In late 2019, a new coronavirus emerged in Wuhan Province, China, causing lung complications similar to those produced by the SARS coronavirus in the 2002-2003 epidemic. This new disease was named COVID-19 and the causative virus SARS-CoV-2.
The SARS-CoV-2 virus enters the airway and binds, by means of the S protein on its surface to the membrane protein ACE2 in type 2 alveolar cells. The S protein-ACE2 complex is internalized by endocytosis leading to a partial decrease or total loss of the enzymatic function ACE2 in the alveolar cells and in turn increasing the tissue concentration of pro-inflammatory angiotensin II by decreasing its degradation and reducing the concentration of its physiological antagonist angiotensin 1-7. High levels of angiotensin II on the lung interstitium can promote apoptosis initiating an inflammatory process with release of proinflammatory cytokines, establishing a self-powered cascade, leading eventually to ARDS. It has recently been proposed the tentative use of ACE-I/ARBs such as Ramipril, Losartan and Telmisartan as alternative options for treating COVID-19 patients prior to development of ARDS.
The current SARS-CoV-2 pandemic has a high burden of morbidity and mortality due to development of the so-called acute respiratory distress syndrome (ARDS). The renin-angiotensin-system (RAS) plays an important role in the development of ARDS.
ACE2 is one of the enzymes involved in the RAS cascade. Virus spike protein binds to ACE2 to form a complex suitable for cellular internalization. The downregulation of ACE2 results in the excessive accumulation of angiotensin II, and it has been demonstrated that the stimulation of the angiotensin II type 1a receptor (AT1R) increases pulmonary vascular permeability, explaining the increased lung pathology when activity of ACE2 is decreased. Currently available AT1R blockers (ARBs) have the potential to block this pathological process mediated by angiotensin II. There are presently two complementary mechanisms suggested:
1) ARBs block the excessive angiotensin mediated AT1R activation
2) They upregulate ACE2, which reduces angiotensin II concentrations and increases the production of the protective vasodilator angiotensin 1-7.
Considering the above, ARBs may prevent the development of ARDS and avert morbidity (admission to intensive care unit (ICU) and mechanical ventilation) and mortality.
Photo: Angiotensin II (Ang II) drives lung injury by activating the type 1 angiotensin receptor (AT1R), causing inflammation and fibrosis. Diminishing production of Angiotensin II with an ACE-I or blocking Ang II–AT1R actions with an ARB enhances the generation of Ang-(1–7) by ACE2 and activation of the Mas receptor (MasR), which attenuates inflammation and fibrosis and therefore attenuates lung injury. (From South et al Nature Reviews Nephrology 2020)
Currently, 15 clinical trials are ongoing for different ACE-I/ARBs. Results are expected in coming months that will provide sufficient evidence for role of ACE-I/ARBs in managing COVID 19 infection especially seriously ill patients.
Clinical Trials of ACE-I/ARBs in treatment of COVID 19 infection
| Sr No. | NCT ID | Study Title | Product | Phase |
|---|---|---|---|---|
| 1 | NCT04335123 | Study of Open Label Losartan in COVID-19 | Losartan | Phase 1 |
| 2 | NCT04359953 | Efficacy of Hydroxychloroquine, Telmisartan and Azithromycin on the Survival of Hospitalized Elderly Patients With COVID-19 | Telmisartan | Phase 3 |
| 3 | NCT04355936 | Telmisartan for Treatment of COVID-19 Patients | Telmisartan | Phase 2 |
| 4 | NCT04366050 | Ramipril for the Treatment of COVID-19 | Ramipril | Phase 2 |
| 5 | NCT04351724 | Austrian CoronaVirus Adaptive Clinical Trial (COVID-19) | Candesartan | Phase 2/3 |
| 6 | NCT04360551 | Pilot Clinical Trial of the Safety and Efficacy of Telmisartan for the Mitigation of Pulmonary and Cardiac Complications in COVID-19 Patients | Telmisartan | Phase 2 |
| 7 | NCT04343001 | Coronavirus Response - Active Support for Hospitalised Covid-19 Patients | Losartan | Phase 3 |
| 8 | NCT04349410 | The Fleming [FMTVDM] Directed CoVid-19 Treatment Protocol | Losartan | Phase 2/3 |
| 9 | NCT04335786 | Valsartan for Prevention of Acute Respiratory Distress Syndrome in Hospitalized Patients With SARS-COV-2 (COVID-19) Infection Disease | Valsartan | Phase 4 |
| 10 | NCT04356495 | Treatments to Decrease the Risk of Hospitalization or Death in Elderly Outpatients With Symptomatic SARS-CoV-2 Infection (COVID-19) | Telmisartan | Phase 3 |
| 11 | NCT04328012 | COVID MED Trial - Comparison Of Therapeutics for Hospitalized Patients Infected With SARS-CoV-2 | Losartan | Phase 2/3 |
| 12 | NCT04355429 | Efficacy of Captopril in Covid-19 Patients With Severe Acute Respiratory Syndrome (SARS) CoV-2 Pneumonia (CAPTOCOVID) | Captopril | Phase 2 |
| 13 | NCT04312009 | Losartan for Patients With COVID-19 Requiring Hospitalization | Losartan | Phase 2 |
| 14 | NCT04311177 | Losartan for Patients With COVID-19 Not Requiring Hospitalization | Losartan | Phase 2 |
| 15 | NCT04340557 | Do Angiotensin Receptor Blockers Mitigate Progression to Acute Respiratory Distress Syndrome With SARS-CoV-2 Infection | Losartan | Phase 4 |
For more information on repurposing of existing drugs in COVID 19 treatment, please contact gupta.pk@pharmintel.co.in
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