Ouabain - Hauke Fürstenwerth - ebook
Opis

Ouabain is a natural substance that occurs in African plants. Until the 1980s, it was used in Europe and especially in Germany for the treatment of heart failure. Ouabain has polarized the medical profession like hardly any other drug. Supporters celebrated Ouabain as insulin of the heart, opponents denigrated this drug as placebo. Euphoric praise and devastating criticism characterised an extremely polemical and emotional dispute between general practitioners and university clinicians. Also in current research qualities of Ouabain are fiercely disputed. Like in the past, the dispute again is dominated by hubris and personal vanity. A group of scientists is convinced that Ouabain is an endogenous hormone. It is asserted that Ouabain not only is a key factor in the pathogenesis of hypertension and heart failure but has significant implications in the pathogenesis of many common diseases. Hauke Fürstenwerth describes the rise and fall of Ouabain. He presents an objective, fact-based analysis of the true history of Ouabain. With previously unreported facts, he describes the eventful history of this drug. The story of Ouabain is not finished yet. Current research results allow a new interpretation of the many years of therapeutic experience. Ouabain has an untapped therapeutic potential. The book documents how Ouabain can be reapproved for the benefit of patients. The history of Ouabain is integrated into the development of pharmacy and medicine. Today, the statistical risk for a probable disease has been established as an independent clinical indication. Even patients without symptoms are treated with drugs. Standard values for blood pressure, cholesterol and blood sugar define disease. This change is also part of the unfinished Ouabain story.

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acknowledgement

I would like to thank Dr.Waltraud Kern-Benz, Stuttgart, for providing me with extensive documents on the work of Dr. Berthold Kern.

Table of Contents

Preamble

William Withering and the Red Foxglove

From arrow poison to medicine

Info Box: cardiac glycosides

Schmiedeberg and the Digitaline

The quality of Digitalis preparations

Intravenous Strophanthin therapy

Kombetin

Ernst Edens - The Treatment of Angina Pectoris

Info-Box: The heart and its function

Berthold Kern and Left Failure

Info Box: Heart Failure

Oral Strophanthin treatment

Strophoral

The Strophoral Dispute

Bioavailability

Myocardial Infarction

Berthold Kern and Left Myocardiology

The Heidelberg Tribunal

The Medicines Act

Endogenous Ouabain

Ouabain and its effects

Ouabain and Coronary Heart Disease

Ouabain and the energy balance of the heart

Ouabain and Digitalis

Ouabain protects the kidney and the brain

Paradigm shift in pharmaceutical research

Medicine and Science

Cornavita

References

preamble

Ouabain is a natural substance that occurs in African lianas of the genus Strophanthus and in the shrub Acokanthera ouabaio, also native to Africa. Its chemical structure is similar to that of digitalis glycosides. Like the digitalis glycosides digoxin and digitoxin, ouabain has been used to treat heart disease. For the locals in Africa, Strophanthus was poison and remedy in one. In the mythology of the tribe of the Wilé in Upper Volta, this plant was sent from paradise to the earth to heal or punish people according to their merit. Ouabain (known as g-Strophanthin in German literature) has polarized the medical profession like hardly any other drug. Euphoric praise and devastating criticism characterised an extremely polemical and emotional dispute. "The time will come, in which failure to timely start ouabain therapy will be condemned as medical malpractice." With this prophecy the internist Ernst Edens (1876 - 1944), who held a chair at the University of Dusseldorf, in 1943 summarized his experiences with the cardiac glycoside ouabain. In 1985, the Munich cardiologist Erland Erdmann stated: "there is no longer a reliable indication for ouabain, whether orally, perlingually or intravenously. What was the reason for this change of mind? From which new findings could Erdmann derive his assessment? There were no studies in which ouabain had been compared with new drugs and proven to be inferior. Erdmann's assessment marked the end of a scientific debate in medicine that had been fiercely fought out over decades.

