an extensive overview with many historical details on ouabain is presented in the book

'Strophanthin - die wahre Geschichte'.

 

1859 – 1948

In 1859 the English botanist Kirk discovered the rapid onset of cardiac action of Strophanthus glycosides by the careless use of a toothbrush contaminated with seed of Strophanthus. Based on this random discovery the Scottish pharmacologist Thomas Fraser developed on the basis of Strophanthus an alcoholic extract "tinctura strophanthia", which first in England but soon also in France and Germany was used to treat heart diseases. Extracts of different Strophanthus species were used, which contained different glycosides with chemically related structures. For his studies on Strophanthus Fraser had used extracts of Strophanthus hispidus [1]. However, for therapeutic use Strophanthus kombé with the glycoside k-Strophanthin and Strophanthus gratus with the glycoside g-Strophanthin have been used. In 1888 the French chemist Arnaud isolated from Strophanthus gratus the pure active ingredient g-Strophanthin. This has later been isolated also from the African tree Acokanthera ouabaio and had been named "ouabain". Today, in the English literature the term "ouabain" is used internationally as the common name. In the German literature not until the 1970s, the term g-Strophanthin has been used. In 1904 a standardized solution of the pure substance became available that was commercialized by E. Merck, Darmstadt and Boehringer Mannheim: "g-Strophanthin Thoms". This ouabain solution was used both intravenously [17] and orally administered in the treatment of heart diseases. In 1909, the French physician and cardiologist Henri Vaquez introduced the iv-application of g-Strophanthin in France [15a,15b]Some medical centers in the United States, too, have used the "French preparations" to treat heart diseases [18].

 

In 1906 the pharmaceutical company Boehringer Mannheim in cooperation with the internist Albert Fraenkel introduced an iv formulation of k-Strophanthin under the trade name Kombetin. An economic success of this product turned out to be delayed. Even 20 years after launch the annual revenues of Kombetin were "only a few hundred marks" [2]. Only after Ernst Edens, University of Dusseldorf, based on systematic investigations had demonstrated the safety of intravenous administration of ouabain and had extended the therapeutic use of ouabain to treat angina pectoris and to prevent and treat acute myocardial infarction, Kombetin has been increasingly used in hospitals and in medical practice. In 1914, Albert Fraenkel was awarded the title Professor "for the fact that he transformed the uncontrollable oral Strophanthin therapy into the qualitative application of digitalis according to pharmacological principles." [12].

 

In 1934 Edens first published his experience with ouabain in the treatment of angina pectoris [16]. In this publication he claimed "the intravenous Strophanthin treatment is the safest treatment of organic caused angina pectoris including myocardial infarction." Aschenbrenner praised the successes of Edens with the Strophanthin treatment as a "great feat of internal medicine, comparable to the discovery of insulin." Particularly stressed were the advantages over digitalis. Eden himself was convinced: “The time will come, in which failure to timely start ouabain therapy will be condemned as medical malpractice." [3].

 

Already in 1901, Ludwig Krehl, in whose clinic Albert Fraenkel had carried out his studies with the intravenous administration of Strophanthin, had praised the "often excellent successes" with the "excellent, especially suitable oral ouabain". The Heidelberg pharmacologist Eichholtz in 1947 described in his textbook the use of ouabain "as absolutely the biggest advance in the therapy of heart since Withering in 1785." It should be noted that up in the 1950s in scientific and clinical reports often no distinction was made which Strophanthin, k or g, was used. Due to the fact that the therapeutic effects were largely identical [14] the term "Strophanthin" was used for both, k-and g-Strophanthin.

 

1949 – 1970, „Strophoral dispute“

For oral treatment with ouabain especially Strophanthus extracts and solutions of pure g-Strophanthin/ouabain have been used. Both solutions lead to unreliable therapeutic results with severe side effects. There have been repeated attempts to improve the efficacy of oral dosage forms of ouabain. Already in the 1920s g-Strophanthin/Ouabain had been available in tablet form [4,5]. In 1949, Boehringer Mannheim "following numerous and insistent requests from the medical practice" [6] introduced a new version of g-Strophanthin formulated as a tablet for sublingual application under the brandname "Strophoral" and was "surprised to note shortly after the introduction that the interest for such a preparation was unusually large."

