Ignite Creation Date:
2024-05-06 @ 3:14 PM
Last Modification Date:
2024-10-26 @ 1:45 PM
Study NCT ID:
NCT04568096
Status:
UNKNOWN
Last Update Posted:
2020-10-26
First Post:
2020-09-26
Brief Title:
Combination of Chemopreventive Agents All- Trans Retinoic Acid and Tamoxifen as Potential Treatment for the Lung Complication of COVID-19
Sponsor:
Kafrelsheikh University
Organization:
Kafrelsheikh University
Study Overview
Official Title:
Combination of Chemopreventive Agents All- Trans Retinoic Acid and Tamoxifen as Potential Treatment for the Lung Complication of COVID-19
Status:
UNKNOWN
Status Verified Date:
2020-10
Last Known Status:
NOT_YET_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Combination of Chemopreventive agents All- Trans Retinoic Acid and Tamoxifen as potential treatment for the Lung Complication of COVID-19
Abstract
Angiotensin-converting enzyme ACE2 protein found on the cell membranes is the target of SARS-CoV-2 for entering into the host cells Viral spike protein-binding with ACE2 down-regulates it As ACE2 is known to protect the lung from injuries SARS-CoV-2-induced ACE2 deficiency may expose patients to lung damage In this Review we use established and emerging evidence based on the findings of previous studies and researches to propose a testable hypothesis that Combination of chemopreventive agents All Trans Retinoic acid and Tamoxifen can be tested to prevent inflammatory complication in severe acute respiratory syndrome coronavirus 2 infection via two mechanisms by inhibiting bradykinin B1B2 receptors expression and upregulating the depleted ACE2 in COVID-19 Bradykinin B1 receptors are not expressed under physiological conditions but are induced under inflammatory conditions Here we hypothesize that permanent attack and invasion of COVID-19 to lung epithelial cells via binding to ACE2 leads to tissue injury and inflammation and that increases BK levels and BK-B2-receptor B2R stimulation A study reported that tissue injury and inflammation increases BK levels and BK-B2-receptor B2R stimulation We suggest that Bradykinin mediates and induces lung injury proinflammatory cytokines and inflammation likely precipitates life threatening respiratory complications in COVID-19 Further experiments showed that BK treatment stimulated IL-6 production On the other hand a study reported that cells treated with Retinoic acid and Tamoxifen for 48 h significantly decreased the BK-B2 receptor protein levels 703 06 vs 100 of control P 005 Retinoids inhibit bradykinin B1 receptor-sensitized responses and this action could participate in their anti-inflammatory and immunomodulatory effects In addition retinoic acid is known to possess in vivo anti-inflammatory anti-platelet and fibrinolytic activities A study investigated the in vitro thrombin and platelet aggregation inhibitory activities of retinoic acid and retinaldehydeRetinoic acid retinaldehyde and retinol exhibited potent inhibition of thrombin with IC50 values of 67μgml 74μgml and 152μgml respectively for the inhibition of thrombin Sigma and 49μgml 74μgml and 178μgml respectively for the inhibition of thrombin plasma Amongst vitamin A and its derivatives retinoic acid showed the highest inhibition of both the forms of thrombin Beside the effectiveness of TAM on cancer cells it also has other effects on numerous microbes including parasite fungi bacteria and some viruses such as Ebola virus and human immunodeficiency virus HIVFurthermore Tamoxifen can block the action of interleukin 6 and inhibit neutrophils A study demonstrated that tamoxifen has side effects associated with neutropenia Since tamoxifen can cause neutropenia and subsequently influence the neutrophil-to-lymphocyte ratio NLR value In addition it has anti malarial effect similar to chloroquine In conclusion
Keywords COVID 2019 Retinoic acid Endosomal toll-like receptor 3T Cells IFN type1 AT1 ACE2TMPRSS2
Abstract
Angiotensin-converting enzyme ACE2 protein found on the cell membranes is the target of SARS-CoV-2 for entering into the host cells Viral spike protein-binding with ACE2 down-regulates it As ACE2 is known to protect the lung from injuries SARS-CoV-2-induced ACE2 deficiency may expose patients to lung damage In this Review we use established and emerging evidence based on the findings of previous studies and researches to propose a testable hypothesis that Combination of chemopreventive agents All Trans Retinoic acid and Tamoxifen can be tested to prevent inflammatory complication in severe acute respiratory syndrome coronavirus 2 infection via two mechanisms by inhibiting bradykinin B1B2 receptors expression and upregulating the depleted ACE2 in COVID-19 Bradykinin B1 receptors are not expressed under physiological conditions but are induced under inflammatory conditions Here we hypothesize that permanent attack and invasion of COVID-19 to lung epithelial cells via binding to ACE2 leads to tissue injury and inflammation and that increases BK levels and BK-B2-receptor B2R stimulation A study reported that tissue injury and inflammation increases BK levels and BK-B2-receptor B2R stimulation We suggest that Bradykinin mediates and induces lung injury proinflammatory cytokines and inflammation likely precipitates life threatening respiratory complications in COVID-19 Further experiments showed that BK treatment stimulated IL-6 production On the other hand a study reported that cells treated with Retinoic acid and Tamoxifen for 48 h significantly decreased the BK-B2 receptor protein levels 703 06 vs 100 of control P 005 Retinoids inhibit bradykinin B1 receptor-sensitized responses and this action could participate in their anti-inflammatory and immunomodulatory effects In addition retinoic acid is known to possess in vivo anti-inflammatory anti-platelet and fibrinolytic activities A study investigated the in vitro thrombin and platelet aggregation inhibitory activities of retinoic acid and retinaldehydeRetinoic acid retinaldehyde and retinol exhibited potent inhibition of thrombin with IC50 values of 67μgml 74μgml and 152μgml respectively for the inhibition of thrombin Sigma and 49μgml 74μgml and 178μgml respectively for the inhibition of thrombin plasma Amongst vitamin A and its derivatives retinoic acid showed the highest inhibition of both the forms of thrombin Beside the effectiveness of TAM on cancer cells it also has other effects on numerous microbes including parasite fungi bacteria and some viruses such as Ebola virus and human immunodeficiency virus HIVFurthermore Tamoxifen can block the action of interleukin 6 and inhibit neutrophils A study demonstrated that tamoxifen has side effects associated with neutropenia Since tamoxifen can cause neutropenia and subsequently influence the neutrophil-to-lymphocyte ratio NLR value In addition it has anti malarial effect similar to chloroquine In conclusion
