1H-pyrrolo[2,3-f]quinoline and isoquinoline derivatives: synthesis and antiproliferative activity.

Fischer indol synthesis is reported for the preparation of some 2-substituted 1H-pyrrolo[2,3-f]quinoline and isoquinoline derivatives having a structural correlation with naturally occurring compound ellipticine. The prepared compounds proved capable of forming in vitro molecular complexes with native double-stranded DNA by intercalation between two base pairs and showed a relatively good activity in inhibiting the DNA synthesis in Ehrlich ascites tumor cells.

Antispasmodic effect of amiodarone on gastrointestinal smooth muscle: possible involvement of calcium.

The influence of amiodarone on contractions induced by acetylcholine (ACh) was studied in isolated preparations of guinea-pig ileum, duodenum and stomach fundus as well as in rat stomach fundus. In the guinea-pig ileum a concentration-dependent antispasmodic effect of amiodarone (20-70 microM) was observed after 30 min exposure to the drug, but not after 15 min. The inhibition of ACh-induced contraction further increased with time after removal of amiodarone from the bathing fluid. Similar results were obtained in ileum preparations maintained in a low Ca2+ medium (0.35 mM CaCl2) and under these conditions the response to ACh was restored by washing the tissue with a normal Ca2+ medium (1.4 mM CaCl2). Both low Ca2+ and amiodarone depressed the tonic component of ACh-induced contraction more than the phasic one. Guinea-pig duodenum was more susceptible than the ileum to the antispasmodic action of amiodarone and again this effect was slow in onset and not reversible. The highest inhibition of ACh-induced contractions by amiodarone was obtained in guinea-pig stomach fundus. In these preparations treated with a low amiodarone concentration (20 microM) the response to ACh was restored after drug removal. In rat stomach fundus the effect of amiodarone was low and not reversible. Like amiodarone, Ca2+ lowering caused a decrease in the response to ACh with the following order of effectiveness: guinea-pig stomach greater than guinea-pig duodenum greater than guinea-pig ileum greater than rat stomach. The inhibitions caused by amiodarone and by low Ca2+ were always additive. These results indicate that amiodarone exerts an antispasmodic effect on the gastrointestinal tract and that regional and species differences exist for this action. The possible involvement of Ca2+ in this effect is discussed.

Effects of amiodarone on oral and intravenous digoxin kinetics in healthy subjects.

The effect of amiodarone on oral and intravenous pharmacokinetics of digoxin was studied in healthy volunteers. A single 0.5-mg dose of digoxin was administered orally to three subjects both before and after 2 weeks of oral amiodarone (200 mg daily), while three subjects received a 0.5-mg intravenous dose of the glycoside under the same experimental conditions. Two other subjects were given both oral and intravenous doses of digoxin at different times, in the absence and in the presence of amiodarone. After oral digoxin treatment, amiodarone increased peak serum concentration, total area under the serum concentration-time curve (AUC), and 5-day urinary recovery of the glycoside, without changes in peak time and absorption rate constant. During the intravenous study, no significant change occurred in AUC and urinary recovery after amiodarone administration. Absolute bioavailability, for the two subjects who received both oral and intravenous digoxin, increased by 36 and 43%, respectively, after amiodarone treatment. Bioavailability derived from the mean values of oral and intravenous AUCs was 33% greater with amiodarone treatment. Apparent volume of distribution and systemic, extrarenal, and renal clearances of oral digoxin were not modified by amiodarone, when corrected for the bioavailability factor. Amiodarone had no effect on these pharmacokinetic parameters during the intravenous study with the glycoside. Our data indicate that increased oral bioavailability is the most relevant change in digoxin pharmacokinetics during the interaction with amiodarone and this can account for the increase in the glycoside concentrations.