Effects of thiofedrine on platelet aggregation, thromboxane B2 and 6-keto-PGF1 alpha in rats.

Thiofedrine inhibited rat platelet aggregation and intraplatelet thromboxane B2 (TxB2) generation induced by arachidonic acid. The IC50 values were 0.18 and 0.21 mmol/l, respectively. Thiofedrine, 1.25-5.00 mg/kg i.v., showed a significant inhibition of rat platelet aggregation and intraplatelet TxB2 generation induced by arachidonic acid, with ID50 values of 2.4 and 3.3 mg/kg. Thiofedrine, 0.5-2.0 mg/kg i.v., reduced TxB2 generation but increased 6-keto-PGF1 alpha formation in rat plasma.

Influence of thiofedrine on platelet aggregation, intraplatelet cyclic cAMP and malondialdehyde in rats.

Platelet aggregation and cyclic adenosine monophosphate (cAMP) production were studied by turbidimetry and competitive protein binding assay, respectively, in rats. Thiofedrine (Thi) significantly inhibited adenosine diphosphate (ADP)-induced and thrombin-induced platelet aggregation in vitro, with IC50 values of 0.56 and 0.16 mmol/l, respectively. In vivo, Thi 1.25-5.0 mg/kg i.v. significantly inhibited ADP-induced platelet aggregation at rate of 17.1-40.3%. Thi caused a dose-dependent increase in cAMP levels in rat washed platelets. Malondialdehyde (MDA) levels in rat platelets were measured by colorimetry. Thi had an inhibitory effect on thrombin-induced platelet MDA production. The results suggest that the antiaggregatory action of Thi may be related to metabolism of arachidonic acid (AA) and elevation of cAMP levels.

Effects of the novel beta-adrenergic partial agonist alifedrine on cardiac performance in dogs with acute ischemic left ventricular failure.

Acute ischemic left ventricular failure was induced in dogs by coronary embolization with plastic microspheres, resulting in reduced cardiac output (CO), increased left ventricular end-diastolic pressure (LVEDP), pulmonary capillary pressure (PCP), and total peripheral resistance (TPR). Intravenous (i.v.) administration of alifedrine, a beta-adrenergic partial agonist (0.3 mg/kg as bolus and 0.3 mg/kg/h as infusion), significantly improved performance of the failing heart. Left ventricular contractility was increased up to 50%, heart rate (HR) up to 28%, and CO up to 30%. LVEDP, PCP, and TPR were markedly decreased. Myocardial oxygen consumption was increased only to a minor degree despite the positive inotropic effect; coronary flow was augmented up to 26%. Thus, alifedrine in this model markedly improved left ventricular function by balanced stimulation of the myocardium and reduction of pre- and afterload.

Acute haemodynamic effects of different doses of alifedrine in congestive heart failure.

The haemodynamic effects of single oral doses of alifedrine 40 mg, 50 mg, 60 mg and placebo were compared in 30 patients with mild to moderate heart failure. Individual patients received either alifedrine 60 mg and placebo (15 patients) or alifedrine 40 mg and 50 mg (15 patients). All doses of alifedrine produced qualitatively similar haemodynamic responses, with maximum changes between 90 and 180 min after drug administration. The cardiac index was increased by +39%, +57%, and +50% by 40 mg, 50 mg and 60 mg, respectively. The increases were due to rises in stroke volume index (SVI) and in heart rate of +15%, +20% and +23%. Mean arterial blood pressure fell in a dose-related fashion, with a maximum fall of 11% by 120 min after 60 mg. The systemic vascular resistance index (SVRI) fell by 28%, 39% and 41%, and pulmonary vascular resistance index (PVRI) by 32%, 44% and 32% after 40 mg, 50 mg and 60 mg, respectively. The optimum dose appears to be 40 mg, which caused very little fall in blood pressure or increase in heart rate, yet significantly improved cardiac output. Alifedrine may have a place in the treatment of heart failure as an oral by active, positive inotropic agent.

Alifedrine, a positive inotropic agent that moderately reduces the severity of ischaemia and reperfusion-induced ventricular arrhythmias.