 

For Boehringer as surprising as the commercial success of Strophoral and its high acceptance by the physicians "was the literary echo, which the drug created in the pharmacological and clinical literature. It has been almost spoken of a "Strophoral dispute" [6]. In clinical practice, with the use of Strophoral very different experiences have been made, which provoked doubts about the reliability of the therapeutic effects. Subsequently, several medium-sized companies offered many more ouabain-containing preparations for oral application, which were characterized by improved and reliable efficiencies. The database of the German Institute for Medical Documentation and Information records more than 20 orally administered ouabain preparations that have been used in Germany after 1950. Of particular importance were the "Purostrophan Dragees" from Kali Chemie and the "Strophoperm" from Permicutan KG. The Purostrophan Dragees were enteric-coated tablets of ouabain with the addition of sodium lauryl sulfate. Strophoperm was a solution of ouabain with the addition of permeation enhancer for sublingual administration. With both preparations the necessary dosage for reliable therapeutic results have been achieved at a considerably lower dosage than with Strophoral. The daily dose of Strophoral often amounted to 20 - 30 mg ouabain [19], for the Purostrophan-enteric coated tablets 2 -6 mg per day were sufficient [20]. The daily dose of Strophoperm with 0.5 - 1 mg ouabain [21] stood in the magnitude of the daily dosage of iv-administered ouabain.

 

In parallel to the launch of Strophoral, in the 1950s in Germany drugs based on pure digitalis glycosides, imported from America and England, substituted raw extracts and leaf-based formulations. The new digitalis preparations contained pure active ingredients and replaced the hitherto used extracts and dried leaves of Digitalis. These preparations were advocated to be "modern" and "progressive" while Strophanthus preparations henceforth were stigmatized as "old" and "German" preparations. The scientific dispute focused on the question whether with the new Digitalis formulations equally good or even better effects can be achieved as with the Strophanthus preparations.  A great deal of the dispute focused on the question whether Strophanthus preparations are bioavailable after oral administration. While high bioavailability of Digitalis (digitoxin> 90 percent, digoxin> 60 percent) had been determined the bioavailability of oral ouabain had been found to be 2 percent [8] to 15 percent [9]. The knowledge formulated by Edens "every heart needs its own dose of Strophanthin" [3] according to which the individual dose for each patient should be determined by titration – today a common practice for many drugs ("the patients are adjusted to the drug") - was interpreted by the proponents of the Digitalis and critics of the Strophanthus therapy as evidence of fluctuating absorption rates of ouabain. As the large number of follow-on products to Strophoral indicates, the scientific "Strophoral dispute" has hardly hurt at first the acceptance for ouabain by practitioners and thus the practical application. In the early 1970s, more than 99 percent of the world production of ouabain was consumed orally [7].

 

1971 - 1975, Heidelberg Tribunal

Boehringer Mannheim had developed Strophoral in cooperation with the Stuttgart internist Berthold Kern. In his studies Kern had focused on establishing a systematic classification of heart diseases. His differentiation between diseases of the left ventricle and the right ventricle, which is generally accepted today, was new territory for its time and was initially received with skepticism in science. Kern had in his practice also observed that ouabain is the treatment of choice for diseases of the left ventricle. Therewith he was able not only to confirm the findings of Edens but to also conceptually support them. A key priority that Kern dealt with was the question of the origin of heart attack. He took the view that heart attacks are not caused by impaired coronary arteries but are of myocardial origin. His insights and views he published in 1951 in the book "Die orale Strophanthin-Behandlung” (The oral ouabain-treatment) [10].

 

In the 1960s, the "cholesterol-fever" reached its first climax. Cholesterol-rich diet was blamed for high cholesterol levels that lead to atherosclerosis and thus by means of impaired circulation to heart failure and heart attack. This dogma today still is the subject of intense scientific debate. In the late 1960s, the head of the science section of the magazine "Bunte Illustrierte”, Peter Schmidsberger, took hold of this topic. Previously Schmidsberger had already caused furor with articles about miracle cures for cancer treatment. Other magazines, the radio and eventually television reported about Schmidsberger's campaign.

In his series of articles with provocative headlines he insinuated that doctors by their adherence to false theories of the cause of heart attack knowingly accept the death of patients due to false treatment. As a witness for his allegations he used Berthold Kern. The science organizations responded with harsh statements. Kern was summoned to a public hearing in the presence of the press, radio and television to Heidelberg in the restaurant Molkenkur on November 19, 1971. After a tribunal-like hearing Kern views on the origin of heart attack were rejected. "The attending scientists are of the opinion that it is irresponsible if the theses of Dr. Kern are redistributed to the public before its truthfulness is sufficiently established in a prospective, controlled study." [11] Reputable magazines (Spiegel Hungernde Herzen“, ZEIT „Kein Infarkt für „Bunte“-Leser“) took over this judgment. Even if the actual dispute had been the importance of atherosclerosis for the development of heart attack, ouabain was included in the condemnation of Kern's theses. After the Heidelberg tribunal ouabain was officially outlawed in German medicine. It was said to be toxic, non-bioavailable and thus not suitable for the treatment of heart diseases. Sales and market potential were reduced significantly. Even today, the Heidelberg Tribunal is the starting point for frequently spread obscure conspiracy theories.

