously, orally, intramuscularly, subcutaneously by procedures through direct injections, osmotic mini-pumps and reciprocating perfusion systems.

4. The method of claim 2, wherein centhaquine or its analogues are conjugated with either microparticles or nanoparticles.

5. The method of claim 2, wherein centhaquine or its analogues dose range is about 0.00001 to 1 mg/kg.

6. The method of claim 2, wherein the dosage of centhaquine or its analogues may be administered once or multiple times in a day or in weeks or in months.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0035] These and other features, aspects, and advantages of the present disclosure will become better understood with regard to the following description, appended claims, and accompanying drawings where:

[0036] FIG. 1 illustrates a proposal to use centhaquine as an add-on treatment to provide hemodynamic stability, improve acute respiratory distress syndrome (ARDS), multiple organ dysfunction score (MODS) and reduce mortality.

[0037] FIG. 2 illustrates a graphical representation of significant improvement in oxygen saturation (SpO2) of COVID-19 patients by intravenous administration of centhaquine in the dose of 0.01 mg/kg was observed;

[0038] FIG. 3 illustrates a graphical representation of Centhaquine improved SpO2/FiO2 in all 10 patients irrespective of age of the patient. Basal SpO2/FiO2 was found to be slightly poor in aged patients and the slope was −1.062, however, treatment with centhaquine started flattening the slope to −0.5905 at 2 hours and −0.2718 at 4 hours of treatment with centhaquine;

[0039] FIG. 4 illustrates a graphical representation of Centhaquine improved SpO2/FiO2 in COVID-19 patients. SpO2/FiO2 was found to improve following administration of centhaquine by 34.48 units within 2 hours and by 41.42 units in 4 hours;

[0040] FIG. 5 illustrates a graphical representation of Centhaquine improved clinical outcome of COVID-19 patients as determined by the WHO Ordinal Scale. Improvement started in 24 hours after treatment with centhaquine and at 72 hours of treatment a statistically significant (p=0.0169) improved was observed.

DETAILED DESCRIPTION OF THE DISCLOSED EMBODIMENTS

[0041] As used herein, the term “an amount sufficient to” refers to amount that enables the achievement of the intended effect. Such an amount may be determined through various assays known in the art based on the intended effect. As used herein, the terms “applying” or “administering” refer to all means of introducing the specified agent, composition, or force to the specified region or subject. “Administration” or “application” can be effected in one dose, continuously or intermittently throughout the course of treatment. Methods of determining the most effective means and dosage of administration are known to those of skill in the art and will vary with the composition used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician. Suitable dosage formulations and methods of administering the agents are known in the art. Route of administration can also be determined and method of determining the most effective route of administration are known to those of skill in the art and will vary with the composition used for treatment, the purpose of the treatment, the health condition or disease stage of the subject being treated, and target cell or tissue. Non-limiting examples of route of administration include oral administration, nasal administration, inhalation, injection, and topical application. Administration can be for use in industrial as well as therapeutic applications. As used herein, the term “biodegradable” is used herein to describe substances, such as polymers, compositions, and formulations, intended to degrade during use. Biodegradable substances may also be “biocompatible,” i.e. not harmful to living tissue.

[0042] As used herein, the term “therapeutically effective amount” refers to a quantity sufficient to achieve a desired effect. In the context of therapeutic applications, the effective amount will depend on the type and severity of the condition at issue and the characteristics of the individual subject, such as general health, age, sex, body weight, and tolerance to pharmaceutical compositions. The skilled artisan will be able to determine appropriate amounts depending on these and other factors. In the case of an in vitro application, in some embodiments the effective amount will depend on the size and nature of the application in question. It will also depend on the nature and sensitivity of the in vitro target and the methods in use. The skilled artisan will be able to determine the effective amount based on these and other considerations. The effective amount may comprise one or more administrations of a composition depending on the embodiment. The dose range of centhaquine could be from 0.00001 to about 1 mg/kg and may be administered once or multiple times in a day or in weeks or in months.

[0043] As used herein, the term “treating” or “treatment” includes preventing a disease, disorder or condition from occurring in a subject predisposed to or having a disease, disorder and/or condition; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving or reversing the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition. Treating a disease or condition may also include ameliorating at least one symptom of the particular disease or condition.

[0044] The term “ARDS” refers to Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs (30). The signs and symptoms of ARDS often begin within two hours of an inciting event but can occur after 1-3 days. Signs and symptoms may include shortness of breath, fast breathing, and a low oxygen level in the blood due to abnormal ventilation (31). Other common symptoms include muscle fatigue and general weakness, low blood pressure, a dry, hacking cough, and fever (31).

