Aqueous Ethanolic Extract of the Roots of Pelargonium sidoides - New Scientific Evidence for an Old Anti-Infective Phytopharmaceutical

• Abstract
• Introduction
• History of Stevens’ Consumption Cure
• Pelargonium sidoides Forming the Origin of Umckaloabo®
• In Vitro Anti-Infective Activities
• Clinical Studies and Safety Evaluation
• Conclusion
• References

Abstract

Among the Pelargonium-based herbal remedies that are widely used in traditional medical systems in the Southern African region is a highly valued root medicine (commonly termed umckaloabo) of initially unknown botanical origin for the treatment of infectious conditions of the respiratory tract including tuberculosis. Nowadays, a modern aqueous-ethanolic formulation of the roots of Pelargonium sidoides (EPs® 7630), developed from this traditional medicine, is successfully employed for the treatment of bronchitis. The article summarizes the fascinating story of this herbal medicine including its way to Europe, identification of the botanical origin, and provides background information of the many profound anti-infectious actions and clinical studies. In spite of considerable effort, the underlying chemical principle is still not clear.

Introduction

The genus Pelargonium (Geraniaceae) includes approximately 270 distinct species of annual and perennial small shrubs which are limited in their geographical distribution. The majority of Pelargonium species occurs in the Southern hemisphere predominantly in South Africa with the centre of diversity in the Cape Province, while a few members are found in Australia, New Zealand and on the islands of Madagascar in the Indian Ocean and, e. g., St. Helena in the southern Atlantic Ocean [1], [2]. As with a number of plants, the discovery of the Pelargoniums by Europeans is closely associated with the history of exploration and the establishment of trade routes, here the one around the southern tip of Africa to the East. Naturalists on board collected tuberous rooted Pelargonium species. The tuberous roots not only survived the long navigation back but also served as foodstuff when supplies were short and as a remedy for the sailors. Although settlers had been made aware of the medicinal uses of some Pelargonium species by the native population, there was little interest by the medical practice about Pelargoniums at that time. As very popular ornamental plants with a characteristic scent of many species, Pelargoniums were shipped to England for cultivation. When first introduced into the great botanic gardens of Europe in the 17^th century, all Pelargoniums were called Geraniums, and although botanists reclassified them under two distinct genera within the Geraniaceae, the incorrect naming of Pelargonium species by the general public, but also in scientific papers is still noted today.

Among the Pelargonium-based herbal medicines, a mysterious root material with a long tradition of use for the treatment of respiratory tract-related health problems has survived historical trial-and-error scrutiny and found its place in modern phytotherapy in Europe, in the Commonwealth of Independent States, in Baltic States and in Mexico (Umckaloabo®, marketed by Spitzner Arzneimittel, Ettlingen, Germany). Only in the past three decades have serious attempts been made to identify its botanical origin, to evaluate its true efficacy, and identify the underlying active principle(s) and reveal the mechanism(s) of action. To this end, significant progress has been made and this report gives an overview of its fascinating history including a brief summary of chemical and activity-related facets. More recent advances are presented in detail in the series of impending papers of the Workshop on Umckaloabo®, held at the 55^th Annual Meeting of The Society for Medicinal Plant Research, September 2 - 6, Graz 2007.

History of Stevens’ Consumption Cure

Pelargonium species indigenous to the Southern African region were recognized for their curative and palliative effects by generations of several ethnic groups including Zulu, Bantu, Xhosa and Miengu and are still extensively used to treat wounds, gastrointestinal disorders, colds and respiratory tract infections including tuberculosis [3], [4]. For this, infusions and decoctions of the tubers have been used by the native population.

The discovery of the Zulu medicine of previous unknown botanical identity for the treatment of respiratory tract infections dates back to the Englishman Charles Henry Stevens. At age 17 he suffered heavily from tuberculosis and a medical specialist advised him to travel to South Africa for a cure in healthful climates [5], [6], [7]. In what is today Lesotho, Stevens met an old Zulu medicine man who gave him a brew prepared from the roots of a local plant that were crushed between stones and a herb he named ‘chichitse’ to drink twice a day. Stevens described this medicine in his own words as ”awful looking stuff”. After three months of treatment, Stevens recovered completely and imported the putative miracle roots to England. Under the name ”Stevens Consumption Cure” the essence was popular for a while as an active substance against tuberculosis. The British Medical Association, however, called his remedy forgery and himself a swindler that gave rise to some lawsuits. For more information concerning the dispute some recent excellent overviews may be consulted [6], [7].

As for umckaloabo, this name was used by Stevens to describe the mysterious root material but it had never been recorded in any recognized document at that time. Etymologically, umckaloabo was suggested to derive from the Zulu words umKhulkane for complaints associated with lung diseases and uHlabo which means chest pain.

In 1920, the former missionary Dr. Adrien Sechehaye at the University of Geneva heard of Stevens’ cure, treated about 800 patients in the following 9 years and reported successful cases to the Medical Society of Geneva, culminating in the publication of the case histories of 64 patients recorded in meticulous detail [8], [9], [10].