 

H. Christophersen quotes in his book „Der Schlüssel zur Infarktverhütung“ (The key to infarct prevention) an unnamed head of research of a major pharmaceutical company, who characterizes the situation of ouabain after the Heidelberg tribunal: "We would immediately commercialize g-strophanthin if we could conceal the real name. The name g-strophanthin has been discredited too much in recent decades. Only when a world-wide rehabilitation of the g-strophanthin is done, we can change our position." [13].

 

1976 – 2012

In 1961 in Germany a Medicines Act was adopted as an obligation of the EU treaties. First, it governed only the registration of substances "whose efficacy is not common knowledge". As response to the thalidomide scandal the Medicines Act was tightened in 1976. Since then for all drugs safety and effectiveness must be proven by appropriate studies. Drugs that had been on the market before 1978 were classified as "fictitiously approved". The manufacturers were obliged to demonstrate safety and efficacy of their products by appropriate studies (Nachzulassung, re-registration) within a generous transition period of 12 years. The implementation of these legal requirements was handled generously. In 1997, a variety of re-registrations had not yet been completed. The "fictional approvals" were extended until the end of 2004. The European Commission initiated an infringement procedure against the Federal Republic. In the process, the Federal government undertook to complete the processing of re-registrations until the end of 2005.

 

The requirements of the Medicines Act applied for all old drugs including the many ouabain-products. Almost all manufacturers of ouabain products were medium-sized businesses, who did not see themselves in a position to fund the required studies. In addition, with the introduction of beta-blockers and ACE inhibitors by international pharmaceutical companies, new competitors had appeared that smaller companies could not compete with. Of the many companies that have offered ouabain in the 1950s to the 1970s, none exists today. Until 1990, almost all of ouabain preparations had been taken off the market. Strodival, offered by Herbert Arzneimittel GmbH, was the only product left. Herbert Arzneimittel GmbH has been taken over by Brahms Arzneimittel AG, which has been acquired by the Swedish generic manufacturer Meda in 2003. Meda also has not conducted the necessary studies for re-registration of Strodival. End of 2005 the fictional approval for Strodival threatened to be discontinued. A group of doctors, alternative practitioners and patients intervened with the Ministry of Health and the parties represented in the Bundestag, with the aim to obtain an extension. The BfArM (Federal Institute for Drugs and Medical Devices) in collaboration with the Ministry of Health then again extended the fictional approval of Strodival under the condition that the required studies on safety and efficacy of the product had to be submitted until July 2011. Meda has not submitted the requested data. Therefore on July 15, 2011 the BfArM has withdrawn the fictional approval of Strodival. Meda was allowed to sell the Strodival stock already produced. Sales officially ended on August 1, 2012. Since then in Germany as well as in any other country ouabain based drugs are no longer available.

 

The clinical efficacy of ouabain in the treatment of heart failure is well documented by decades of practical experience. It is still unknown how the effectiveness of ouabain compares to the current standard therapy with beta-blockers and ACE inhibitors. Comparative clinical studies do not exist. This question can therefore only be clarified by appropriate studies.

 

Endogenous Ouabain

In 1991 ouabain has been identified as an endogenous substance [22]Ouabain was found in extracts from bovine adrenal gland, hypothalamus, hypophysis, and adrenal gland tumors. In the majority of these studies endogenous ouabain was measured by use of specific antibodies (immunoassays). These results have not yet been verified by chromatographic-spectroscopic methods [23], so that a final identification of ouabain as an endogenous substance is still pending. Despite this fact, the discovery that ouabain may be endogenously produced in mammals and circulates in plasma has fueled the interest in this molecule as a potentially important hormone in normal physiology and disease. The role of the Na,K-ATPase as a signal transducer revealed a novel facet for ouabain in the regulation of a myriad of cell functions, including cell proliferation, hypertrophy, apoptosis, mobility and metabolism. The specific physiological functions of endogenous ouabain are still subject of ongoing research.

