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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.
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)
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.
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"
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.
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.
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.
..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.
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.
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.
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)
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.
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"
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.
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.
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.
..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.
philipn authored on Nov. 30, 2020, 3:01 a.m. 
