Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Levosimendan has been developed for the treatment of decompensated heart failure and is used intravenously when patients with heart failure require immediate initiation of drug therapy. It increases cardiac contractility and induces vasodilatation. The pharmacokinetics of levosimendan are linear at the therapeutic dose range of 0.05-0.2 microg/kg/minute. The short half-life (about 1 hour) of the parent drug, levosimendan, enables fast onset of drug action, although the effects are long-lasting due to the active metabolite OR-1896, which has an elimination half-life of 70-80 hours in patients with heart failure (New York Heart Association functional class III-IV). Although levosimendan is administered intravenously, it is excreted into the small intestine and reduced by intestinal bacteria to an amino phenolpyridazinone metabolite (OR-1855). This metabolite is further metabolised by acetylation to N-acetylated conjugate (OR-1896). The circulating metabolites OR-1855 and OR-1896 are formed slowly, and their maximum concentrations are seen on average 2 days after stopping a 24-hour infusion. The haemodynamic effects after levosimendan seem to be similar between fast and slow acetylators despite the fact that the enzyme N-acetyltransferase-2, which is responsible for the metabolism of OR-1855 to OR-1896, is polymorphically distributed in the population. Levosimendan reduces peripheral vascular resistance and has direct contractility-enhancing effects on the failing left ventricle. It also improves indices of diastolic function and seems to improve the function of stunned myocardium. Despite an improvement in ventricular function, levosimendan does not increase myocardial oxygen uptake significantly. An increase in coronary blood flow and a reduction in coronary vascular resistance have been observed. Levosimendan reduces plasma brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) levels substantially, and a decrease in plasma endothelin-1 has been observed. Levosimendan also exerts beneficial effects on proinflammatory cytokines and apoptosis mediators. The effects of a 24-hour levosimendan infusion on filling pressure, ventricular function and BNP, as well as NT-proBNP, last for at least 7 days.
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PMID:Clinical pharmacology of levosimendan. 1759 1

The selective Cu(II)-chelator, triethylenetetramine (TETA), is undergoing clinical trials for the treatment of heart failure in patients with diabetes. Recently, the authors showed that 2 acetylated metabolites, N(1)-acetyltriethylenetetramine (MAT) and N(1),N(10)-diacetyltriethylenetetramine (DAT), are formed in humans following oral TETA administration. Thus, it became necessary to determine whether the N-acetyltransferase (NAT) 2 phenotype has any effects on the pharmacological properties and safety profile of TETA. Twelve fast and 12 slow NAT2-phenotype healthy participants were recruited. After oral drug administration, the authors collected plasma and urine samples, measured plasma concentrations of TETA and its 2 metabolites along with concomitant urinary copper concentrations, and performed safety tests. They present, for the first time, the complete 24-hour pharmacokinetic profiles of TETA, MAT, and DAT in humans. There was no evidence for clear-cut differences in pharmacokinetic profiles between fast and slow acetylators. Pharmacodynamic analysis showed no significant differences in cupruresis between the 2 NAT2 phenotypes. Safety results were consistent with TETA being well tolerated, and no significant differences in safety profiles were observed between the 2 phenotypes. Based on these data, NAT2 phenotype does not affect TETA's pharmacokinetic, pharmacodynamic, or safety profiles. TETA may be acetylated via an alternative mechanism, such as that catalyzed by spermidine/spermine N(1)-acetyltranferase.
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PMID:Pharmacokinetics, pharmacodynamics, and metabolism of triethylenetetramine in healthy human participants: an open-label trial. 2014 62