PMC:7408073 / 104650-109175 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7408073","sourcedb":"PMC","sourceid":"7408073","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7408073","text":"8.3. Chelating Agents: CaNa2EDTA\nAs already mentioned, chelating agents, by limiting zinc cellular availability, might influence hyperactivity, synthesis and conformation of both ACE2 and ACE, which may impair not only ACE2 (and ACE) enzymatic activity but also its availability on cell surface for viral entry. For these reasons, chelating agents might be effective to counter SARS-CoV-2 infection, and in particular when (e.g., induced by hypoxia) both arms of the RAS are likely upregulated. Differently from renin inhibitors, more chelating agents are commercially available and both classes of drugs might be administered, alone or in combination with other therapies for COVID-19. Of note, these classes of drugs might be beneficial not only for SARS-CoV-2 infection but also for other disease in which both arms of the RAS (and of the inflammatory system) are upregulated, as for example ARDS, PAH and other pathologies associated to chronic hypoxia and cardiac failure. Indeed, both Ang-II and Ang-(1–7) upregulation and a cytokine storm are common aspects in patients not only with ARDS and PAH but also with critical coronary artery disease [182], suggesting an upregulation of both arms of the RAS and of the inflammatory system in several different dysfunctions. Notably, a number of clinical trials have indicated the utility of CaNa2EDTA in coronary heart disease. It was believed that chelation therapy might alter plaque morphology and volume, or improve endothelial function [123]. However, the evidence was not convincing [123]. Future clinical trials on selected patients with both ACE and ACE2 upregulation might be more convincing. It is clear that similar pathways of activation can lead to different outcomes depending on individual predisposition/background. Therefore, future efforts to understand the genetic, morpho-physiological, environmental and lifestyle factors that individually affect the predisposition to a specific disease with a precision medicine must be pursed.\nTo avoid disrupting extracellular calcium levels, CaNa2EDTA formulation is typically employed as an antidote for lead poisoning or as an extracellular zinc chelator [123]. CaNa2EDTA is poorly absorbed in the gastrointestinal tract therefore can be preferentially administered by parenteral route or by inhalation. Nevertheless, oral tablets (e.g., 250–500 mg/tablet) or suppositories of CaNa2EDTA might also work in reducing plasma zinc levels by inhibiting intestinal zinc absorption (the only physiological way of zinc uptake by the organism) [188,189]. In this regard, eight men showing elevated lead concentrations were given a seven-day course of CaNa2EDTA, 4 g/day in divided doses. Oral CaNa2EDTA caused a rise in lead excretion within few hours, suggesting that orally administered drug was partially absorbed [188]. Importantly, the trial in the eight lead workers demonstrated that oral administration of CaNa2EDTA was safe and produced no side-effects [188]. However, the FDA-approved method for delivery of CaNa2EDTA in treatment of lead poisoning is intravenously or intramuscularly and the recommended dose for asymptomatic adults and pediatric patients with elevated blood lead levels is 1000 g/m2/day (~0,05 g/kg/day) [190]. CaNa2EDTA was usually administered for 5–10 days followed by an interval of at least 5–10 days before a second administration. Unfortunately, intravenous administration is very painful. Administration of CaNa2EDTA via nebulizer has also been pursued for inhalation therapy in pulmonary metal poisonings to protect lung tissue and reduce its systemic uptaken [123]; moreover, nebulized solutions containing EDTA have been proven safe, not inducing adverse effects [191]. For the sake of completeness, the unconventional methods for administering chelating agents such as rectal or inhalatory administration are not FDA approved methods for delivery and they have not been studied in detail [192]. CaNa2EDTA diffuses mainly in the extracellular fluids, where it is not significantly metabolized, and it is excreted rapidly by glomerular filtration. The chelator has a half-life of 1.4 to 3 h in adults and is completely excreted within 24 h [123]. For all of the above reasons, CaNa2EDTA might be employed in therapy of COVID-19. However, before beginning any therapy with medication, particularly in the case of new diseases (such as COVID-19) or new treatments, a careful patient selection for these new treatments is essential to prevent unnecessary toxicity (“first do not