Effects of a new loop diuretic (muzolimine) in cirrhosis with ascites: comparison with furosemide.

Muzolimine is a loop diuretic with both the dose-dependent increasing effectiveness of loop diuretics and the long-lasting effect of thiazides. This is a potential advantage in the treatment of ascites in advanced cirrhosis since these patients have a low tolerance to sudden reductions of blood volume. Equivalent single, oral doses of furosemide (40 mg) and muzolimine (30 mg) were given to 10 cirrhotic patients with ascites and reduced renal perfusion (glomerular filtration rate = 30 to 75 ml per min). The study was preceded by 4 days of equilibration (dietary sodium 40 mmoles per day), and the drugs were alternated via a single-blind, cross-over protocol after a wash-out period of 3 days. Renal function was monitored under basal conditions and after diuretic administration through 4-hr clearance periods for 24 hr. The renin-aldosterone axis was evaluated before diuretic administration and after 8 and 24 hr. Muzolimine led to a 12-hr cumulative diuresis [AUC0-12 = 2.52 +/- 0.42 (S.E.) ml per min] and natriuresis (5.14 +/- 1.05 mmoles per hr), which were comparable to those of furosemide (2.85 +/- 0.29 ml per min and 6.75 +/- 1.63 mmoles per hr). Its effect, however, was distributed over a longer period (8 hr) than furosemide (4 hr). Muzolimine activity mainly differed from furosemide because of: significantly lower 12-hr potassium excretion (AUC0-12 = 0.28 +/- 0.82 vs. 2.69 +/- 0.46 mmoles per hr; p less than 0.005); greater sodium/chloride excretion ratio (0.45 +/- 0.08 vs. 0.26 +/- 0.06; p less than 0.025), and absence of rebound phenomena.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of somatostatin on plasma ammonia and amino acid profile during fasting and after protein feeding in cirrhotic patients.

The effects of somatostatin on fasting and absorptive plasma ammonia and amino acids were studied in 12 cirrhotic patients. They received a 6 h intravenous infusion of somatostatin (500 micrograms/h) or saline, starting 90 min before protein feeding. During the fasting period somatostatin significantly reduced plasma ammonia (-18%) and total tryptophan (-39%), increased plasma leucine (+19%), isoleucine (+17%), glutamine (+22%), glycine (+13%), arginine (+14%) and lysine (+12%), and prevented the significant fall of phenylalanine (-8%), tyrosine (-6%), alanine (-8%) and threonine (-9%) seen with saline. The percent changes in ammonia and glutamine concentrations were inversely correlated (r = -80; p less than 0.001) After protein ingestion, somatostatin slowed the maximal plasma increase in ammonia and alpha-nitrogens by at least two hours, but their total 5 h plasma response was not reduced, and even, in some instances, significantly increased (valine, leucine, glutamine, alanine and serine) with respect to saline. The results suggest that in fasting cirrhotics somatostatin reduces plasma ammonia, probably through an impaired intestinal ammoniogenesis from circulating precursors, and inhibits the disposal of branched chain, aromatic (except tryptophan) and gluconeogenic amino acids. Furthermore, it delays, but does not reduce, the plasma increase in nitrogen after protein ingestion.

Comparative pharmacodynamics of furosemide and muzolimine in cirrhosis. Study on renal sodium and potassium handling and renin-aldosterone axis.

Ten male cirrhotic patients with ascites and reduced renal function were randomly given equivalent doses of furosemide and muzolimine by the oral route, through a single blind cross-over protocol. Renal function, electrolyte plasma concentrations and urinary excretions and renin-angiotensin-aldosterone system components were evaluated under basal conditions and after drug administration. The diuretic and saluretic effects being equal, the response to muzolimine was initially weaker but more prolonged than to furosemide, without rebound phenomena. The furosemide-induced natriuresis was in part related to the filtered sodium load, whereas muzolimine natriuresis was only correlated to the inhibition of tubular sodium reabsorption. No potassium wasting effect was seen after muzolimine administration. Transient plasma potassium concentration reduction observed during muzolimine suggests an ion shift within the intracellular compartment. Therefore, a possible interaction of the drug with cellular sodium active transport systems can be hypothesized. A significant increase of plasma renin activity was observed after furosemide. No significant changes were seen after muzolimine administration.

Importance of plasma aldosterone concentration on the natriuretic effect of spironolactone in patients with liver cirrhosis and ascites.

23 cirrhotics with ascites and sodium retention, whose aldosteronemia had been evaluated after an equilibration period at controlled sodium intake at the occasion of previous studies, were retrospectively investigated. The dosage of spironolactone needed to induce a negative sodium balance correlated significantly with plasma aldosterone concentration: r = 0.64; p less than 0.001. However, in cases with plasma albumin concentration less than 3 g/dl, glomerular filtration rate less than 80 ml/min, and plasma sodium concentration less than 136 mmol/l such a relationship was no longer significant. The diuretic response to spironolactone is mainly linked to plasma aldosterone concentration. Factors affecting the removal of ascites from the peritoneal cavity and renal sodium handling can influence the expected diuretic response to the drug.