Keywords COVID 2019 Retinoic acid Endosomal toll-like receptor 3T Cells IFN type1 AT1 ACE2TMPRSS2
Detailed Description:
This is a Phase 2 randomized 11 placebo-controlled 2-weeks proof-of-concept study to evaluate the safety and tolerability as well as the mechanistic effect of Aerosol administration of Inhaled All trans retinoic acid and oral Tamoxifen in subjects infected with COVID -19
After randomization and standard treatment The infected patients will receive Aerosolized All-Trans Retinoic Acid in gradual in 2 divided doses increases from 02 mgkgday to 4 mgkgday as inhaled All-Trans Retinoic Acid therapy plus tamoxifen 20mg orally once daily for 14 days
Inclusion Criteria
Adult SARI patients with 2019-ncov infection confirmed by PCR Absolute value of lymphocytes 0 6x 109L Severe respiratory failure within 48 hours and requires admission to ICU severe respiratory failure was defined as PaO2FiO2 200 mmHg and was supported by positive pressure mechanical ventilation including non-invasive and invasive mechanical ventilation PEEP5cmH2O
Exclusion Criteria
Age 18 Pregnant Allergic to experimental drugs and patients have the following conditions
Hypercholesterolemia Hypertriglyceridemia Liver disease Renal disease Sjögren syndrome Pregnancy Lactation Depressive disorder Body mass index less than 18 points or higher than 25 points Contraindications for hormonal contraception or intrauterine device Autoimmune diseases A history of organ bone marrow or hematopoietic stem cell transplantation Patients receiving anti-hcv treatment Permanent blindness in one eye History of iritis endophthalmitis scleral inflammation or retinitis 15-90 days of retinal detachment or eye surgery The competent physician considered it inappropriate to participate in the study Previous history of deep vein thrombosis or pulmonary embolism in the last 12 months
Patients with postmenopausal vaginal bleeding with no defined etiology Patients with breast cancer who need to use tamoxifen for this neoplasm Another synchronous neoplasm that requires systemic treatment Patients with aggressive disease requiring cytotoxic therapy or locoregional therapies eg hepatic embolization A history of serious clinical or psychiatric illness that by clinical judgment may involve participation risk in this study Patients participating in other protocols with experimental drugs Patients with oral food difficulties Patients who underwent major recent surgery less than 4 weeks previously Patients receiving chemotherapy or other oncologic therapy for less than 3 weeks
Study Type Interventional Primary Purpose Treatment Study Phase Phase 2 Interventional Study Model Parallel Assignment Number of Arms 2 Masking None Open Label Allocation Randomized Enrollment 160 Anticipated
After randomization and standard treatment The infected patients will receive Aerosolized All-Trans Retinoic Acid in gradual in 2 divided doses increases from 02 mgkgday to 4 mgkgday as inhaled All-Trans Retinoic Acid therapy plus tamoxifen 20mg orally once daily for 14 days
Inclusion Criteria
Adult SARI patients with 2019-ncov infection confirmed by PCR Absolute value of lymphocytes 0 6x 109L Severe respiratory failure within 48 hours and requires admission to ICU severe respiratory failure was defined as PaO2FiO2 200 mmHg and was supported by positive pressure mechanical ventilation including non-invasive and invasive mechanical ventilation PEEP5cmH2O
Exclusion Criteria
Age 18 Pregnant Allergic to experimental drugs and patients have the following conditions
Hypercholesterolemia Hypertriglyceridemia Liver disease Renal disease Sjögren syndrome Pregnancy Lactation Depressive disorder Body mass index less than 18 points or higher than 25 points Contraindications for hormonal contraception or intrauterine device Autoimmune diseases A history of organ bone marrow or hematopoietic stem cell transplantation Patients receiving anti-hcv treatment Permanent blindness in one eye History of iritis endophthalmitis scleral inflammation or retinitis 15-90 days of retinal detachment or eye surgery The competent physician considered it inappropriate to participate in the study Previous history of deep vein thrombosis or pulmonary embolism in the last 12 months
Patients with postmenopausal vaginal bleeding with no defined etiology Patients with breast cancer who need to use tamoxifen for this neoplasm Another synchronous neoplasm that requires systemic treatment Patients with aggressive disease requiring cytotoxic therapy or locoregional therapies eg hepatic embolization A history of serious clinical or psychiatric illness that by clinical judgment may involve participation risk in this study Patients participating in other protocols with experimental drugs Patients with oral food difficulties Patients who underwent major recent surgery less than 4 weeks previously Patients receiving chemotherapy or other oncologic therapy for less than 3 weeks
Study Type Interventional Primary Purpose Treatment Study Phase Phase 2 Interventional Study Model Parallel Assignment Number of Arms 2 Masking None Open Label Allocation Randomized Enrollment 160 Anticipated
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None