harm”).","divisions":[{"label":"title","span":{"begin":0,"end":32}},{"label":"p","span":{"begin":33,"end":2001}}],"tracks":[{"project":"LitCovid-PD-FMA-UBERON","denotations":[{"id":"T23","span":{"begin":282,"end":294},"obj":"Body_part"},{"id":"T24","span":{"begin":282,"end":286},"obj":"Body_part"},{"id":"T25","span":{"begin":1031,"end":1039},"obj":"Body_part"},{"id":"T26","span":{"begin":1127,"end":1142},"obj":"Body_part"},{"id":"T27","span":{"begin":1364,"end":1369},"obj":"Body_part"},{"id":"T28","span":{"begin":2210,"end":2232},"obj":"Body_part"},{"id":"T29","span":{"begin":2427,"end":2433},"obj":"Body_part"},{"id":"T30","span":{"begin":2460,"end":2470},"obj":"Body_part"},{"id":"T31","span":{"begin":3184,"end":3189},"obj":"Body_part"},{"id":"T32","span":{"begin":3557,"end":3561},"obj":"Body_part"},{"id":"T33","span":{"begin":3562,"end":3568},"obj":"Body_part"}],"attributes":[{"id":"A23","pred":"fma_id","subj":"T23","obj":"http://purl.org/sig/ont/fma/fma67653"},{"id":"A24","pred":"fma_id","subj":"T24","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A25","pred":"fma_id","subj":"T25","obj":"http://purl.org/sig/ont/fma/fma84050"},{"id":"A26","pred":"fma_id","subj":"T26","obj":"http://purl.org/sig/ont/fma/fma49893"},{"id":"A27","pred":"fma_id","subj":"T27","obj":"http://purl.org/sig/ont/fma/fma7088"},{"id":"A28","pred":"fma_id","subj":"T28","obj":"http://purl.org/sig/ont/fma/fma71132"},{"id":"A29","pred":"fma_id","subj":"T29","obj":"http://purl.org/sig/ont/fma/fma62970"},{"id":"A30","pred":"fma_id","subj":"T30","obj":"http://purl.org/sig/ont/fma/fma7199"},{"id":"A31","pred":"fma_id","subj":"T31","obj":"http://purl.org/sig/ont/fma/fma9670"},{"id":"A32","pred":"fma_id","subj":"T32","obj":"http://purl.org/sig/ont/fma/fma7195"},{"id":"A33","pred":"fma_id","subj":"T33","obj":"http://purl.org/sig/ont/fma/fma9637"},{"subj":"T23","pred":"source","obj":"LitCovid-PD-FMA-UBERON"},{"subj":"T24","pred":"source","obj":"LitCovid-PD-FMA-UBERON"},{"subj":"T25","pred":"source","obj":"LitCovid-PD-FMA-UBERON"},{"subj":"T26","pred":"source","obj":"LitCovid-PD-FMA-UBERON"},{"subj":"T27","pred":"source","obj":"LitCovid-PD-FMA-UBERON"},{"subj":"T28","pred":"source","obj":"LitCovid-PD-FMA-UBERON"},{"subj":"T29","pred":"source","obj":"LitCovid-PD-FMA-UBERON"},{"subj":"T30","pred":"source","obj":"LitCovid-PD-FMA-UBERON"},{"subj":"T31","pred":"source","obj":"LitCovid-PD-FMA-UBERON"},{"subj":"T32","pred":"source","obj":"LitCovid-PD-FMA-UBERON"},{"subj":"T33","pred":"source","obj":"LitCovid-PD-FMA-UBERON"}]},{"project":"LitCovid-PD-UBERON","denotations":[{"id":"T216","span":{"begin":467,"end":470},"obj":"Body_part"},{"id":"T217","span":{"begin":826,"end":829},"obj":"Body_part"},{"id":"T218","span":{"begin":1127,"end":1142},"obj":"Body_part"},{"id":"T219","span":{"begin":1136,"end":1142},"obj":"Body_part"},{"id":"T220","span":{"begin":1205,"end":1208},"obj":"Body_part"},{"id":"T221","span":{"begin":1364,"end":1369},"obj":"Body_part"},{"id":"T222","span":{"begin":3184,"end":3189},"obj":"Body_part"},{"id":"T223","span":{"begin":3557,"end":3561},"obj":"Body_part"},{"id":"T224","span":{"begin":3562,"end":3568},"obj":"Body_part"}],"attributes":[{"id":"A216","pred":"uberon_id","subj":"T216","obj":"http://purl.obolibrary.org/obo/UBERON_0018229"},{"id":"A217","pred":"uberon_id","subj":"T217","obj":"http://purl.obolibrary.org/obo/UBERON_0018229"},{"id":"A218","pred":"uberon_id","subj":"T218","obj":"http://purl.obolibrary.org/obo/UBERON_0001621"},{"id":"A219","pred":"uberon_id","subj":"T219","obj":"http://purl.obolibrary.org/obo/UBERON_0001637"},{"id":"A220","pred":"uberon_id","subj":"T220","obj":"http://purl.obolibrary.org/obo/UBERON_0018229"},{"id":"A221","pred":"uberon_id","subj":"T221","obj":"http://purl.obolibrary.org/obo/UBERON_0000948"},{"id":"A222","pred":"uberon_id","subj":"T222","obj":"http://purl.obolibrary.org/obo/UBERON_0000178"},{"id":"A223","pred":"uberon_id","subj":"T223","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A224","pred":"uberon_id","subj":"T224","obj":"http://purl.obolibrary.org/obo/UBERON_0000479"},{"subj":"T216","pred":"source","obj":"LitCovid-PD-UBERON"},{"subj":"T217","pred":"source","obj":"LitCovid-PD-UBERON"},{"subj":"T218","pred":"source","obj":"LitCovid-PD-UBERON"},{"subj":"T219","pred":"source","obj":"LitCovid-PD-UBERON"},{"subj":"T220","pred":"source","obj":"LitCovid-PD-UBERON"},{"subj":"T221","pred":"source","obj":"LitCovid-PD-UBERON"},{"subj":"T222","pred":"source","obj":"LitCovid-PD-UBERON"},{"subj":"T223","pred":"source","obj":"LitCovid-PD-UBERON"},{"subj":"T224","pred":"source","obj":"LitCovid-PD-UBERON"}]},{"project":"LitCovid-PubTator","denotations":[{"id":"3599","span":{"begin":23,"end":32},"obj":"Chemical"},{"id":"3623","span":{"begin":179,"end":183},"obj":"Gene"},{"id":"3624","span":{"begin":188,"end":191},"obj":"Gene"},{"id":"3625","span":{"begin":219,"end":223},"obj":"Gene"},{"id":"3626","span":{"begin":229,"end":232},"obj":"Gene"},{"id":"3627","span":{"begin":1601,"end":1604},"obj"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