Journal of Ethnopharmacology 164 (2015) 385–387

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Letter to the Editor

Xysmalobium undulatum (Uzara) research– how everything began

art ic l e i nf o Keywords: Xysmalobium undulatum Uzara Hopf Wilhelm H.A.

a b s t r a c t Ethnopharmacological relevance: Xysmalobium undulatum (Uzara) is a traditionally used medicinal plant from South Africa. It found its way into European research in the early 20th century and is widely used as a remedy against diarrhoea. The purpose of this study was to explore the circumstances of knowledge transfer and early research into phytochemistry and therapeutic potential of Xysmalobium undulatum. Results: The drug was brought to Europe through a former soldier, Wilhelm Heinrich AdolphHopf (1887– 1929). Some details about his life are provided here the first time, as well as some aspects of early research on the drug, which has mainly been done at the University of Marburg, Germany. & 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Xysmalobium undulatum (L.) W.T. Aiton (Apocynaceae), also known as Uzara, is a traditionally used South African medicinal plant commonly used for the treatment of gastrointestinal and many other disorders (Watt and Breyer-Brandwijk, 1962). Recently, the plant is again in the focus of pharmacological research in order to explore the molecular mechanisms of its antidiarrheal action (Schulzke et al., 2011), to investigate cardiovascular effects (Schmiedl et al., 2012) and to determine its efficacy against dysmenorrhoea (Abd-El-Maeboud et al., 2014). The plant, however, has been used therapeutically for a long time in South African traditional medicine. The plant and its preparations have almost continuously been investigated, initially in Germany, from the early twentieth century up to the present day which is reflected by three review articles published more than 50 years ago (Geßner, 1961), in the early 1990s (Schmitz et al., 1992) and just recently in this journal (Vermaak et al., 2014). Publications usually give not more than a rough overview about historical developments, although the most comprehensive of the three reviews mentioned (Schmitz et al., 1992), starts with a comparatively large historical section. Thus, some details about the person who introduced Uzara into the European market and the early years of scientific investigations are given in this comment.

2. Early European reports and research What is now called Uzara was described in European scientific literature under the synonymous name Asclepias undulata as early as 1795 by Carl Peter Thunberg (1743–1828), a student of Linnaeus, who laid the foundations for the modern biological naming scheme of binomial nomenclature. Thunberg travelled a lot around South Africa, Java, Sri Lanka, and Japan (Meve and Liede, 1999). The plant which was also part of Thunbergs herbarium, was said to be used “for the purpose of expelling urine in the dropsy” and “as a remedy for the colic” (Thunberg, 1795). Both indications were also http://dx.doi.org/10.1016/j.jep.2014.12.022 0378-8741/& 2014 Elsevier Ireland Ltd. All rights reserved.

given by Rosenthal (1862). Andrew Smith (1828–1898) used the synonym Xysmalobium lapathifolium and mentioned the use of the roots as a tonic and that of the milky plant juice to treat maggots in open wounds (Smith, 1895). It was also mentioned in early botanical publications on Asclepiaceae without therapeutic information (Brown, 1808). Concerning the introduction of Uzara into the European Materia Medica, most authors refer to the landmark publication by August Gürber (1864–1937), professor of pharmacology at the University of Marburg from 1910 to 1929 (Gürber, 1911). He reported on his own investigations into the chemistry and pharmacology of Uzara root. It is said that the roots were brought to Europe by H.W.A. Hopf from Melsungen, who had travelled a lot through South Africa and became familiar with the use of Uzara by the natives. Hopf had suffered from severe dysentery which was cured by chewing Uzara roots the traveller had received from a medicine man. After having returned to Melsungen which is not far away from Marburg, Hopf left specimens of the roots to the pharmacological institute for further investigations, most probably in 1909. Grüber isolated three compounds of initially unknown structure out of root extracts. Without going into details, he reported on the development of a combination product which was marketed by a newly founded Uzara company in Melsungen soon thereafter as early as in autumn 1910. Gürber performed laboratory and animal experiments in a rabbit, a pig, and a cat, as well as studies in humans, namely himself, his family and friends (Gürber, 1911). He also reported experiences by physicians in tropical countries with patients suffering from amoebiasis, found effects on the cardiovascular system and suggested a therapeutic use against dysmenorrhoea, an indication re-investigated just recently (Abd-El-Maeboud et al., 2014).

3. Heinrich Wilhelm Adolph Hopf (1887–1929) While no details about the live and work of Hopf (Fig. 1) have been known so far, some facts can now be reported for the first time. Heinrich Wilhelm Adolph Hopf was born as one of eight child-

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Letter to the Editor / Journal of Ethnopharmacology 164 (2015) 385–387

Although some clinical studies were done in Bonn, Cologne (Eisenheimer, 1912), tropical countries (Werner, 1912, Waldow, 1913, Neubert, 1913, Seyffert, 1914) and elsewhere, most of the initial research was done at the University of Marburg, where several PhD theses were devoted to the subject in the first half of the 20th century (e.g., Theys, 1916, Stordeur, 1920, Grobel, 1925, Schröter, 1930, for details see Schmitz et al., 1992) and remained a central research topic for decades (Geßner, 1961). Uzara was also used and investigated in other countries like Great Britain and it was inlcuded in the 1915 edition of The Extra Pharmacopoeia of Martindale and Westcott (14th edition) soon after Hopf had introduced the drug into therapy (Martindale and Westcott, 1915).