This book describes the eventful history of the heart medication ouabain. The rise and fall of ouabain have already been described several times. Nearly all of the previous presentations concentrate on a public debate in the 1960s and 1970s on the causes of heart attacks between the Stuttgart-based internist Berthold Kern and the Heidelberg pharmacologist Gotthard Schettler. This dispute was not only debated in scientific journals, but also publicly in daily newspapers, magazines, radio and television reports. An objective, fact-based analysis of the history of ouabain is still lacking. I would like to close this gap with this book. This book is also meant to popularize the history of ouabain in the Anglo-Saxon-world. Although ouabain still is the subject of intensive research, its use as a medicine is hardly known in English-speaking countries. Although, even as early as 1948, Sir John McMichael, a pioneer in the field of cardiology in Britain, observed the advantageous qualities of the Strophanthus glycosides compared to digoxin and acknowledged "We must also plead guilty to neglect of the study of the actions of the strophanthins ... ." ouabain hardly has been used in the Anglo-Saxon-world [McMichael 1948].

Today, only a few older physicians remember this heart medication, which was once so popular in Europe and especially in Germany. Younger doctors don't know ouabain anymore. Textbooks mention it, if at all, only as a historical side note. Ouabain-based preparations are only available as over-the-counter homeopathic products or as Defekturarzneimittel1 that require a prescription. Is there more than just a historical interest in dealing with this "old" drug at all?

Two findings indicate that a reassessment of ouabain in the treatment of heart failure is also appropriate for scientific reasons. On the one hand, there is an urgent need for effective means of treating heart failure. Heart failure is the only disease whose incidence and prevalence are steadily increasing in many developed countries. Despite modern treatment with beta-blockade and full angiotensin II modulation, the five-year mortality rate of heart failure is over 50% and corresponds to that of cancer. The efficacy of today's standard medication for the treatment of heart failure in absolute terms is only a few percentage points better than placebo. On the other hand, current research results show that ouabain has previously unknown therapeutic qualities which justify subjecting this drug to clinical re-evaluation.

Also in the current research on ouabain, qualities of ouabain are fiercely disputed. Like in the past, the dispute on ouabain again is dominated by hubris and personal vanity. A group of scientists is convinced that ouabain is an endogenous hormone. It is asserted that ouabain not only is a key factor in the pathogenesis of hypertension and heart failure but has significant implications in the pathogenesis of many common diseases, including renal failure, essential hypertension and heart failure.

These assertions are in stark contrast to decades of positive clinical experiences with ouabain in the treatment of heart diseases. In fact, recent research results confirm the cardio-protective effect of ouabain. In samples of human plasma that contained considerable levels of "endogenous ouabain" as detected by radioimmunoassay, with highly sensitive analytical methods no ouabain could be detected. These results confirm: there is no endogenous ouabain in human plasma. Thus the hypothesis of endogenous ouabain is refuted.

To understand the rise and fall of ouabain, one has to deal with the scientific basis of this drug, which has been uncovered in centuries of research, as well as with the findings on the causes of heart diseases. Scientific findings are not timelessly and irrevocably valid laws. They are subject to various influences and changes that can only be understood in a historical context.

Generations of researchers and physicians have shaped the history of ouabain. Outstanding personalities have developed fundamental findings that build on each other and have put them into clinical practice. The history of ouabain is also embedded in the development of the pharmaceutical industry and in the changes in the scientific disciplines on which it is founded. Pharmacology, genetics, molecular biology and other scientific disciplines have replaced clinical observations at the bedside as the starting point for the development of new drugs. Today, patients are treated with medication even without symptoms. The statistical risk for a probable disease has been established as an independent clinical manifestation. Guideline values for blood pressure, cholesterol and blood sugar define diseases. This change is also part of ouabain’s history. The history of this cardiac glycoside is also marked by failures, false generalisations, ingenious intuition, polemical criticism, academic vanity, material interests and personal profit-seeking.

The story of ouabain is not over. Ouabain is still the subject of intensive basic research. Current research results enable a new interpretation of many years of therapeutic experience. These new findings - also in the context of current findings on the pathogenesis of heart diseases - show that this cardiac glycoside has untapped therapeutic potential. It is a matter of the heart of this book to illustrate this potential and hopefully to contribute to efforts to re-assess ouabain’s therapeutic qualities fort he benefit of patients.

The history of ouabain is almost exclusively documented in German literature. In this book I make use of many original citations and literal quotations. For a better understanding I have translated these quotations into English. If some of the quotations appear to be incomprehensible, it is exclusively due to my translation and not to the original text.

