A validated stability-indicating ultra performance liquid chromatography method for the determination of potential process-related impurities in eplerenone.

A simple, sensitive, and accurate stability-indicating analytical method has been developed and validated using ultra high performance liquid chromatography. The developed method is used to evaluate the related substances of eplerenone (EP). The degradation behavior of EP under stress conditions was determined, and the major degradants were identified by ultra high performance liquid chromatography with tandem mass spectrometry. The chromatographic conditions were optimized using an impurity-spiked solution, and the samples, generated from forced degradation studies. The resolution of EP, its potential impurities, and its degradation products was performed on a Waters UPLC BEH C18 column (50 × 2.1 mm, 1.7 µm) by linear gradient elution using a mobile phase consisting of 10 mmol/L ammonium acetate adjusted to pH 4.5, methanol and acetonitrile. A photo-diode array detector set at 245 nm was used for detection. The flow rate was set at 0.3 mL/min. The procedure had good specificity, linearity (0.02-3.14 µg/mL), recovery (96.1-103.9%), limit of detection (0.01-0.02 µg/mL), limit of quantitation (0.03-0.05 µg/mL), and robustness. The correction factors of the process-related substances were calculated.

Antagonistas de la aldosterona: ¿de la cirrosis a la insuficiencia cardiaca?. Respuesta / Response: Aldosterone antagonists: from cirrhosis to heart failure?

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Eplerenone: new drug. Recent myocardial infarction with heart failure: a spironolactone me too.

(1) Heart failure is diagnosed on the basis of both clinical symptoms and evaluation of cardiac function (preferably measured by echocardiography). Left ventricular dysfunction is defined as a left ventricular ejection fraction (LVEF) below 40%. The drugs of choice for chronic heart failure are certain angiotensin-converting-enzyme (ACE) inhibitors, some diuretics, some betablockers, and spironolactone. In one trial, spironolactone greatly reduced mortality at 24 months (35%, compared with 46% on placebo, p <0.001). (2) Eplerenone, a spironolactone derivative, is marketed for the treatment of left ventricular dysfunction in heart failure patients with recent myocardial infarction. (3) The EPHESUS study, a double-blind, placebo-controlled trial involving 6632 patients, showed a significant reduction in the overall mortality rate among patients with heart failure and recent myocardial infarction treated with eplerenone for 16 months (16.7% versus 14.4%; p = 0.008). This improvement was mainly due to a reduction in mortality during the first month of treatment. Eplerenone has not been compared with spironolactone, although the latter was known to be effective before the EPHESUS trial was conducted. (4) Severe hyperkalemia is frequent with eplerenone, occurring in 5.5% of patients. The risk of hyperkalaemia increases with renal failure and co-administration of potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists and nonsteroidal antiinflammatory drugs. (5) In the short term, the incidence of gynecomastia in patients taking eplerenone seems to be low. (6) In patients who develop heart failure after myocardial infarction, an indirect comparison of available data favours spironolactone over eplerenone (better efficacy, lower risk of hyperkalemia). (7) In France, treatment with eplerenone is about 9 times more expensive than spironolactone. (8) Spironolactone remains the treatment of choice for patients with heart failure and incapacitating dyspnea despite ACE inhibitor and diuretic therapy. Eplerenone may possibly be useful for patients who have non severe heart failure after recent myocardial infarction.

A new approach for dealing with the stability of drugs in biological fluids.

The purpose of this study was to develop a procedure for investigating the stability of drugs in biological fluids based on sound experimental design and to use a statistical procedure which would allow conclusions to be made concerning stability with an acceptable degree of certainty (95%). The experimental procedure involved replicate analysis of the drug in stored and freshly prepared samples on the same day. The relative difference in response between these two sets of samples and a 90% confidence interval for the true change in response was calculated. This confidence interval enabled us to detect a pharmacokinetically relevant degradation. It is argued that this approach is superior to the stability test procedures based on the t test. The application of the method to the assessment of the stability of three different drugs in biological fluids is described.

Identification of aldosterone secretion inhibitory factor in bovine adrenal medulla.

We report the first demonstration of an Aldosterone Secretion Inhibitory Factor (ASIF) in acid extracts of bovine adrenal medulla. Following separation from catecholamines and enkephalins, this factor leads to an 80% inhibition of PGE1-stimulated secretion of aldosterone from bovine adrenal zona glomerulosa. ASIF is retained on cation exchange gels and behaves as a small 5K-dalton peptide on Sephadex G-50. This factor cross-reacts in a radio-receptor assay for [125I] atrial natriuretic factor (ANF). ASIF is distinct from all neuropeptides formerly detected in the adrenal medulla, e.g. somatostatin, enkephalin, neuropeptide Y, dynorphin, neurotensin. In the adrenal gland, this ANF-like factor is predominantly found in the medulla (4 pmol/mg protein), with only trace amounts in the cortex (0.1 pmol/mg protein). ASIF might perhaps correspond to the endogenous ligand for the receptor sites that we have previously identified with [125I]ANF in bovine adrenal cortex and could contribute to the formerly reported attenuating influence of the adrenal medulla on mineralocorticoid production.