 

The website “endogenous ouabain” lists abstracts of recent publications, which give an overview of the current state of research on endogenous ouabain. This list will be updated as new interesting articles are published. It is noteworthy that in almost all current work on endogenous ouabain there is no reference to the decades of therapeutic use in the treatment of heart diseases. This part of the history of ouabain today is virtually unknown in science.

 

Literature

 

[1] Fraser ThR, The action and uses of digitalis and ist substitutes, with spezial reference to strophanthus hispidus, Brit Med J, 1885: 904 ff

 

[2] Berthold Kern, Der Myokardinfarkt, 3. Auflage, Haug Verlag, 1974, page 152

 

[3] Ernst Edens, Die Digitalisbehandlung, Dritte Auflage, Verlag Urban&Schwarzenberg, 1948

 

[4] Samolewitz E, Klinische Erfahrungen mit Purostrophan, Medizinische Klinik, 1921, S. 1417 ff,

 

[5] Bellon E, L’action toni-cardiaque des comprimés d’Ouabaine, Thèse pour le Doctorat des Médecine, Paris, 1922

 

[6] C. F. Boehringer & Soehne G.m.b.H. (Hrsg.) Für und wider die orale Strophanthin-Therapie / Strophanthintherapie (Studienreihe Boehringer), Mannheim 1952, page 5

 

[7] Berthold Kern, Der Myokardinfarkt, 3. Auflage, Haug Verlag, 1974, page 166

 

[8] H.-P. Erdle, K.-D. Schultz, E. Wetzel, F. Gross, Resorption und Ausscheidung von g-Strophanthin nach intravenöser und perlingualer Gabe, Dtsch med Wochenschr 1979; 104: 976-979.

 

[9] Marchetti G V, Marzo A, de Ponti C, Scalvini A, Merlo L, Noseda V, Blood levels and tissue distribution of 3H-Ouabain administered per os: Arzneimittel-Forsch 1971;21: 1399 – 1403.

 

[10] Berthold Kern, Die orale Strophanthin-Behandlung, Ferdinand Enke Verlag, Stuttgart, 1951

 

[11] Journal of Molecular Medicine, 1972;50(6):343-346.

 

[12] Gillmann H, Stellungnahme zur peroralen Strophanthinprophylaxe des Herzinfarkt, Deutsches Ärzteblatt, 1971: 2929-2936.

 

[13] H. Christophersen, Der Schlüssel zur Infarktverhütung, Kindler Verlag GmbH, München, 1973, page 113

 

[14] Pfeifer E, Über die Verträglichkeit und den Wirkungsunterschied von g- und k-Strophanthin. Scientia pharmaceutica, 1960;28:216–228

 

[15a] Vaquez H, Leconte, Les injections intraveneuses de strophanthine dans le traitement de l'insuffisance cardiaque, Bull. et mem. Soc. med d'hop, Paris, 1909, xvii, 662-679

 

[15b] Vaquez H, Lutembacher L. Ouabaine. Arch Mal Coeur 1917; 10: 197.

 

[16E. Edens, Die Strophanthinbehandlung der Angina Pectoris. Münchn. Med. Wschr. 1934;37:1424 – 1427.

 

[17] Fleischmann P / Wjasmensky H, Über intravenöse Strophanthintherapie bei Verwendung von gratus - Strophanthinum crystallisatum Thoms, Deutsche Medizinische Wochenschrift - DMW

1909  Band 35, Heft 21, 918–921.

 

[18Levine S A, The Potency of Some French Digitalis Preparations,

Boston Med Surg J 1920; 182:64-66.

 

[19] Halhuber M, Lantscherat T, Meusburger K. Zur Strophoraltherapie.

Med Klin. 1954;36:1440-1443.

 

[20] Wiesend W, Über perorale Strophanthinbehandlung, besonders beim Altersherz.

Münchener medizinische Wochenschrift, 1956; 98(26)26:900–904.

 

[21] Altmann K, Beitrag zur peroralen Strophanthintherapie.

Medizinische Klinik (Munich) 1952;47(14):446–448.

 

[22] Hamlyn, J.M., Blaustein, M.P., Bova, S., DuCharme, D.W., Harris, D.W., Mandel, F., et al., 1991. Identification and characterization of a ouabain-like compound from human plasma. Proc. Natl. Acad. Sci. USA 88, 6259–6263.

 

[23] Baecher S, et al, No endogenous ouabain is detectable in human plasma by ultra-sensitive UPLC-MS/MS, Clin Chim Acta. 2014 Feb 7;431C:87-92. doi: 10.1016/j.cca.2014.01.038

 

 

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