Hauke Fürstenwerth

1 Defekturarzneimittel are drugs that are manufactured in pharmacies in quantities of up to one hundred ready-to-deliver packages per day without the need for a manufacturing permit or drug approval according to the German Medicines Act.

William Withering and the Red Foxglove

Plants and herbs have been used in all epochs of human history to produce remedies. Therapeutic experiences with plants and plant extracts have always been collected and described. The oldest traditional recipe collection for herbal remedies is more than 5,000 years old. It comes from Mesopotamia, the land between Euphrates and Tigris. Egyptian records for the use of medicinal plants date back to around 1,500 BC. Chinese records date back to 1,100 BC. In India, descriptions of the use of medicinal plants in the context of Ayurvedic medicine have already emerged around 1,000 BC. In the Middle Ages it was mainly the monasteries that preserved, documented and practiced the traditional knowledge about the use of medicinal plants. With the invention of letterpress printing in the 16th century, the knowledge of the healing power of plants was then laid down in the form of herbal books and thus made generally available. In the 18th century, scientists began to investigate the effects of medicinal plants in a targeted manner. Initially, the aim was to clarify which medicinal plant works best for which disease. In later centuries the investigations were extended to the pure ingredients contained in the medicinal plants, the elucidation of their chemical structure and their pharmacological effects. Towards the end of the 19th century, the chemical modification of the active ingredients was added. Many of the drugs used today are variations of natural substances found in plants.

One of the first systematic studies of the effects of a medicinal plant, the Red Foxglove (Digitalis purpurea), comes from the English physician William Withering. In 1785 he published the results of his studies under the title "An Account of the Foxglove and some of its Medical Uses: with Practical Remarks on Dropsy and other Diseases". Only one year later a German and a French translation were published. Interest in Withering's results also was expressed in America. Since the Red Foxglove is not found in America, Withering supplied his American colleague Hall Jackson with seeds of the plant. Jackson cultivated the Red Foxglove and introduced Digitalis therapy of dropsy with Foxglove in America [Skou 1986].

Withering (1741 - 1799) studied medicine, botany and mineralogy at the University of Edinburgh. In 1766 he began his professional career as a clinician in a practice in Stafford, County Staffordshire. In 1775 Withering and his colleague John Ash took over a practice in Birmingham. In 1779 he was appointed to the medical team of the General Hospital in Birmingham, where he worked until his retirement in 1792. In addition, he continued his flourishing private practice.

Shortly before moving to Birmingham, Withering became aware of a herbal mixture for the treatment of dropsy (an abnormal accumulation of body fluids). The recipe for the mixture came from an old woman in Shropshire County. It also achieved healing successes in patients for whom treatment by doctors had failed. The healer's herbal mixture contained more than 20 different herbs. Withering, who also was trained as a botanist, writes that "it was not very difficult for one conversant in these subjects, to perceive that the active herbs could be no other than Foxglove". Withering's decision to investigate the effect of Foxglove was reinforced by the experience of his colleague Dr. Cawley from Oxford, who suffered from an incurable water retention in his chest (hydrops pectoris) and could be cured by taking Foxglove roots [Skou 1986].

The Foxglove belongs to the plant genus of the plantain family (Plantaginaceae). There are about 25 species, which are native to Europe, North Africa and Western Asia. Of medical importance are the Red Foxglove (Digitalis purpurea) and the woolly Foxglove (Digitalis lanata). The use of Foxglove as a medicinal plant was first mentioned in a Valaisan herbal book in 1250 under the name "foxes glofa". In his book "Historia Stirpium" published in 1542, the German botanist and physician Leonhard Fuchs describes various Foxglove species in detail and gives them the name Digitalis [Greef 1981].

A Digitalis ointment and Digitalis tablets are mentioned 1650 for the first time in the official English list of medicines "Pharmacopeia Londoniensis". In 1748, the French doctor Francois Salerne describes the extreme toxicity of Gigitalis plants when fed to turkeys and urges caution when using these plants. When Withering began his Foxglove studies, this plant species was already an official part of several drug lists: 1744 Edinburgh Pharmacopeia, 1748 Paris Pharmacopeia, 1771 Wittenberg Pharmacopeia. Foxglove was recommended for the treatment of a wide range of diseases. Wound healing, headaches, asthma, rheumatism, and convulsions were only some of many diseases for which Foxglove preparations were used.

