If ARBs (or other drugs modulating the renin-angiotensin system) help in COVID-19, what would be the ideal dosing and medication to use? This page explores this question.
Dose & medication used in animal studies
ACE2-knockout animal studies:
- 15 mg/kg losartan, intraperitoneal, in mice. This was an acute injury. Result: attenuation of lung injury from SARS spike protein + acid combination. Note that this was an acute injury: the mice were challenged with acid once after losartan was given.
- Human equivalent dose (80kg human): 97 mg losartan.
- Confirmed as intraperitoneal in correspondence with authors.
- 50 mg/kg/day (route of administration unspecified) irbesartan in mice. Result: "rescued the systolic dysfunction, normalized altered signaling pathways, flow-mediated dilation, and the increased oxidative stress in the cardiovascular system."
- Human equivalent dose (80kg human): 324 mg irbesartan.
- 15 mg/kg losartan, intravenous, in mice. Result: attenuation of RSV-induced lung injury in ACE2-KO mice.
- Human equivalent dose (80kg human): 97 mg losartan.
- 10 mg/kg/day losartan in drinking water. Result: improvements in lung fibrosis model.
- Human equivalent dose (80kg human): 65 mg losartan.
Other animal studies of AT1R blockade:
- 30 mg/kg losartan, intravenous, in mice. Ang II and thrombosis. This was an acute injury. Result: "losartan abolished prothrombotic effect of Ang II"
- Cannot be easily translated to human dosing, as was given I.V. Losartan is metabolized by the liver into longer-lasting AT1R agonist EXP3174. But if this was oral, the human equivalent dose (80kg human) would be 195 mg losartan.
- 30mg/kg losartan, p.o., in mice. Induced arterial thrombosis. This was an acute injury. Result: significantly attenuated thrombosis (42% versus control)
- Human equivalent dose (80kg human): 195 mg losartan.
- 10 mg/kg losartan, p.o., in mice. Induction of venous thrombosis. This was an acute injury. Result: significantly decreased thrombus weight.
- Human equivalent dose (80kg human): 65 mg losartan.
- 30 mg/kg losartan, in drinking water, in mice. ACE2 deficiency increases NADPH‐mediated oxidative stress. Result: normalization of NADPH oxidase activity in ACE2-knockout mice.
- Human equivalent dose (80kg human): 195 mg losartan.
- 3 mg/kg losartan, intraperitoneal, in rats. This was an acute injury in surfactant‐depleted rat lungs. Result: attenuation of increase of TUNEL positivity in pneumocytes.
- Human equivalent dose (80kg human): 39 mg losartan.
- 30mg/kg losartan, p.o., in rats. This was a semi-acute injury; losartan was given 30 minutes before the first of two daily smoke exposures. Result: "ameliorated pulmonary vascular remodeling, inhibited the smoke-induced RVSP and Ang II elevation and partially reversed the ACE2 decrease in rat lungs"
- Human equivalent dose (80kg human): 389 mg losartan.
- 15 mg/kg losartan, intraperitoneal, in mice. Result: "alleviated the severity of influenza H7N9 virus-induced lung injury significantly in WT mice" and greatly improved lung injury in H7N9-infected ACE2-knockout mice.
- Human equivalent dose (80kg human): 97 mg losartan.
- 50 mg/kg losartan, intravenous once per day, in mice. Result: "significantly improved the survival rate in H5N1 virus-infected mice", alleviated lung edema and improved lung histopathology.
- Cannot be easily translated to human dosing, as was given I.V. Losartan is metabolized by the liver into longer-lasting AT1R agonist EXP3174. But if this was oral, the human equivalent dose (80kg human) would be 324 mg losartan.
- 200 mg losartan, p.o., in swine. Losartan was given orally 30 minutes before infusion of Ang II and bolus of ACE2 blocker MLN-4760. Result: partial attenuation of lung damage in dysregulated renin-angiotensin system model.
- Human equivalent dose (80kg human): Swine to human conversion not available on calculator.
Dose & medication used in clinical trials
- Losartan:
- 12.5mg bid. 200 participants total.
- 25mg od for 14 days. Multi-arm trial, estimate ~1000 participants given losartan.
- 25mg od for 10 days. 580 participants total.
- 25mg bid. 20 participants total.
- 25mg bid for 14 days. 100 participants total.
- 25 od, escaled to 50mg. 34 participants total.
- 50mg od. 200 participants total.
- 50mg od for 15 days. 176 participants total.
- Titration up to 100mg od over 3 days. 1372 participants total.
- Valsartan:
- Telmisartan:
- Candesartan:
- Unspecified ARB/dose:
Would some ARBs work better than others?
Several of the animal studies use I.V. losartan. When given orally or intraperitoneally, losartan is metabolized by the liver into EXP3174, its longer-lasting, higher-affinity metabolite. When given via I.V., losartan is not metabolized into EXP3174 ("EXP3 174: The Major Active Metabolite of Losartan", Tamaki, et al).
Thrombosis and losartan versus first-pass metabolite EXP3174.
https://ascpt.onlinelibrary.wiley.com/doi/10.1111/cts.12916 - mechanical activation of AT1R versus Ang II-activation of AT1R
..however, in this trial losartan was given both intraperitoneally (first dose), and then via i.v. With i.v. administration, the first-pass effect would be skipped and losartan would not be metabolized into EXP3174, its longer-lasting, higher-affinity metabolite.
..but in a follow-up study, olmesartan, but not irbesartan, attenuated ventilator-induced diaphragm dysfunction as well.