5. Discussion

Fig. 1. Heinrich W. A. Hopf (1887–1929) in South Africa (ca. 1906, courtesy of L. Hopf, Hermannsburg).

ren January 10, 1879 in Melsungen and received his education at “Vilmars Erziehungs- und Lehranstalt”. His father Heinrich Wilhelm Leonhard Hopf (1842–1921) was a theologian and a publisher. A younger half-brother, Friedrich Wilhelm Hopf (1910–1982) also was a famous priest and author (Bohne, 2001). At the age of 16, H. W. A. Hopf joined the German navy, but some years later he moved to South Africa, where he was engaged in the Boer War. He married Mary Annie Langham Thomson (1876–1967) December 16, 1906. Most probably in 1909, the family returned to Melsungen (along with the Uzara roots) and stayed until the end of World War I. Then, Hopf and his wife moved to England, lived in Rugby and changed their name from Hopf to Hopford, as published in the London Gazette of 31 January 1919 on 19 November 1918 (Hopford, 1919). They had two children. He died December 27, 1929 in Rugby (Personal communication Mrs. Lydia Hopf, Hermannsburg, July 2014; www. ancestry.org). Hopf stayed in South Africa after the War at least once; his re-entry into England after passage on a ship named “Arundel Castle” was registered at the port of Southampton October 1922; most interestingly, his professional occupation is given as “chemist” (UK passenger lists).

4. Marburg and elsewhere Hopf also sent specimens to the University of Bonn, where Professor Karl (Carl) Bachem (1880–1935) also did some studies with the material the same year. He tested an alcoholic extract in rabbit and dog models of diarrhoea with considerable success and found only low oral toxicity. Intravenous application, however, led to cardiovascular effects and blood pressure irregularities (Bachem, 1911).

Xysmalobium undulatum (Uzara) was brought to Europe by the German soldier Heinrich Wilhelm Adolph Hopf (1887–1929) whose biographical details were completely unknown so far. Some of the details are reported here for the first time. Uzara made its way to a commercial product in a remarkably short time and underwent extensive scientific investigations in parallel. Most probably, this is reflecting a strong commercial interest by the founders of the Uzara company, which was built up within two years after Hopf had brought drug specimens to Europe. Relying on local healing traditions, Hopf's personal experiences and preliminary pharmacological tests, Uzara preparations were marketed as drugs against a variety of dysenteric symptoms. It is reported that the company initially supplied physicians with sample preparations in large quantities to test the remedy also in tropical countries and the army (Ujlaki, 1916, Waldow, 1912). They reported their results in the medical literature as soon as they had treated a couple of patients, which was a usual procedure that time (Schneider and Helmstädter, 2015). Although there is no proof for this so far, Hopf himself might have strongly triggered commercialisation, as it is unknown how he made his living after his career as a soldier. The fact that he classified himself as a chemist, a profession which he was obviously not trained in, might additionally support this theory. Strong and rapid commercialisation of Uzara reminds of Umckaloabo, another product containing the extract of a South African plant, brought to Europe and immediately marketed by a European salesmen in the early 20th century. Umckaloabo, now a trade mark of a Pelargonium sidoides preparation against bronchitis, was brought to Britain by a former soldier in the Boer War, Charles Henry Stevens, in 1903 (Helmstädter, 1996). It was ethnopharmacologically used against dysentery as well; systematic research on the drug started in the 1920s and continued, as is the case with Uzara, up to the present day (Brendler and van Wyk, 2008). References Abd-El-Maeboud, K.H., Kortam, M.A., Ali, M.S., Ibrahim, M.I., Mohamed, R.M., 2014. A preliminary pilot randomized crossover study of uzara (Xysmalobium undulatum) versus ibuprofen in the treatment of primary dysmenorrhoea. PLoS One 13, e104473. Bachem, C., 1911. Uzara, ein neues Antidiarrhoikum. Beliner Klinische Wochenschrift 48, 1514–1515. Brendler, T., van Wyk, B.-E., 2008. A historical, scientific and commercial perspective on the medicinal use of Pelargonium sidoides (Geraniaceae). Journal of Ethnopharmacology 119, 420–433. Bohne, D., 2001. Friedrich Wilhelm Hopf (1910-1982). Pfarrer, Kirchenpolitiker, theologischer Publizist, Mann der Mission. Lit-Verlag, Hamburg. Brown, R., 1808, Über die Asclepiadeen, eine natürliche Pflanzenfamilie, welche von Jussieu's Apocyneen abgesondert werden muss, p. 376. Eisenheimer, A., 1912. Uzara, ein neues Antidiarrhoikum. Deutsche Medizinische Wochenschrift 38, 2415–2416. Geßner, O., 1961. Entwicklung und Praxis der Uzaratherapie. Medizinische Klinik 56, 1492–1496.