The effects of alifedrine, a positive inotropic agent, were examined in greyhounds anaesthetised with chloralose. An intravenous dose of 0.3 mg kg-1 resulted in a substantial increase in myocardial contractility (increased dP/dtmax, cardiac output and stroke volume) without significantly affecting heart rate. The effects of alifedrine on the severity of arrhythmias resulting from both coronary artery occlusion and reperfusion were also determined. A mild antiarrhythmic effect was observed during early ischaemia when the incidence of ventricular tachycardia was reduced from 90% in controls to 50% in treated dogs. There was also a significant reduction in the number of extrasystoles appearing as ventricular tachycardia (from 511 +/- 138 to 151 +/- 84). The total number of extrasystoles during the first 30 min of ischaemia was also reduced, although not significantly, from 846 +/- 193 to 527 +/- 86. Following release of a 40 min coronary artery occlusion there was a marked reduction in reperfusion-induced ventricular fibrillation from 75% in controls, to 37% in the alifedrine-treated dogs. The overall survival from the combined occlusion-reperfusion insult was increased from 20% in controls to 50%. These results suggest that alifedrine has an unusual and useful spectrum of pharmacological activity in that it combines antiarrhythmic activity with an ability to improve cardiac function.

Haemodynamic effects of intravenous and oral alifedrine in patients with cardiac failure.

A randomized, double-blind, double-crossover, placebo-controlled haemodynamic study was undertaken in patients with Grade II/III (NYHA) cardiac failure to examine the acute effects of intravenous alifedrine, 20 mg and 40 mg (17 patients), and oral 40 mg alifedrine (8 of these patients). Patients received single doses of alifedrine and placebo on separate days, with invasive monitoring. Alifedrine resulted in a significant (p less than 0.001), dose-dependent increase in cardiac output. The peak effect (+23% with 20 mg i.v., +42% with 40 mg i.v. and +29% with 40 mg orally) was seen approximately 1 hour after intravenous administration (with about half of these increases still apparent at 3 hours) but developed progressively over 3 hours after oral administration. There were significant reductions (p less than 0.001) in peripheral resistance (peak mean changes -21% with 20 mg i.v., -31% with 40 mg i.v. and -23% with 40 mg orally), but little (less than +/- 6%) observed change in arterial pressure. With intravenous alifedrine, there were significant increases in stroke volume (+19% with 20 mg, +35% with 40 mg, p less than 0.001) with little (5%) change in heart rate (+3% and +7%, respectively, N.S.). With the 40 mg oral dose, there was a small increase in heart rate (+12%, p less than 0.005) associated with a 19% (N.S.) increase in stroke volume. Peak haemodynamic responses to 40 mg alifedrine orally were 50% to 75% of those seen after administration of the same dose intravenously. When assessed 3 hours after administration, responses to the two routes of administration were similar. There were no clinically or statistically significant changes in arterial (non-invasive), pulmonary artery, pulmonary capillary or right atrial pressures with any dose of alifedrine. No significant arrhythmias were noted clinically with the doses studied. Alifedrine, therefore, is an interesting agent, available both orally and intravenously, which is well tolerated and appears to produce marked acute increases in cardiac output with little change in heart rate or blood pressure. Further studies should determine whether these effects are maintained during longer-term therapy and clarify the relative contributions of positive inotropic and peripheral vasodilator activity to the effects observed.

[Acute hemodynamic effects of alifedrine in patients with heart failure]. / Hämodynamische Akutwirkung von Alifedrin bei Patienten mit Herzinsuffizienz.

The newly synthesized cardiotonic agent alifedrine (1-cyclohexyl-3-[(1S, 2R)-2-hydroxy-methyl-2-phenylethylamino]-propan-1-one) was shown to have vasodilating and positive inotropic effects in experimental animals. The effectiveness was tested in 8 patients with congestive heart failure already receiving digitalis and diuretics. After the intravenous administration of 40 mg alifedrine, cardiac output and stroke volume index increased and systemic vascular resistance and left ventricular filling pressure decreased. Left ventricular ejection fraction improved and there were no significant changes in heart rate and mean aortic pressure. Alifedrine, therefore, improves left ventricular performance in patients with congestive heart failure treated with digitalis and diuretic agents.

[Syntheses of 14C-1-erythro-norephedrine and its N-substitution products 14C-oxyfedrine and 14C-D 13,625]. / Synthesen von 14C-1-erythro-Norephedrin sowie seiner N-Substitutionsprodukte 14C-Oxyfedrin und 14C-D 13 625.

Starting from 14C-benzene (--)-erythro-norephedrine (14C-1-norephedrine) was obtained in a 6-step synthesis. 14C-1-Norephedrine functioned as an intermediate for the synthesis of the carbon labelled partial beta-agonist oxyfedrine hydrochloride (ildamen) and the new positive inotropic agent D 13 625 (alifedrine hydrochloride).