The Beat Goes On: The Story of Five Ageless Cardiac Drugs.

This article traces the history of 5 cardiac drugs-Aspirin, Atropine, Digitalis, Nitroglycerine, and Quinidine-that have been in continuous use for centuries and some for longer. Four of the 5 started life as botanicals and 4 have as also served widely varied functions far removed from their current purposes. Collectively, they have played a role in the history of royalty, religious leaders, assassinations and military campaigns in addition to their place in medical therapy. Their present clinical status has evolved from long-term clinical observation without the need for controlled clinical trials, detailed statistical analyses or FDA approvals. This review of their background illustrates the varied means by which markedly different substances from widely separated sources can come together to participate in the management of circulatory disorders.

In Carthage ruins: the illness of Sir Winston Churchill at Carthage, December 1943.

This paper reviews Churchill's illness in Carthage in December 1943. It was characterised by fever that lasted 6 days, left lower lobe pneumonia and two episodes of atrial fibrillation. He was managed in a private villa by Lord Moran, his personal physician, with the assistance of two nurses and the expert advice of colleagues. Sulphadiazine and digitalis leaf were prescribed and Churchill recovered. It is remarkable that, despite the severity of his illness, he continued to direct the affairs of State from his bed.

[A tribute to the memory of the illustrious maestro and academic Dr. Rafael Méndez Martínez, pioneer in the pharmacological studies of digitalis and digitalis glycosides]. / Breve historia de la digital y los digitálicos. Homenaje a la memoria del ilustre maestro y académico Dr. Rafael Méndez Martínez, pionero de los estudios farmacológicos sobre la digital y los glucósidos digitálicos.

Since the end of the XVIII century, digitalis glycosides were employed in heart failure. They were considered initially as diuretics and later as cardiotonic agents or as positive inotropics. At the present time there are varied groups of positive inotropic agents, which have a beneficial action on the failing human myocardium. For example, the beta adrenergics, the phosphodiesterase III inhibitors such as milrinone, or the sensibilizers of myocardial proteins to Ca++ such as levosimendan and omecamtiv mecarbil. However, following the opinion of distinguished cardiologists, in the case of heart failure associated to atrial fibrillation, digitalis cannot be substituted.

A fond farewell to the foxglove? The decline in the use of digitalis.

Since William Withering's report on the foxglove in 1785, digitalis, in 1 form or another, has remained a mainstay in the treatment of congestive heart failure and as a means of rate control in atrial fibrillation. Recently, with the introduction of potent diuretics and other agents for the treatment of these conditions, there has been a deemphasis on the role of digitalis despite its therapeutic value. Continued evidence of the frequent usefulness of digitalis in both conditions suggests that this venerable drug should remain within the therapeutic armamentarium of cardiologists and other physicians.

William Withering's legacy--for the good of the patient.

The lessons that the physician William Withering learned from his studies of digitalis are still relevant today. This paper highlights four of these lessons and updates them using the tools of clinical pharmacology and pharmacoepidemiology. First, Withering learned that failure to prepare digitalis from the foxglove in a standard manner resulted in a product with unpredictable clinical effects. Preparation of medicines from plants since then has not followed similar good practice and medicines have often not been granted marketing authorisation because of variability in their quality. Second, differences in the response to digitalis were noted by Withering, but he had little idea of their basis. Clinical pharmacology has shown that for drugs such as digitalis differences are caused by variability both in receptor sensitivity and in drug disposition. Third, the dose-response characteristics of digitalis were well known to Withering. Modern techniques of measuring response, such as the use of biomarkers, have made such studies easier, although clinical observations remain the gold standard. Fourth, Withering documented many of the adverse effects of digitalis. The use of various modern databases has facilitated the analysis of clinical toxicology and thus of risk-benefit profiles.

[Digitalic therapy. Historical outline]. / Acerca de la terapéutica digitálica. Bosquejo histórico.

The action of medical drugs obtained from many vegetables aroused a great interest of naturalists and physicians in all time. Moreover, it was always required that those persons destined to medical practice have a good knowledge of botany. Among the medicinal plants utilized by ancient peoples of the Anahuac, yoloxochitl or heart flower (Talauma mexicana) is mentioned, which seems to have a digitalis-like action. Research in our century demonstrated a positive inotropic and bradycardic effect of the leavels of Magnolia grandiflora or Talauma mexicana extract. Since the end of the XVIII century, digitalis was employed. It was considered initially as a diuretic and later as a cardiotonic agent. The action of digitalic glycosides upon the cardiac tissues was studied experimentally in Mexico. At the present-time there are positive inotropic agents derived from pyridine, as is the case of Milrinone, which have a beneficial action on the failing human myocardium. However, following the opinion of distinguished pharmacologists, "in the case of heart failure associated to atrial fibrillation, digitalis cannot be substituted".

Acerca de la terapéutica digitálica. Bosquejo histórico / On digatalic therapy

La acción de medicamentos derivados de muchas especies vegetales ha siempre despertado el más vivo interés de naturalistas y médicos. Además, en todas las épocas, se ha exigido un buen conocimiento de la botánica médica de parte de quienes se destinaban a ejercer la medicina. Entre las plantas medicinales utilizadas por los antiguos pueblos del Anáhuac, se cita el yoloxóchitl o flor del corazón (Talauma mexicana) que, al parecer, tiene acción simildigitálica. Investigaciones de nuestro siglo han demostrado un efecto inotrópico positivo y bradicardizante del extracto de Magnolia grandiflora o Talauma mexicana. Desde fines del siglo XVIII se ha utilizado la digital, considerada inicialmente como un diurético y después como un cardiotónico. La acción de los glucósidos digitálicos sobre los tejidos cardiácos ha sido estudiada experimentalmente sobre todo en México. Hoy en día existen agentes inotrópicos positivos derivados de las piridinas, como la milrinona, que se emplean útilmente en la insuficiencia cardiaca refractaria. Pero, según la opinión de distinguidos farmacólogos, ® en el caso de le insuficiencia cardiaca asociada a fibrilación auricular, la digital resulta insustituible".

Charles Darwin (1758-1778) and the history of the early use of digitalis. 1934.

The evidence which I have just summarized establishes priority of publication concerning the action of digitalis for Erasmus Darwin, but on every other ground, Withering deserves full credit for the discovery. Charles Darwin, the medical student, had been informed of its action by his father and had attempted to account for it on the basis of improvement of lymphatic drainage. But the work, accomplished by the first Charles Darwin is less significant than the abundant evidence of his intellectual ability and precocity, and I have ventured to lay the details of his career before you because of their intrinsic interest and in the hope that the information will serve in a small way to clarify the unsolved problem of the relation of nature to nurture in establishing mental traits and capacities.