[Molecular adaptation of the heart to hypertension].

in Zeitschrift fur Kardiologie (1995), 84 Suppl 4

Because myocardial hypertrophy is an independent risk factor for sudden death and cardiac failure, it is important to understand its molecular mechanisms to be able to devise new treatment strategies in ... [more ▼]

Because myocardial hypertrophy is an independent risk factor for sudden death and cardiac failure, it is important to understand its molecular mechanisms to be able to devise new treatment strategies in the future. Stretch is the putative primary stimulus triggering hypertrophy. Further signal transduction steps such as auto- and paracrine secretion of growth factors or transmission via the cytoskeleton are beginning to be unravelled. Subsequent to hypertrophic stimuli some important proteins undergo an isoform switch; questitatively, however, the most important step is an increase in translational capacity for each mRNA. Myocardial specific gene expression is achieved by coordinate interaction of several transcription factors, some of which may be involved in nuclear transmission of hypertrophic signals. One of the genes capable of transmitting hypertrophic signals is the "early growth response gene-1 (Egr-1)". We have also shown that nuclear estrogen receptors act as transcription factors in the myocardium and may therefore be involved in the sex-specific modulation of cardiac hypertrophy. At present, pharmacological interventions aiming at reduction of hypertrophy by interfering with the signal transduction pathway from the membrane to the nucleus are actively being sought. These transduction pathways are composed of a series of proteinkinases which may be amenable to drugs. In the future, gene transfer may become an option for treatment. [less ▲]

[Concentrations of amiodarone and flecainide in plasma and saliva--indications for the active transport of flecainide].

in Zeitschrift fur Kardiologie (1988), 77(2), 99-102

Only the free protein-unbound drug concentration in plasma is pharmacologically active. The concentration of some drugs in saliva is equal to the free drug level. We compared concentrations (in plasma ... [more ▼]

Only the free protein-unbound drug concentration in plasma is pharmacologically active. The concentration of some drugs in saliva is equal to the free drug level. We compared concentrations (in plasma before, 30 and 60 min after the morning dose, in saliva before, 30, 60, 90 and 120 min after the morning dose) of amiodarone (n = 8, 2 x 200 mg orally per day) and flecainide (n = 16, 2 x 100 mg) administered as chronic antiarrhythmic treatment. Drug levels were measured by "high performance liquid chromatography". Results: Just prior to the first morning dose, amiodarone concentrations in plasma were 1.0-2.9 (2.0 +/- 0.6) micrograms/ml, in saliva 0.02-0.25 micrograms/ml; flecainide in plasma 80-560 (316 +/- 163) ng/ml, in saliva 630-3700 (1749 +/- 963) ng/ml. After the morning dose we found maximal flecainide plasma levels of 462 +/- 203 and saliva levels of 3218 +/- 2857 ng/ml. The highest flecainide concentrations in the saliva (13,400 and 11,300 ng/ml) were found in two patients 30 and 60 min after the morning dose. Flecainide, but not amiodarone, is excreted actively in the saliva, probably indicating an enteroenteric circulation. This should be considered to reduce life-threatening flecainide intoxications by gastric and intestinal lavage and suction. The concentration of flecainide in the saliva does not represent the non-protein-bound free drug level in the plasma. [less ▲]