Withering knew from the healer's accounts from Shropshire County that the Foxglove has strong diuretic effects, often accompanied by severe vomiting and diarrhoea. He also knew about the extreme toxicity of the Foxglove. Accordingly carefully he planned his experiments. In the introduction to his book Account of the Foxglove, Withering lists four possibilities which he considered suitable for investigating the effects of the Foxglove. The investigations could be carried out chemically. At Withering's time, however, this method was limited to burning the substance and had proved useless until then. As a second possibility he saw the observation of Foxglove effects on animals. There were few reliable observations about the effects of medicinal herbs on animals and their significance for the effects on humans. Withering also rejected this method. For the same reason, he dispensed with a possible third alternative, the comparison with medicinal plants with similar effects. As the only reliable way to study the effects of the Foxglove, he chose the empirical use and observation of the effects on patients. Today we know that Digitalis has little effect on healthy humans and animals. If Withering had decided to study animals, he would not have found the effect of Digitalis. He was only able to study these in sick patients.

Such experiments in humans cannot be justified under current ethical standards. But it is not appropriate to judge Withering's actions by today's standards on the basis of today's knowledge. In the 18th century it was still common practice in many regions of Europe to burn women as witches for trivial reasons on the pyres. Withering's actions can only be judged in the cultural-historical context of his time and against the background of the knowledge available to him. At Withering's time there was no knowledge of the causes of the diseases to be treated, nor was it known how and why medicinal herbs and other remedies unfold their effects. The scientific disciplines of pharmacology and toxicology did not yet exist. William Withering's great merit is to replace the previously customary procedure of "trial and error" with a systematic approach and thus to open up new healing possibilities. It was not until 200 years after Withering's work on the Red Foxglove that drug laws were passed that today require extensive preclinical studies to be carried out before new drugs can be tested on humans.

Dr. Small, one of Withering's predecessors at the General Hospital in Birmingham, had arranged for one hour a day of free treatment for the destitute at the General Hospital. Withering continued this tradition. In this way, two to three thousand poor patients were treated each year. Withering selected suitable patients for his Foxglove studies from this patient pool. From 1776 to 1785 Withering treated 163 patients with different Foxglove preparations in graduated doses [Skou 1986].

The first task was to find a suitable dosage form for the Foxglove. Which parts of the plant are particularly suitable? How do they need to be prepared? In what dosage should they be administered? Powdered, dried leaves, which had been collected during the flowering period of the Foxglove, proved to be particularly suitable and effective. Aqueous extracts were only weakly effective, alcoholic extracts had too strong side effects. Withering observed such side effects even after the dried leaves were administered, but tried to exclude them to a large extent by reducing the dose. As optimal dosage Withering describes to administer Digitalis until side effects occur: "let it be given 1-3 graine two times per day (65 - 200 mg) of powder of the digitalis leaves ... and let it be continued till it either acts on the kidneys, the stomach, the pulse or the bowles; let it be stopped upon the first appearance of any one of these effects". To suppress the side effects - especially nausea and vomiting - he recommended the simultaneous administration of opium [Somberg 1985].

In his experiments Withering found the extreme toxicity of the Foxglove confirmed. As toxic effects he lists: "Illness, vomiting, diarrhoea, dizziness, visual disturbances, objects appear green and yellow; increased secretion of urine, slow pulse, down to 35 beats in a minute, cold sweat, cramps, fainting, death." These effects occurred mainly at the high doses with which Withering began his investigations. "I administered it in much too high doses over a much too long period of time." Deaths were the result.