[0045] In some embodiments, the basic composition, may be combined with remdesivir or lopinavir or ritonavir or arbidol or favipiravir or ribavirin or interferon beta-1B or alpha-interferon or mesenchymal stem cells or their exosomes or chloroquine or chloroquine phosphate or hydroxychloroquine or pirfenidone or antibodies like REGN3048 and REGN3051 or mRNA-1273 or bevacizumab or bromhexine or fingolimod or T89 or eculizumab or carrimycin or oxygen treatment or corticosteroids or methylprednisolone or inhaled nitric oxide gas or losartan or darunavir or tocilizumab or tetrandrine or aviptadil or thalidomide or sarilumab or vitamin C or plasma therapy.

[0046] Preclinical and clinical studies have demonstrated that centhaquine effectively addresses the major challenges associated with COVID-19. First, studies in swine model of shock centhaquine significantly reduced pulmonary edema and improved The Horowitz index the PaO2/FiO2 ratio. Second, improved tissue blood perfusion by centhaquine can rapidly clear inflammatory cytokines and prevent oxidative and apoptotic damage. Third, in phase III clinical trial centhaquine was effective in reducing ARDS and MODS. Fourth, in clinical studies centhaquine statistically significantly reduce mortality of patients.

[0047] Centhaquine) is a first-in-class resuscitative agent that is final stages of approval in India. Centhaquine acts through a unique mechanism of action that is completely different from any of the existing resuscitative agents. It increases blood pressure and cardiac output by augmenting venous blood return to the heart (venous alpha2B-adrenergic receptor stimulation) (32-36). It also produces arterial dilation by acting on central α2A-adrenergic receptors to reduce sympathetic activity and systemic vascular resistance (37). A significant number of patients with COVID-19 are admitted to the ICU and many of them are intubated and kept on positive pressure ventilation. A very high mortality is associated with patients who are on ventilator support. About 30% of patients encounter life-threatening hypotension due a decrease in venous return to the heart following endotracheal intubation and/or positive pressure ventilation (38, 39). As a result of its unique mechanism of action, centhaquine is expected to attenuate positive pressure ventilation induced decrease in venous return to the heart and prevent life-threatening hypotension. Centhaquine is likely to provide hemodynamic stability, improve tissue oxygenation, reduce pulmonary edema, reduce ARDS, reduce MODS and decrease mortality in COVID-19 patients.

[0048] Recently, guidelines on the management of critically ill adults with COVID-19 were published (40, 41). These guidelines authored by 36 experts from 12 countries were developed by The Surviving Sepsis Campaign (SSC). They have been grouped in four categories: (1) infection control and testing; (2) hemodynamic support; (3) ventilatory support and (4) therapy. It is recommended that acute resuscitation of adults with shock be done with a conservative fluid administration and preferring crystalloids over colloids. Norepinephrine has been suggested as the first-line vasoactive, adding vasopressin as a second-line agent is suggested if the target (60-65 mmHg) mean arterial pressure cannot be achieved by norepinephrine alone (40, 41). Acute hypoxemic respiratory failure despite conventional oxygen therapy requires close monitoring, and if worsening occurs an early intubation along with positive pressure ventilation is recommended. A mortality rate in the intensive care unit (ICU) of COVID-19 patients has been reported to be more than 79% (42). It has been found that using centhaquine as a resuscitative agent in shock (hypovolemic) significantly reduced 28-day all-cause mortality from 11.76% in patients receiving standard treatment to 2.94% in patients that received centhaquine (P=0.0742). In a metanalysis of phase II and III trials of centhaquine in hypovolemic shock mortality was reduced from 10.71% to 2.20% (Odds ratio 5.340, 95% CI 1.27-26.50, p=0.0271). It is quite likely that centhaquine as a resuscitative agent will help patients with COVID-19 and reduce mortality.

[0049] The outbreak of COVID-19 disease which is evolving and expanding at a rapid pace has created major challenges to resuscitation efforts. Critically ill COVID-19 patients are managed for ARDS and continued intensive care management. Patients with COVID-19 usually have hypovolemia and fluids are administered with caution keeping in mind pre-load responsiveness. A high incidence of myocardial dysfunction has been reported in COVID-19 patients (43-45). Using centhaquine as a resuscitative agent can be beneficial because it has also been shown to be highly effective in a swine model of in hospital cardiac arrest (46).