Letter to the Editor / Journal of Ethnopharmacology 164 (2015) 385–387

Grobel, K.J., 1925. Beiträge zur Kenntnis der Uzara-Bestandteile. Univ. of Marburg (PhD thesis). Gürber, A., 1911. Ueber Uzara, ein neues organotrop wirkendes Antidiarrhoikum. Münchener Medizinische Wochenschrift 58, 2100–2104. Helmstädter, A., 1996. Umckaloabo – Late vindication of a secret remedy. Pharmaceutical Historian 26, 2–4. Hopford, H.W.A., 1919, The London Gazette, 31, January 1919, 1577. Martindale, W.H., Westcott, W. W., 1915, The Extra Pharmacopoeia, 16th ed. London, p. 854. Meve, U., Liede, S., 1999. Asclepiadoideae and Periplocoideae (Apocanaceae s.l.) of the Thunberg herbarium. Nordic Journal of Botany 19, 129–138. Neubert, 1913. Über die Wirkung von Uzara und geronnener Milch bei Darmerkrankungen. Archiv für Schiffs- und Tropenhygiene 17, 840–842. Rosenthal, D.A., 1862, Synopsis Plantarum diaphoricarum. Systematische Uebersicht der Heil-, Nutz- und Giftpflanzen aller Länder. Erlangen. Schmiedl, S., Ritter, A., Szymanski, J., Schneider, F., Plecko, T., Alken, R.G., Thuermann, P.A., 2012. Cardiovascular effects, pharmacokinetics and cross-reactivity in digitalis glycoside immunoassays of an antidiarrheal uzara root extract. International Journal of Clinical Pharmacology and Therapeutics 50, 729–740. Schmitz, B., El Agamy, R., Lindner, K., 1992. Uzarawurzel – seit 80 Jahren bewährt bei akuten Durchfallerkrankungen. Pharmazeutische Zeitung 137, 1697–1713. Schneider, A., Helmstädter, A., 2015. The evil of the unknown. Risk-benefit evaluation of new synthetic drugs in the 19th century. Pharmazie 70, 60–63. Schröter, H., 1930. Zur Pharmakologie der Uzara-Droge. Univ. of Marburg (PhD Thesis). Schulzke, J.D., Andres, S., Amasheh, M., Fromm, A., Günzel, D., 2011. Anti-diarrheal mechanism of the traditional remedy Uzara via reduction of active chloride secretion. PLoS One 6, e18107. Seyffert, 1914. Bericht über Uzara bei Amöbenruhr. Archiv für Schiffs- und Tropenhygiene 18, 415–421. Smith, A., 1895. A contribution to South African materia medica chiefly from plants in use among the natives. Capetown, pp. 81, 61–62. Stordeur, K., 1920. Ueber die Wirkung des Uzarons auf das Froschherz. Univ. of Marburg (PhD thesis).

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Theys, E., 1916. Zur Kenntnis der zentralen Wirkung des Uzarons. Univ. of Marburg (PhD thesis). Thunberg, C.P., 1795, Travels in Europe, Africa, and Asia made between the years 1770 and 1779, 2nd ed., Vol. 1, London, pp. 167–290. Ujlaki, P., 1916. Über Uzara-Behandlung im Felde. Deutsche Militärärztliche Zeitschrift 45, 117–123. UK Passenger Lists 1878–1960 at www.ancestry.org. Vermaak, I., Enslin, G.M., Idowu, T.O., Viljoen, A.M., 2014. Xysmalobium undulatum (uzara) – review of an antidiarrhoel traditional medicine. Journal of Ethnopharmacology 156, 135–146. Waldow, 1913. Uzara, ein neues Heilmittel bei Darmerkrankungen. Archiv für Schiffs- und Tropenhygiene 17, 126–130. Waldow, Gühne, 1912. Erfahrungen mit Uzara bei Dysenterie. Archiv für Schiffsund Tropenhygiene 16, 190. Werner, 1912. Über Uzara bei Amöbendysenterie. Archiv für Schiffs- und Tropenhygiene 16, 190–193. Watt, J.M., Breyer-Brandwijk, M.G., 1962. The medicinal and poisonous plants of Southern and Eastern Africa. Edinburgh and London, pp. 70, 138–141.

Axel Helmstädter Department Biochemistry, Chemistry, and Pharmacy, Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany Received 27 October 2014 15 December 2014 15 December 2014 Available online 23 December 2014

Xysmalobium undulatum (Uzara) research- how everything began.

Xysmalobium undulatum (Uzara) is a traditionally used medicinal plant from South Africa. It found its way into European research in the early 20th cen...
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