According to Withering's observations, Digitalis primarily acts as a diuretic, which was superior to all other diuretics known to date in the treatment of water retention in tissue. Withering also mentions the effect of Foxglove on cardiac activity: Digitalis has "a power over the motion of the heart to a degree yet unobserved in any other medicine, and that this power may be converted to salutary ends." At Withering's time, the causes of dropsy were not yet known. The realization that water retention is a consequence of heart failure only became established towards the end of the 19th century. Therefore, Withering did not attach any particular importance to the effect of Digitalis on the heart. The discovery that Digitalis is a potent means of treating heart disease has been reserved for later generations of physicians and scientists. Nevertheless, William Withering is regarded today as the father of Digitalis therapy. His studies of the Red Foxglove are a prime example of systematic studies that have ushered in a new era in medical research. The physician and Digitalis expert Albert Fraenkel (1864-1938) formulated in 1936: "Withering's feat was that of an intuitive pharmacological-clinical concept. The use of Digitalis is not his glory title. He owes his immortality to the searching and finite finding of the correct dosage even today and the recognition and scheduled use of the pulse frequency as an indicator of the application and success of the therapy." In recognition of his scientific achievements, William Withering was admitted to the Royal Society in London in 1785, the society with the greatest social prestige in 18th century England.

Withering's work on the effects of the Red Foxglove met with great interest among physicians, not only in England, but also in France and Germany. But the success was of limited duration. Although Withering gave precise instructions in the Account of the Foxglove on collecting Foxglove leaves - location of the plant, time of collection, storage method and more - many Digitalis preparations were of dubious and varying quality. Digitalis was used as a panacea against many diseases for which no effect could be achieved. The doses used were too high. Poisoning due to overdose was the rule. Until the late 19th century, Digitalis remained a controversial remedy with limited acceptance among doctors. This only changed when the causes of dropsy were recognized and advances in chemistry and pharmacology made it possible to isolate the active ingredients contained in Digitalis plants and study their pharmacological properties.

From arrow poison to medicine

The Strophanthus and Acokanthera species, which are native to Africa and parts of Asia, contain cardiac glycosides that are structurally similar to those of the Digitalis species. The glycosides serve the plants as a defense against predators. Humans and animals have also taken advantage of the toxicity of these plants. The African crested rat (Lophiomys imhausi) uses it for an extraordinary defense strategy. It chews the bark of highly toxic acokanthera shrubs, which contain the cardio-active glycoside g-Strophanthin (ouabain), and then applies the toxic saliva to the hair of its prominent crest. The sponge-like structure of the hair secures the saturation of the coat with poison loaded saliva by capillary forces. Dogs that attack the crested rat and come into contact with the poisonous coat show severe poisoning symptoms that can lead to death [Kingdon 2012]. Rats themselves are much less sensitive to steroid glycosides than other species. That's why the Acokanthera poison has no effect on them.

Many tribes in Africa have used preparations of Strophanthus and Acokanthera plants as arrow poisons. These were used both on the hunt for wild animals and in acts of war. Even large animals like elephants could be killed with the highly poisonous arrows. Poison arrows were important weapons in the arsenal of the African population in resisting invaders, slave hunters and colonial masters. In the British colonies the natives were forbidden to produce and possess arrow poisons and were threatened with drastic punishments. Even the cultivation of Strophanthus plants and the collection of Strophanthus seeds was punishable [Osseo-Asare 2014]. The recipes for the preparation of the poison mixtures were passed on as secret recipes only within the own tribe. Outsiders were not told which parts of the plant had to be harvested at what time and how they had to be processed and often enriched with other ingredients such as snake or scorpion poison.

African healers knew the medical value of Strophanthus plants very early on. Alcoholic extracts were produced by soaking the plant roots with subsequent fermentation. The bitter-tasting solutions were administered in small sips over a period of days or weeks. To avoid poisoning, the amount administered was carefully dosed by the healer. Muscle pain, open wounds, constipation, food poisoning, sexual diseases and heart disease were treated [Osseo-Asare 2014]. To the locals, Strophanthus was poison and remedy in one. In the mythology of the Wilé tribe in Upper Volta, this plant was sent from paradise to earth to heal or punish people according to their merit [Leuenberger 1972].