[0050] An improved blood perfusion will enhance the clearance of toxic cytokines produced as a result of overactive immune reaction in patients with COVID-19. Plasma cytokine levels depend on several factors: the intensity of production, the number of cell receptors availability, the clearance of cytokines, the affinity of the receptors for cytokines (47). Centhaquine can help and promote rapid clearance of these cytokines. It will be particularly useful when centhaquine is combined with various agents that are either available or being developed to counter the overwhelming reaction of the immune system to the virus, causing a cytokine storm. Blood purification systems to remove cytokines such as high-volume continuous hemofiltration or cytokine and/or endotoxin removal have been suggested but with little success (47). There are several methods being developed to remove cytokines from blood circulation using devices such as Cytosorb (extracorporeal cytokine removal), Hemofeel (continuous venovenous hemodiafiltration) and EMiC2 (continuous venovenous hemodialysis) (48, 49). Most of these devices are extremely expensive, complicated to operate, and are available only at a limited number of institutions. Centhaquine increases stroke volume, cardiac output (32, 36, 50, 51) and blood flow to the vital organs, prevents organ failure and improves survival in rat, rabbit and swine models of hypovolemic shock (32, 36, 50, 51). Enhancing tissue perfusion is a significant advantage in reducing the volume of resuscitation and preventing extravasation of fluid and adverse effect of lung edema. Centhaquine does not act on beta-adrenergic receptors, and therefore the risk of arrhythmias is alleviated. Centhaquine has several advantages because improved tissue blood perfusion will not only remove toxic cytokines but also provide oxygenation and nutrition to the tissues. Since there are limited therapeutic options for this life-threatening condition, centhaquine may fulfil the unmet need for serious, life-threatening condition of COVID-19 during this pandemic outbreak. Centhaquine is likely to restore the immune balance and correct the overreaction of immune responses in patients with COVID-19 that develop cytokine storm.

[0051] Studies in a swine model of shock showed that, centhaquine significantly reduced pulmonary edema and improved Horowitz index (ratio of partial pressure of oxygen in blood and the fraction of oxygen in the inhaled air (36).

[0052] Improvement in ARDS and MODS: In randomized, controlled, multicentric clinical trial patients (N=155) with hypovolemic shock, centhaquine significantly improved ARDS scores and MODS score (MODS). In a phase 3 study of hypovolemic shock, ARDS and MODS were secondary endpoints and they were both achieved with a significant p-value with centhaquine (33, 52).

[0053] ARDS in Shock Patients (N=105): Acute Respiratory Distress Syndrome (ARDS) was compared between day 1 (before resuscitation) and day 3 of resuscitation. In control patients receiving standard treatment the difference between means was 0.04839±0.05696 (P=0.4023). On the other hand, in centhaquine treated group the ARDS difference between means was 0.1065±0.04464 (P=0.0202). These results indicate that centhaquine treatment significantly improved ARDS following resuscitation, whereas in control group there was insignificant improvement.

[0054] MODS in Shock Patients (N=105): Multiple Organ Dysfunction Score (MODS) was compared between day 3 and day 7 of resuscitation. There was no improvement in MODS in the control group and the difference between means was 0.00±0.2697 (P>0.999), whereas in centhaquine group the difference between means was 0.9091±0.1964 (P=0.0001). Centhaquine treatment significantly decreased MODS whereas in control the improvement was not significant.

[0055] Centhaquine has been evaluated for its safety, sensitivity and toxicity in various species for single and multiple doses and acute as well as chronic exposure (33). Centhaquine has been found to be safe and well tolerated in preclinical and clinical studies. Its safety has also been demonstrated in a Phase I study (NCT02408731) in 25 human subjects (53, 54). There were NO adverse events related to centhaquine reported in phase II (NCT04056065) and phase III (NCT04045327) clinical studies.

[0056] Results of clinical phase II study (CTRI/2017/03/008184; NCT04056065) indicate that, centhaquine is a novel, first-in-class, highly effective resuscitative agent for hypovolemic shock as it demonstrated highly significant efficacy in improving blood pressure (p<0.0001), lactate levels (p=0.0012), base-deficit (p<0.0001), reduction in use of vasopressors and reduced mortality (33, 55-57). In a 105-patient randomized, blinded, multicenter study (CTRI/2019/01/017196; NCT04045327) a total of 34 (22 male and 12 female) patients in control and 68 (41 male and 27 female) patients in centhaquine groups completed the study. Blood lactate levels at day 3 of resuscitation were found to be significantly lower in centhaquine group compared to control group receiving standard treatment (P=0.046). Base-deficit improved in patients treated with centhaquine by 1.430±1.047 mmol/L compared to control patients receiving standard treatment (33). In total 180 human subjects have been studied (combined phase I, II and III), out of which 155 were patients with hypovolemic shock. Centhaquine reduced the mortality from 9.68% in patients receiving standard treatment to 2.15% in patients that received centhaquine (odds ratio 4.875; 95% CI 1.162-24.18; P=0.0190).

