Follow Your Nose: A Key Clue to Understanding and Treating COVID-19.

This paper suggests that ATP release induced by the SARS-CoV-2 virus plays a key role in the genesis of the major symptoms and complications of COVID-19. Infection of specific cells which contain the Angiotensin-Converting Enzyme 2 (ACE2) receptor results in a loss of protection of the Mineralocorticoid Receptor (MR). Local activation by cortisol stimulates the release of ATP initially into the basolateral compartment and then by lysosomal exocytosis from the cell surface. This then acts on adjacent cells. In the nose ATP acts as a nociceptive stimulus which results in anosmia. It is suggested that a similar paracrine mechanism is responsible for the loss of taste. In the lung ATP release from type 2 alveolar cells produces the non-productive cough by acting on purinergic receptors on adjacent neuroepithelial cells and activating, via the vagus, the cough reflex. Infection of endothelial cells results in the exocytosis of WeibelPalade bodies. These contain the Von Willebrand Factor responsible for micro-clotting and angiopoietin-2 which increases vascular permeability and plays a key role in the Acute Respiratory Distress Syndrome. To test this hypothesis this paper reports proof of concept studies in which MR blockade using spironolactone and low dose dexamethasone (SpiDex) was given to PCR-confirmed COVID-19 patients. In 80 patients with moderate to severe respiratory failure 40 were given SpiDex and 40 conventional treatment with high dose dexamethasone (HiDex). There was 1 death in the HiDex group and none in the SpiDex. As judged by clinical, biochemical and radiological parameters there were clear statistically significant benefits of SpiDex in comparison to HiDex. A further 20 outpatients with COVID-19 were given SpiDex. There was no control group and the aim was to demonstrate safety. No adverse effects were noted and no patient became hyperkalaemic. 90% were asymptomatic at 10 days. The very positive results suggest that blockade of the MR can produce major benefit in COVID19 patients. Further larger controlled studies of inpatients and outpatients are required not only for SARS-CoV-2 infection per se but also to determine if this treatment affects the incidence of Long COVID.

Pharmacokinetic study of eplerenone in rats after long-term coadministration with buckwheat tea.

The aim of this study was to investigate the effect of long-term intake of Tartary buckwheat tea on the pharmacokinetics (PK) of eplerenone in rats. A validated high-performance liquid chromatography-mass spectrometry (HPLC-MS) method was established to determine the eplerenone in plasma, and the portal vein absorption model was applied to conduct the pharmacokinetic study. Two groups of animals-buckwheat tea group and control group-were involved in this study. Plasma samples were obtained at different time points after administration, and were separated on Shimadzu HPLC-MS 2020 instruments. The method showed good linearity (r=0.9988) over a wide dynamic range (0.20-50 µg/mL). Within- and between-batch precisions ranged from 2.13% to 7.90%. The extraction recovery rates ranged from 91.96% to 94.96%. The data showed that in the Tartarian buckwheat group the area under the curve and maximum concentration of eplerenone were reduced compared with those of the blank group (p<0.01), but the time to reach peak concentrations of eplerenone (p<0.01) was prolonged. The results suggested that long-term consumption of Tartary buckwheat tea might induce the activities of the hepatic drug metabolizing enzyme, which can accelerate the metabolism of eplerenone. According to the results, the dosage of eplerenone should be adjusted in hypertension treatment trials when administered with Tartary buckwheat or Tartary buckwheat-containing dietary supplements to avoid potential drug interactions.

Clinically insignificant negative interferences of spironolactone, potassium canrenoate, and their common metabolite canrenone in new dimension vista LOCI digoxin immunoassay.

Spironolactone, a potassium-sparing diuretic metabolized to canrenone is often used with digoxin to treat various conditions including congestive heart failure. Potassium canrenoate is a similar drug, which is also metabolized to canrenone. Due to reported both positive and negative interference of spironolactone, potassium canrenoate, and their common metabolite canrenone with digoxin immunoassays, we investigated potential interference of these compounds with the new homogenous sequential chemiluminescent assay for digoxin based on the luminescent oxygen channeling technology (LOCI digoxin) for application on the Dimension and Vista platform. When aliquots of a drug-free serum pool were supplemented with various amounts of spironolactone, potassium canrenoate, or canrenone and apparent digoxin values were measured using Dimension Vista LOCI digoxin assay, we observed no detected value except when aliquots were supplemented with very high amounts of potassium canrenoate or canrenone. However, we observed that apparent digoxin concentrations were very low. When aliquots of a serum digoxin pool (prepared by pooling specimens from patients receiving digoxin), were further supplemented with various amounts of spironolactone, potassium canrenoate, or canrenone and serum digoxin concentrations were remeasured using the LOCIdigoxin assay, only statistically significant falsely lower digoxin values (negative interference) were observed in specimens containing very high amounts of canrenone or potassium canrenoate. However, such small bias may not have any clinical significance. We conclude that new Dimension Vista LOCI digoxin assay is virtually free from interferences of spironolactone, potassium canrenoate, and their common metabolite canrenone.

Abbott ARCHITECT clinical chemistry and immunoassay systems: digoxin assays are free of interferences from spironolactone, potassium canrenoate, and their common metabolite canrenone.

