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March 2002
Vol. 5, No. 3, pp 46, 48.
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the timeline
Flowers for the heart
Since the distant past, the beauty of foxglove has given us drugs to help the heartsick.

opening art
William Withering (1741–1799) holding foxglove.
Whatever the controversies over herbal medicine’s effectiveness, there has been one mainstay of medical practice derived from the country garden that has helped ease the hearts (literally) of countless patients throughout the centuries. The drug—a category of drugs, really—isolated from the garden herb foxglove (Digitalis purpurea), is digitalis.

And although the mechanism of digitalis’s effect on human metabolism has only recently been discovered, its usefulness has been the stuff of folklore, legends, and medical legerdemain. The drug traveled a hidden road through history from ancient Roman times (when it was merely one of a host of herbal remedies) to the 18th century, when William Withering, English physician and herbalist, first brought Enlightenment science to bear on a village goodwife’s secret brew.

Whether the drug’s toxic effects truly helped create the unique style and color palette of a yellow-obsessed Vincent van Gogh or the questionable poetry written by Erasmus Darwin (Charles’s grandfather), there is no doubt that digitalis has helped prolong lives for centuries. The success of digitalis triggered research into the various plant glycosides and helped launch the development of modern pharmacology and the pharmaceutical industry.

A Withering gaze
In 1775, Withering was asked his opinion on a folk remedy for dropsy (an often deadly edema most commonly resulting from congestive heart failure). As Withering related, the remedy “had long been kept a secret by an old woman in Shropshire who had sometimes made cures after more regular practitioners had failed.” Of the 20-odd herbal ingredients in her mixture, the botanically trained Withering noticed only one that he considered potentially “active”—foxglove.

He became determined to investigate digitalis as a potential medicine and over a period of a decade, he achieved a great measure of success.

In his 1785 paper, An Account of the Foxglove and Some of Its Medical Uses; With Practical Remarks on Dropsy and Other Diseases, detailing his investigations and conclusions, Withering was bluntly honest about his own mistakes in determining effective and safe dosages for the drug. In almost diary fashion, he confessed to years of overmedicating patients to dangerous levels with a host of painful side effects, sometimes leading to more rapid death, in his efforts to get things right in the ad hoc, patient-by-patient “clinical trials” of the day.

Withering had strong sympathies for the disadvantaged and became associated with a hospital for the poor. He wrote that this “gave me the opportunity of putting my ideas into execution for a variety of cases: for the number of poor who thus applied for advice amounted to between two and three thousand annually. I soon found Foxglove to be a powerful diuretic: but then and for a considerable time afterwards I gave it in doses very much too large, and urged its continuance too long. . . . In this mode of prescribing, when I had so many patients to attend to in the space of one or at most two hours, it will not be expected that I could be very particular, much less could I take notes of all the cases which occurred.”

A foxglove farm in Minnesota, ca. 1900
A foxglove farm in Minnesota, ca. 1900.
After finding out that a Dr. Carvley of Brasenose College, Oxford, had been cured of hydrops pectoris (a form of dropsy) by the use of foxglove after most physicians had given up on him, Withering became “determined to pursue my former ideas more vigorously.” With amazing foresight, he realized, as do researchers in modern pharmacology, the problems inherent in using botanicals as a source for medicines. Too often, the tissues used for the extract, whether roots, stems, or leaves, affect the drug’s activity, as does the time of year in which harvesting occurs. Withering chose to routinely use foxglove leaves as his source material and only when the biennial was flowering, to guarantee a defined medication. He believed that such care was especially important because of the powerful and toxic effects that even small doses of powdered digitalis leaves could produce.

One of the biggest problems in his series of “trials” was to determine whether the profound nausea and vomiting that occurred well before the diuretic effects (which he came to believe were the true therapeutic value) were necessary to the ultimate cure. Eventually, because of the pronouncedly toxic effects (often delayed) of the leaf decoction, Withering determined that only small doses should be given sequentially until either nausea or a diuretic effect was observed and then stopped. Sometimes he added cinnamon or juniper to the composite to hide the disagreeable taste.