[0057] Results of phase II and phase III clinical studies indicate that, centhaquine treatment can provide hemodynamic stability and prove to be beneficial in improving ARDS, MODS and shock symptoms in patients infected with COVID-19. Centhaquine can reduce morbidity and mortality in COVID-19 by reduction of edema in the lungs, improved ARDS scores and better oxygenation of tissues.

[0058] Centhaquine has been evaluated for its safety, sensitivity and toxicity in various species for single and multiple doses and acute as well as chronic exposure (33). Centhaquine was found to be safe and well tolerated in healthy human subjects (53, 54). Safety and efficacy of centhaquine is established (Phase I, phase II and phase III clinical studies)

[0059] Centhaquine has shown efficacy in improving ARDS, MODS and survival in serious and life-threatening condition of hypovolemic shock and it has the potential to improve morbidity and mortality in patients with COVID-19. Preclinical and clinical studies have demonstrated that centhaquine effectively addresses the major challenges associated with COVID-19.

[0060] First, studies in swine model of shock centhaquine significantly reduced pulmonary edema and improved The Horowitz index the PaO2/FiO2 ratio. Second, improved tissue blood perfusion by centhaquine can rapidly clear inflammatory cytokines and prevent oxidative and apoptotic damage. Third, in phase III clinical trial centhaquine was effective in reducing ARDS and MODS. Fourth, in clinical studies centhaquine statistically significantly reduce mortality of patients.

[0061] Centhaquine has shown efficacy in improving ARDS, MODS, and survival in a serious life-threatening condition of hypovolemic shock; hence, it can improve morbidity and mortality in patients with COVID-19. Preclinical and clinical studies have demonstrated that centhaquine effectively addresses the major challenges associated with COVID-19. Studies in the swine model of shock, centhaquine significantly reduced pulmonary edema and improved The Horowitz index (PaO2/FiO2 ratio). Improved tissue blood perfusion by centhaquine can rapidly clear inflammatory cytokines and prevent oxidative and apoptotic damage. In phase III clinical trial, centhaquine was effective in reducing ARDS and MODS. In clinical studies, centhaquine statistically significantly reduce the mortality of patients. We propose using centhaquine at a dose of 0.01 mg/kg, along with the standard of care, to be administered to patients meeting the eligibility criteria. There will be no change in the current standard of care of critically ill COVID-19 patients. Patients will continue receiving standard of care, and centhaquine will be an add-on treatment to provide hemodynamic stability and improve ARDS, MODS scores and reduce mortality.

[0062] The effect of centhaquine (Lyfaquin®) was determined COVID-19 patients. A significant improvement in oxygen saturation (SpO2) of COVID-19 patients by intravenous administration of centhaquine in the dose of 0.01 mg/kg was observed (FIG. 2). An improvement of SpO2 improved by 12.40 units within 2 hours of administration of centhaquine and further treatment with centhaquine led to an improvement of SpO2 by about 20 units. Four out of 10 patients did not even need oxygen therapy at 72 hours of treatment with centhaquine.

[0063] We also determined the effect of age on the improvement in ratio of SpO2 and FiO2 (SpO2/FiO2) after administration of centhaquine (FIG. 3). We found that centhaquine improved SpO2/FiO2 in all patients irrespective of age of the patient. Basal SpO2/FiO2 was found to be slightly poor in aged patients and the slope was −1.062, however, treatment with centhaquine started flattening the slope to −0.5905 at 2 hours and −0.2718 at 4 hours of treatment with centhaquine (FIG. 3). Centhaquine (Lyfaquin®) improved SpO2/FiO2 in COVID-19 patients. SpO2/FiO2 was found to improve following administration of centhaquine by 34.48 units within 2 hours and by 41.42 units in 4 hours (FIG. 4).

[0064] WHO Ordinal Scale was used to determine whether centhaquine (Lyfaquin®) improved the outcome of patients with COVID-19 (FIG. 5). A statistically significant (mean difference 0.7444, 95% 0.1010 to 1.388, p=0.0169; N=10) improvement in WHO Ordinal Scale was observed at 72 hours of resuscitation with centhaquin (Lyfaquin®) in COVID-19 patients.

[0065] While the disclosed embodiments have been described with reference to illustrative embodiments, this description is not intended to be construed in a limiting sense. Various modifications and combinations of the illustrative embodiments as well as other embodiments of the present disclosure, will be apparent to persons skilled in the art upon reference to the description. It is, therefore, intended that the appended claims encompass any such modifications or embodiment.