Spironolactone, which is metabolized to canrenone, is often used in combination with digoxin. Potassium canrenoate is a similar drug that is also metabolized to canrenone. As a result of reported interference of spironolactone, potassium canrenoate, and their common metabolite canrenone with digoxin immunoassays, we investigated potential interference of these compounds with two relatively new digoxin assays for application on ARCHITECT clinical chemistry platforms (cDig, particle-enhanced turbidimetric inhibition immunoassay) and ARCHITECT immunoassay platforms (iDig, chemiluminescent microparticle immunoassay), both from Abbott Diagnostics. When aliquots of drug-free serum pool were supplemented with various amounts of spironolactone, potassium canrenoate, and canrenone, no apparent digoxin concentration was observed using cDig assay on ARCHITECT c4000, c8000, and c16000 or iDig assay on i1000SR and i2000SR analyzers. In addition, we observed no false increase in serum digoxin value when aliquots of a digoxin pool were further supplemented with various amounts of spironolactone, potassium canrenoate, or canrenone. We conclude that both the cDig and iDig assays on the ARCHITECT analyzers are free from interferences by spironolactone, potassium canrenoate, and canrenone.

Effect of spironolactone, potassium canrenoate, and their common metabolite canrenone on Dimension Vista Digoxin Assay.

Spironolactone, a potassium sparing diuretic metabolized to canrenone, is often used with digoxin to treat various conditions including congestive heart failure. Potassium canrenoate is a similar drug that is also metabolized to canrenone. Due to reported interference of spironolactone, potassium canrenoate, and their common metabolite canrenone with digoxin immunoassays, we investigated potential interference of these compounds with Dimension Vista Digoxin immunoassay using Flex reagent cartridge. Aliquots of a drug-free serum pool were supplemented with various amounts of spironolactone, potassium canrenoate, or canrenone and apparent digoxin values were measured using Dimension Vista digoxin assay, we observed none-detected value except when aliquots were supplemented with higher amounts of spironolactone or canrenone. Similarly, when aliquots of a serum digoxin pool (prepared by pooling specimens from patients receiving digoxin) where further supplemented with various amounts of spironolactone, potassium canrenoate, or canrenone, we observed moderately falsely elevated digoxin values only in specimens containing higher amounts of spironolactone or canrenone. We conclude that spironolactone and canrenone but not potassium canrenoate may cause modest interference with Dimension Vista digoxin assay but such interferences may not be clinically significant except with very high amounts of canrenone.

Effect of spironolactone, potassium canrenoate and their common metabolite canrenone on serum digoxin measurement by digoxin III, a new digoxin immunoassay.

Spironolactone and potassium canrenoate (aldosterone antagonist diuretics) are often used with digoxin in clinical practice. It has been well documented in the literature that spironolactone, potassium canrenoate, and their common metabolite canrenone cross-react with several digoxin immunoassays at concentrations expected after therapeutic usage of these drugs and falsely elevate or lower serum digoxin concentrations. Recently, Abbott Laboratories marketed a new Digoxin III immunoassay for application on the AxSYM analyzer. We studied the potential interference of these compounds with this new digoxin assay. The Tina-quant assay was used as the reference method because spironolactone, potassium canrenoate, and canrenone do not interfere with serum digoxin measurement using this assay. Aliquots of drug-free serum were supplemented with therapeutic and above therapeutic concentrations of spironolactone, canrenone, and potassium canrenoate, and apparent digoxin concentrations were measured using the Digoxin III assay and Tina-quant assay. Significant apparent digoxin concentrations were observed when the Digoxin III digoxin assay was used, but no apparent digoxin levels was observed using the Tina-quant assay. When serum pools prepared from patients receiving digoxin were further supplemented with these compounds in concentrations expected in sera of patients receiving these medications, falsely elevated digoxin levels were observed using Digoxin III assay, but no statistically significant change was observed using the Tina-quant assay. We conclude that spironolactone, potassium canrenoate, and their common metabolite canrenone interfere with the serum digoxin measurements using the new Digoxin III assay.

A new turbidometric digoxin immunoassay on the ADVIA 1650 analyzer is free from interference by spironolactone, potassium canrenoate, and their common metabolite canrenone.

Spironolactone and potassium canrenoate (aldosterone antagonist diuretics) are often used with digoxin in clinical practice. It has been well documented in the literature that spironolactone, potassium canrenoate, and their common metabolite canrenone cross-react with the fluorescence polarization immunoassay (FPIA) for digoxin and falsely elevate measured serum digoxin concentrations. Recently a new turbidometric assay for digoxin became commercially available from Bayer Diagnostic for application on the ADVIA 1650 Chemistry analyzer. We studied the potential interference of these compounds in this new digoxin assay. Aliquots of drug-free serum were supplemented with therapeutic and above-therapeutic concentrations of spironolactone, canrenone, and potassium canrenoate, and apparent digoxin concentrations were measured. We observed apparent digoxin concentrations with the FPIA digoxin assay as expected but observed no apparent digoxin levels with the new turbidometric immunoassay. When serum pools prepared from patients receiving digoxin were supplemented with these compounds in concentrations expected in serum in patients receiving these medications, we observed falsely elevated digoxin levels with the FPIA digoxin assay, but no statistically significant change was observed with the new turbidometric assay. We conclude that the new turbidometric assay for digoxin is free from interference by spironolactone, potassium canrenoate, and their common metabolite canrenone.