Comparative study of therapeutic effects of short- and long-acting loop diuretics in outpatients with chronic heart failure (COLD-CHF).

BACKGROUND: Loop diuretics have two different classes with different duration of activity: short-acting such as furosemide (duration of activity, 6h) and long-acting such as azosemide (duration of activity, 10-12h). We conducted a multicenter, randomized, controlled trial in order to compare the therapeutic effects of azosemide, a long-acting loop diuretic, and furosemide, a short-acting one, on neurohumoral factors and cardiac function in outpatients with chronic heart failure (CHF). METHODS: We enrolled 98 patients with CHF who were receiving furosemide and an angiotensin-converting enzyme inhibitor, and they were randomly divided into furosemide (n=49) and azosemide (n=49) groups. The furosemide group continued furosemide at the same dosage, and the azosemide group switched from furosemide to azosemide. At baseline and after 3 months, we measured body weight, and levels of brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), norepinephrine, active renin, creatinine, blood urea nitrogen, sodium, potassium, and hematocrit. Chest X-ray and echocardiography were also performed. RESULTS: Body weight and plasma levels of BNP and ANP significantly decreased after 3 months in the azosemide group compared to the furosemide group. There were no significant differences in changes of levels of creatinine, blood urea nitrogen, sodium, potassium, hematocrit, norepinephrine, and active renin after 3 months between the furosemide and azosemide groups. Echocardiography and chest X-ray did not demonstrate significant differences between the two groups. CONCLUSIONS: Long-acting azosemide is suggested to be useful for the improvement of neurohumoral factors compared with short-acting furosemide in patients with CHF.

Classification of torasemide based on the Biopharmaceutics Classification System and evaluation of the FDA biowaiver provision for generic products of CLASS I drugs.

The biopharmaceutical properties of an in-house developed new crystal modification of torasemide (Torasemide N) were investigated in comparison with the most well known crystal modification form of torasemide (Torasemide I) in order to classify the drug according to the Biopharmaceutics Classification System (BCS), and to evaluate the data in line with current US Food and Drug Administration (FDA) guidance (with biowaiver provision for Class I drugs) to determine if the biowaiver provision could be improved. The solubility profiles of Torasemide I and Torasemide N were determined, and tablets prepared from both forms of the drug were studied for in-vitro release characteristics in media recommended by the current FDA guidance for biowaiver of generic products, and in other media considered more appropriate for the purpose than the ones recommended by the FDA. Two separate bioequivalence studies in healthy humans (following oral administration) were performed with two test products (both prepared from Torasemide I) against a single reference product (prepared from Torasemide N). The absorption profiles of the drug from the tablets were determined by deconvolution for comparison with the in-vitro release profiles to determine the appropriateness of some dissolution media for predicting in-vivo performance and to determine the comparative rate and extent of absorption. The drug was absorbed from the tested products quickly and almost completely (about 95% within 3.5 h of administration). However, one test product failed to meet the bioequivalence criteria and had a significant initial lower absorption rate profile compared with the reference product (P< or =0.05), whereas the other product was bioequivalent and had a similar absorption profile to the reference product. A dissolution medium at pH 5.0, in which torasemide has minimum solubility, was found to be more discriminatory than the media recommended by the FDA. Torasemide has been classified as a Class I drug according to the BCS up to a maximum dose of 40 mg and the data suggest that the current FDA guidance could be improved by giving more emphasis to selection of appropriate dissolution media than is given in its current form for approving biowaiver to generic products of Class I drugs.