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Safety and Outcomes Associated with the Pharmacological Inhibition of the Kinin-Kallikrein System in Severe COVID-19.

ABSTRACT: Background: Coronavirus disease 19 (COVID-19) can develop into a severe respiratory syndrome that results in up to 40% mortality. Acute lung inflammatory edema is a major pathological finding in autopsies explaining O₂ diffusion failure and hypoxemia. Only dexamethasone has been shown to reduce mortality in severe cases, further supporting a role for inflammation in disease severity. SARS-CoV-2 enters cells employing angiotensin-converting enzyme 2 (ACE2) as a receptor, which is highly expressed in lung alveolar cells. ACE2 is one of the components of the cellular machinery that inactivates the potent inflammatory agent bradykinin, and SARS-CoV-2 infection could interfere with the catalytic activity of ACE2, leading to the accumulation of bradykinin. Methods: In this case control study, we tested two pharmacological inhibitors of the kinin-kallikrein system that are currently approved for the treatment of hereditary angioedema, icatibant, and inhibitor of C1 esterase/kallikrein, in a group of 30 patients with severe COVID-19. Results: Neither icatibant nor inhibitor of C1 esterase/kallikrein resulted in changes in time to clinical improvement. However, both compounds were safe and promoted the significant improvement of lung computed tomography scores and increased blood eosinophils, which are indicators of disease recovery. Conclusions: In this small cohort, we found evidence for safety and a beneficial role of pharmacological inhibition of the kinin-kallikrein system in two markers that indicate improved disease recovery.

SUBMITTER: Mansour E

PROVIDER: S-EPMC7920028 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Safety and Outcomes Associated with the Pharmacological Inhibition of the Kinin-Kallikrein System in Severe COVID-19.

Mansour Eli E Palma Andre C AC Ulaf Raisa G RG Ribeiro Luciana C LC Bernardes Ana Flavia AF Nunes Thyago A TA Agrela Marcus V MV Bombassaro Bruna B Monfort-Pires Milena M Camargo Rafael L RL Araujo Eliana P EP Brunetti Natalia S NS Farias Alessandro S AS Falcão Antônio Luís E ALE Santos Thiago Martins TM Trabasso Plinio P Dertkigil Rachel P RP Dertkigil Sergio S SS Moretti Maria Luiza ML Velloso Licio A LA

Viruses 20210216 2

<b>Background:</b> Coronavirus disease 19 (COVID-19) can develop into a severe respiratory syndrome that results in up to 40% mortality. Acute lung inflammatory edema is a major pathological finding in autopsies explaining O<sub>2</sub> diffusion failure and hypoxemia. Only dexamethasone has been shown to reduce mortality in severe cases, further supporting a role for inflammation in disease severity. SARS-CoV-2 enters cells employing angiotensin-converting enzyme 2 (ACE2) as a receptor, which i ...[more]

PMID: 33669276

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Project description:BackgroundHereditary angioedema (HAE) is a rare genetic disease that leads to recurrent episodes of swelling and pain caused by uncontrolled plasma kallikrein (PKa) activity. Current guidelines recommend ready availability of on-demand HAE treatments that can be administered early upon attack onset. This report describes the pharmacological and pharmacodynamic properties of the novel oral small-molecule PKa inhibitor KVD900 as a potential on-demand treatment for HAE.MethodsPharmacological properties of KVD900 on PKa and closely related serine proteases were characterized using kinetic fluorogenic substrate activity assays. Effects of KVD900 on PKa activity and kallikrein kinin system activation in whole plasma were measured in the presence of dextran sulphate (DXS)-stimulation using a fluorogenic substrate and capillary immunoassays to quantify high molecular weight kininogen (HK), plasma prekallikrein and Factor XII cleavage. Pharmacodynamic effects of orally administered KVD900 were characterized in plasma samples from six healthy controls in a first in human phase 1 clinical trial and from 12 participants with HAE in a phase 2 clinical trial.ResultsKVD900 is a selective, competitive and reversible inhibitor of human PKa enzyme with a Ki of 3.02 nM. The association constant (Kon ) of KVD900 for PKa is >10 × 106 M-1 s-1 . Oral administration of KVD900 in a first-in-human clinical trial achieved rapid and near complete inhibition of DXS-stimulated PKa enzyme activity and HK cleavage and reduced plasma prekallikrein and Factor XII activation in plasma. In individuals with HAE, orally administered KVD900 inhibited DXS-stimulated PKa activity in plasma by ≥95% from 45 min to at least 4 h post-dose and provided rapid protection of HK from cleavage.ConclusionKVD900 is a fast-acting oral PKa inhibitor that rapidly inhibits PKa activity, kallikrein kinin system activation and HK cleavage in plasma. On-demand administration of KVD900 may provide an opportunity to halt the generation of bradykinin and reverse HAE attacks.

Dataset Information

Safety and Outcomes Associated with the Pharmacological Inhibition of the Kinin-Kallikrein System in Severe COVID-19.

Publications

Safety and Outcomes Associated with the Pharmacological Inhibition of the Kinin-Kallikrein System in Severe COVID-19.

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