One of his reported cases (which he attended as consulting physician to Dr. Erasmus Darwin) was of a Mrs. H. of A. near N.—the description being an early example of respect for patient privacy. The woman, in her forties, exhibited the classic symptoms of severe dropsy. Withering and Darwin found her “nearly in a state of suffocation, her pulse extremely weak and irregular, her breath very short and laborious, her countenance sunk, her arms of a leaden color. She could not lie down in bed and had neither strength nor appetite, but was extremely thirsty. Her stomach, legs, and thighs were greatly swollen; her urine very small in quantity, not more than a spoonful at a time, and that very seldom.”

Mrs. H. was, in fact, so badly off that Withering hesitated to prescribe digitalis, fearing that “an unfavorable termination would tend to discredit a medicine which promised to be a great benefit to mankind.” But he relented, giving way to “the desire to save the life of this valuable woman” and prescribed it anyway to marvelous effect. Within a week, every sign of dropsy was gone and Withering reported that she was surviving nine years later, still with occasional bouts of the disease that digitalis fought back every time. Darwin was so impressed that he subsequently wrote perhaps one of the most ponderous and frightfully bad poems ever dedicated to a plant.

Although Digitalis had been removed from the Edinburgh pharmacopeia as useless only a few years before, after Withering’s 1785 paper, it was immediately restored to glory and was soon included in almost every other national formulary—unfortunately, too much so. Digitalis was swept up in the fervor of prescription typical of the era and immediately used to treat a wide variety of diseases for which it was totally useless other than in some cases masking symptoms—from every kind of unknown fever to a host of infectious diseases. And, because of the powerful toxicity of digitalis, vastly more harm than good was usually done in these instances.

Getting to glycosides
By 1869, a French pharmacist, Claude Adolphe Nativelle, isolated a much-purified material he called “digitalin” from foxglove. Six years later, German chemist Oswald Schmiedeberg, whom many consider the father of pharmacology (see “A brief history of pharmacology”, Modern Drug Discovery, May 2001, p 87) isolated the first pure glycoside in crystal form from foxglove, which he called “digitoxin”.

By 1888, Boehringer Mannheim was inspired by this work to move into the field of glycoside research and came to produce strophantin, derived from the dogbane family, as a new heart medicine. In 1912, F. Kraft isolated a water-soluble substance called “gitalin” from foxglove leaves which, soon after World War I, Boerhinger Mannheim was producing in a standardized, easily absorbable tablet form that was called Verodigen.

Verodigen proved to be a mixture of six glycosides. Dozens of other glycosides soon were discovered from a variety of Digitalis species. By 1957, the most valuable of these, digoxin, was marketed in pure form as Lanicor and is still used today.

But it is not only in the area of cardiac research that digitalis proved ultimately pertinent. By giving Schmiedeberg and the pharmaceutical industry such a prominent “scientific” success, it helped to launch modern pharmacology, not only as a science, but also as a social force, by creating a demand for more and better medicines.

Moving to mechanisms
Today, researchers have determined that the cardiac glycosides derived from Digitalis species and related genera act in several physiologically significant ways, some of which are still not completely understood. These drugs have an extremely small “therapeutic breadth”, which in this case means that even a small excess dose can cause serious and often life-threatening side effects—as Withering himself noticed in the 18th century.

One of the main physiological effects of these compounds is to inhibit the sodium–potassium pump in cells, contributing to a buildup of intracellular calcium that stimulates increased cellular activity in muscles. The effect in heart muscles is to get them to work more “enthusiastically” at pumping blood, increasing the intensity of heart muscle contractions, while diminishing the rate, there by counteracting some of the detrimental effects of congestive heart failure. Perhaps Withering’s triumph, despite his haphazard (and to modern eyes, ethically suspect) trial-and-error methods, was that his faith in an old woman’s recipe let us use these drugs well before their chemistry was known and understood.

Suggested reading

  • Clendening, L. Source Book of Medical History; Dover Publications: New York, 1942.
  • Fischer, E. P. Selling Science: The History of Boehringer Mannheim; Boehringer Mann-heim GmbH: Mannheim, Germany, 1992.
  • A brief history of digitalis with Erasmus Darwin?s poem. www.csdl.tamu.edu/FLORA/Wilson/481/medbot/bot2.htm.

Mark S. Lesney is a senior editor of Modern Drug Discovery. Send your comments or questions regarding this article to mdd@acs.org or the Editorial Office by fax at 202-776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036.

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