In the report of his expedition to Mozambique, during which he explored the Zambezi tributaries from 1857 to 1863, the Scottish missionary David Livingstone describes a poison that was used by the local warriors in the Shire highlands on Lake Najasasee to kill people and referred to as kombé. "If you touch a tiny piece of this poison with your tongue, it is paralyzed." Livingstone was accompanied on his expedition by the botanist John Kirk. His task was to look for plants that seemed suitable and profitable for commercial products. Kirk reports that a single poisoned arrow was enough to kill a buffalo, but the hunters often had to stay on the wounded animal's heels for half a day before the deadly effect occurred. Kirk kept some examples of the kombé poison arrows in a bag, in which he also kept his toothbrush. When he used it one morning in March 1859, he noticed a bitter taste. Kirk's pulse was elevated due to a feverish cold, but decreased significantly after using the toothbrush. Kirk attributed this rapid effect to a contamination of his toothbrush with the kombé poison. Kirk sent samples of the poison and parts of the plant from which the kombé poison was prepared to the Royal Botanical Institute in London (Kew Gardens). There the plant was first identified as Strophanthus hispidus, later correctly as Strophanthus kombé.

Several researchers have rendered outstanding services in the clarification of the active substance contained in Strophanthus kombé and its pharmacological properties. Thomas Richard Fraser (1841 - 1922) - who taught pharmacognosy, pharmacy, pharmacology and therapy at the same time in Edinburgh - dealt most intensively with the kombé poison. He succeeded in isolating the pure active ingredient and characterised it as a glycoside. He was also able to show that the Strophanthus active ingredient has a pronounced cardiac effect and is suitable for therapy in humans. In 1885 Fraser reported on his first experiences with a Strophanthus tincture in patients and recommended its use in all forms of cardiac fatigue and as a diuretic. Fraser's work today is regarded as the basis for the application of Strophanthin to humans.

At the end of the 19th century, Digitalis preparations were a controversial remedy with limited acceptance by doctors due to their uncertain effects and their dreaded toxicity. Fraser's work nurtured the hope that Strophanthus glycosides might be a suitable replacement for Digitalis preparations. The Strophanthus research that began after 1885 was correspondingly intensive. As early as 1890, the number of scientific publications totalled more than one hundred. Intensive research has also been carried out in France and Germany on Strophanthus active ingredients.

French researchers in particular differentiated between ingredients from different Strophanthus species. Catillon won in 1888 pure substances from the Strophanthus species gratus, hispidus, niger and kombé. He regularly received crystalline products only from Strophanthus gratus, while the others, especially Strophanthus kombé, only supplied amorphous products. At the same time Arnaud was concerned with an arrow poison that the Somalis extracted from the wood of a tree called Acokanthera ouabaio. In 1888 he succeeded in isolating a crystalline active substance, which he called ouabain. Only a short time later, he found an identical active ingredient in an arrow poison made from Strophanthus gratus. The name g-Strophanthin for the Strophanthus gratus glycoside was introduced by Thoms in 1904 to distinguish it from the active ingredients of other Strophanthus species [Gilg 1904]. The glycoside found in the Strophanthus kombé investigated by Fraser was henceforth referred to as k-Strophanthin. Ouabain, which is identical to g-Strophanthin, largely replaced k-Strophanthin preparations in the therapy of heart patients in France after the First World War as "Ouabain Arnaud". In Germany, clinical Strophanthus research only began at the beginning of the 20th century with a publication by Schedel. He refers to Fraser, because after his publication in 1885, "a veritable flood of publications appeared on this new cardiac drug, a sign that the use of digitalis does not meet all requirements." In his work published in 1904 Schedel reports on positive experiences with a Strophanthus gratus tincture containing g-Strophanthin (ouabain). He emphasizes the beneficial effects on respiratory distress (dyspnoea) and pulse in heart patients also observed by other clinicians [Schedel 1904].

~ ~ ~

When Fraser published his groundbreaking work on the effects of Strophanthus' active ingredients in 1885, drugs were usually produced in doctors' pharmacies and home pharmacies. But also herbalists, pedlars and quacks were allowed to sell products declared as remedies. There was practically no regulation and control of the production, quality and efficacy of drugs. The purity and efficacy of drugs depended on the skill and experience of the individual pharmacist. Most pharmacists were still familiar with the use of native medicinal plants such as Foxglove species. However, every pharmacist used recipes he had developed himself to manufacture his products. In order to ensure a minimum quality of medicines, official pharmacopoeias were already being compiled in many countries in the 18th century, listing drugs known to be effective and methods for their production and storage. The first German pharmacopoeia (DAB1) was published in 1872 and the Pharmacopoea Austriaca was valid in Austria from 1812. The United States Pharmacopeia has existed in America since 1820.

