Digitalis Research in Berlin–Buch—Retrospective and Perspective Views

Abstract

“The following remarks consist partially of matter of fact, and partially of opinion. The former will be permanent; the latter must vary with the detection of error, or the improvement of knowledge. I hazard them with diffidence, and hope they will be examined with candour.” These declarations, which stem from the famous book “An Account of the Foxglove and some of its Medical Uses” by physician William Withering in 1785 in which he introduced preparations from digitalis leaves in the therapy of dropsy (cardiac failure), are cited here by the senior author because of his awareness of the difficulties in presenting a balanced report on his life‐long research project on the further development of digitalis. His decision to devote himself to digitalis research originated at the bedside, when as a physician he experienced the grim final stages of cardiac failure in which no real help for the patients is possible. Unfortunately, his research project did not fit into the research program decreed by the Ministry of Science of the German Democratic Republic, so that he was ordered to stop the digitalis project in favor of biomembrane studies. Fortunately, he got round the ban simply by labeling the digitalis‐like acting steroids as probes for the cell membrane‐located Na+/K+‐transporting ATPase which he had just recognized as the digitalis target (receptor) enzyme. These and other ventures by the authors are collated here for the first time. The aim of this review is to foster straightforward research for solving a major challenge: the development of steroidal drugs for the prevention and cure of cardiac failure.

Mechanism of action of verbascoside on the isolated rat heart: increases in level of prostacyclin

“…The involvement of cholinergic and histaminergic receptors could be excluded from the results of Ahmad et al (1995) who showed that the ability of verbascoside to reduce blood pressure in rats was unaffected by atropine (antimuscarinic agent) and chloro-pheniramine/cimetidine (antihistaminic agents). Inhibition of the Na -K -ATPase enzyme seemed unlikely since verbascoside appears to lack the structural requirements necessary to interact with this enzyme (Repke et al, 1995). Attempts to determine whether slow calcium channels were involved by using the clinical agent verapamil were inconclusive.…”

Steroids

“…The cleavage of the C17 side chain begins with the treatment of (81) with hydroxylamine to afford the C20 oxime (82). Beckman rearrangement of (82) affords the ene-amide (83). Mild acid hydrolysis of (83) results in dehydroepiandrosterone acetate [853-23-6] (84) (133).…”

Cardiac Glycosides and Synthetic Cardiotonic Drugs

“…Duration of action can be determined in a similar way. The maximum rate of pressure rise dp/dtmax in this case is 266 mbar/40 ms = 6650 mbar/s [31] [14], [35], [36] The membrane-bound Na + -and K + -dependent adenosine triphosphatase (Na + , K + -ATPase) has been identified as the site of action of digitalis at the molecular level. Under physiological conditions this enzyme hydrolyzes adenosine triphosphate (ATP) to achieve the exchange of intracellular Na + for extracellular K + against concentration gradients.…”