Dealing with tropical plants posed new challenges for pharmacists and doctors. There was no experience with the identification of plants and suitable plant parts (leaves, seeds) and methods of preparing suitable dosage forms. The chemical analysis was not yet at a level that would have enabled an exact determination of the active ingredient content of plants and extracts. Empirical testing was the rule, extreme quality differences of supposedly identical products the inevitable result.

The period at the end of the 19th century was a period of political and economic upheaval. Progress in many scientific disciplines has led to the scientificisation of therapeutic measures in medicine. Empiricism and tradition were replaced by science. Industrial companies based on research were founded. Companies such as Hoechst, Bayer, BASF, Sandoz, Ciba, E. R. Squibb and Sons (now Bristol-Myers Squibb) and Boehringer were all founded in the second half of the 19th century. They were all looking for attractive products. The production of medicines was a promising business field.

In 1851 Ernst Christian Friedrich Schering (1824-1889) founded a pharmacy in Berlin, which in 1864 became the Chemische Fabrik Ernst Schering, which boasted of offering pure preparations. The later gave rise to Schering AG, which today is part of the Bayer Group. The pharmacist Heinrich Emanuel Merck (1794 - 1855) had already started in 1827 selling isolated active ingredients from plants such as caffeine, cocaine, morphine and nicotine to other pharmacists, chemists and doctors. These activities were the cornerstone of the pharmaceutical and chemical company E. Merck Darmstadt. Merck's product range focused on active ingredients derived from tropical plants. Hoping for more valuable plants was the reason why botanists like John Kirk always participated in expeditions like the one from Livingstone to Mozambique. Their task was to look specifically for such plants.

The American Henry Wellcome (1853-1936) had a great personal interest in new developments in medicine, pharmacology and botany. He was convinced of the great potential of tropical plants for new drugs. In the 1870s he had been on the road in South America in search of plants containing quinine. In 1880, together with his partner Silas Burroughs, he founded the company Burroughs, Wellcome & Co in London. The young company was looking for new products. When Fraser reported on his therapeutic experiences with homemade Strophanthus tinctures at the annual meeting of the British Medical Association in Cardiff in 1885, Henry Wellcome was also present. After an intensive discussion with Fraser, Wellcome decided to include the Strophanthus product in the product portfolio of his young company. Fraser supported Burroughs, Wellcome & Co with his knowledge of selecting suitable Strophanthus seeds and producing a tincture suitable for therapeutic use. Already in 1886 the new product Tincture of Strophanthus was on sale, which was sold at seven shillings per ounce in England and America. From 1887 the tincture was also marketed in Germany, Holland and other countries. The tincture was recommended in adults for the treatment of heart murmurs, nervous asthma, typhoid fever and pneumonia. With sweet syrup to mask the bitter taste it was also given to children.

Initially, it proved difficult to obtain sufficient quantities of suitable Strophanthus seeds for the industrial production of Strophanthus tinctures. Only the seeds of Strophanthus kombé were suitable for the production of the tincture developed by Fraser. However, seeds of unsuitable Strophanthus species were often delivered. With the help of John Buchanan, the British Consul of Malawi, Wellcome built a reliable supply chain [Hokkanen 2012]. In 1906, 16 tons of Strophanthus seeds worth 8,000 British pounds were exported from the British Protectorate in Central Africa to England. The seeds were harvested from wild plants. Cultivating the plants did not seem attractive enough. Other companies also began to market Strophanthus products. Some of these were of dubious quality. To distance himself from these, Wellcome advertised that its tincture corresponded to the original recipe of Fraser and was tested by him. Burroughs Wellcome made extensive use of medical and scientific literature in his advertising - especially Fraser's articles. From the beginning of 1886, reprints of Fraser's publications in The Lancet and British Medical Journal were used to promote the Tincture of Strophanthus. The authority of science is still used today by all pharmaceutical companies as an essential part of the marketing strategy for drugs. The Tincture of Strophanthus was a commercial success and founded the rapid growth of Burroughs, Wellcome & Co in the late 19th century.

Initially, no reliable information was available on suitable medical indications for the Strophanthus tincture. Fraser had described the diuretic effect, rapid onset of action and positive effects on edema and respiratory distress in a few patients. Fraser stressed in particular that "strophanthin increases the action of the heart without raising blood pressure." Further clinical and pharmacological investigations were necessary. As Burroughs Wellcome did not yet have its own laboratories, it made its tincture available to doctors and hospitals at home and abroad free of charge for experimental purposes. In 1894 the Wellcome Physiological Research Laboratories were founded, one of the first commercial research laboratories of their time.

In 1930 Burroughs Wellcome began selling digoxin preparations containing pure digoxin isolated from Digitalis lanata that very quickly became a great commercial success.

In America, E. R. Squibb and Sons was one of the first suppliers of Strophanthus products. Particularly popular was a chocolate-coated tablet of a mixture of Digitalis and Strophanthus extracts, which was sold at 16 cents per hundred pieces. The recommended dose for palpitations, smoking heart and as a heart tonic was one tablet every three to four hours. In Germany, Strophanthus preparations were developed by Boehringer Mannheim and E. Merck. In the absence of suitable research departments, these companies also made samples of pure Strophanthus extracts available to interested physicians and scientists for scientific investigations.

Info-Box Heart Glycosides

The drugs known as heart-active glycosides are also known as cardiac glycosides or steroid glycosides. The representatives of this class of chemical agents are found in numerous plant species. In addition to Foxglove species (Digitalis), these include Adonis rose (Adonis), Lily of the Valley (Convallaria majalis), Oleander (Nerium oleander) and the African lianas of the Strophanthus species and the African tree Acokanthera ouabaio. Approximately 200 active ingredients of this class are known. Of medical significance are the Digitalis derivatives digitoxin (from Digitalis purpurea), digoxin (from Digitalis lanata) and the Strophanthus derivatives k-Strophanthin (from Strophanthus kombé) and g-Strophanthin (from Strophanthus gratus), which is identical to the ouabain isolated from Acokanthera ouabaio. Chemically, the steroid glycosides are all constructed according to the same principle: a steroid framework similar to that of sexual hormones and bile acids is connected to a sugar chain consisting of one or more sugar residues. The steroid glycosides differ from each other by different sugar chains and different substituents on the steroid framework. The steroid skeleton is called aglycon or genin.

Digitoxose - Digitoxose - Digitoxose – Digitoxigenin

The Digitoxin contained in the Red Foxglove consists of the aglycon digitoxigenin and a sugar chain consisting of three units of digitoxose. The sugar chain of digoxin contained in Digitalis lanata also consists of three digitoxose units. It differs from digitoxin by a hydroxy group at the C-12 of the aglycon.

Digitoxose - Digitoxose - Digitoxose - Digoxigenin

The structurally related steroid glycosides from the Strophanthus species - k-Strophanthin and g-Strophanthin - contain several hydroxyl groups in the aglycon. These cause a much higher water solubility than Digitalis derivatives. The g-Strophanthin found in Strophanthus gratus and Acokanthera ouabaio in English is named Ouabain.

glucose - glucose - cymarose - k-strophanthidin

Today, this term is used exclusively in scientific literature. In contrast to the hydrolysis stable digoxin, digitoxin and ouabain, k-Strophanthin is very easily cleaved by acid and bases. The k-Strophanthin from Strophanthus kombé (Kombetin) used for therapeutic purposes therefore always contains small amounts of k-Strophanthin-β (produced by the elimination of one unit of glucose) and k-Strophanthin-α (produced by the elimination of two units of glucose). k-Strophanthin-α is identical to Cymarin obtained from the Adonis rose.

Rhamnose - g-Strophanthidin (rhamnose - ouabagenin)

In addition to the natural active ingredients, semi-synthetic digoxin derivatives β -acetyl digoxin (trade name Novodigal) and β -methyl digoxin (trade name Lanitop) have also been successfully used in therapy. These derivatives have an improved absorption compared to digoxin. They release digoxin in the body and therefore have an effect identical to digoxin.