After World War II Umckaloabo® has been produced and marketed by ISO Arzneimittel, Regensburg, Germany. To date, a proprietary extract of the roots of P. sidoides, EPs® 7630 (exclusively contained in Umckaloabo®, marketed by Spitzner Arzneimittel, Ettlingen, Germany) developed for the treatment of respiratory infections, is being successfully employed.

Pelargonium sidoides Forming the Origin of Umckaloabo®

Stevens was either unwilling or unable to disclose the plant origin. Thus, the true botanical nature of this herbal medicine was debated for many years until 1974 when its origin was claimed to be P. reniforme [11], though current evidence points to erroneous identification in favour of P. sidoides [12]. Commissioned by the German company ISO-Arzneimittel, Dr. Sabine Bladt of the University of Munich using ethnobotanical, comparative microscopic and chemical methods in conjunction with a study visit to South Africa and the investigation of a root sample in Kew Botanical Gardens in England came to the conclusion that the roots must have originated from a Pelargonium species [11]. In the absence of striking morphological features and other parts of the plant, the proposed botanical identity reflects a careful piece of work that has provided the basis for a later comparative study between P. reniforme and P. sidoides aimed at identifying conclusively the plant origin of this herbal medicine [12], [13], [14].

It should also be noted that the existence of gradual variations between these two species added to general problems of taxonomic classification, as reflected in the past by numerous revisions in the framework of the Linneaen taxonomic system [15]. At the turn of the 18^th century, the botanical names Pelargonium reniforme Curt and Geranium sidaefolium Thunb, the latter being subsequently changed into the present taxon Pelargonium sidoides DC, have been given to two newly discovered species. However, in their revision of the Geraniaceae, Harvey and Sonder (1859) considered P. sidoides as a variety of P. reniforme and turned it to P. reniforme Curt. var. sidaefolium [16]. Adopting de Brutelle’s earlier taxonomic treatment of Pelargonium, these authors divided the genus into 15 sections and placed the titled Pelargonium species in the section Cortusina. The treatment by Knuth (1912) of the Geraniaceae resulted in re-naming of P. reniforme Curt. var. sidaefolium at the species level to P. sidaefolium (Thunb.) R. Knuth [17]. Wettstein’s revision to P. sidoides DC rewards DeCandolle as first author [18]. Based on molecular work, the most recent classification divides Pelargonium into two subgenera, Ciconium and Pelargonium, with the titled species grouped in section Peristera, subsection Reniformia of the latter subgenus [19].

With botanically defined plant materials available through cultivation, a comparative botanical and chemical study on these species was carried out in our group. In its unadulterated form, these species can readily be distinguished by the shape of the leaves, the colour of the flowers and the pollen. P. sidoides DC ([Fig. 1]) is characterized by dark red to almost black flowers, cordate-shaped leaves and yellowish pollen, while the zygomorphous flower heads of P. reniforme Curt ([Fig. 2]) are magenta red with two distinctive stripes on the upper two petals, the pollen is whitish-green, and the reniform leaves represent a characteristic feature that is reflected in its botanical name ’reniforme’. Differentiation of the roots is more difficult and refers to the colour of the root wood and the thickness of the phellem, markedly seen in older pieces ([Fig. 3]).

Systematic chemical examination of the root material showed conspicuously distinct metabolic profiles of each Pelargonium species, including simple phenols, coumarins and tannins [12]. Besides the variation of oxygenation patterns of the coumarin pools, the characterization of coumarin sulfates and coumarin glycosides, hitherto confined to P. sidoides DC, represents a striking discriminating feature. As for the chemical marker 7-hydroxy-5,6-dimethoxycoumarin (umckalin), its 7-O-glucoside and 5,6,7-trimethoxycoumarin, earlier work [20] has documented their natural occurrence by their isolation from P. reniforme Curt, which, however, conflicts with current information showing their presence exclusively in P. sidoides DC [12]. Taking into account marked differences in the composition of the essential oils [15], the prevailing chemical evidence strongly suggests P. sidoides DC to form the origin of Umckaloabo®. Independent support for this conjecture is provided by the various geographical distributions. P. reniforme Curt grows along the coastal regions of South Africa between Port Elizabeth and Durban, while P. sidoides DC, restricted to inland habitats, extends from the north-eastern Cape Province via The Orange Free State and areas of Transvaal to Lesotho, where Stevens met the Zulu traditional healer.

A lesson that may be learnt from the history of Stevens’ cure is the sourcing of authenticated plant materials and their adequate documentation. Without this information all efforts at the various levels of research on herbal medicines is useless.

In Vitro Anti-Infective Activities

Following the documented therapeutic benefits in infectious conditions of the respiratory tract, a modern aqueous-ethanolic formulation of the roots of P. sidoides, EPs® 7630, has been elaborated from the traditionally used medicinal plant and successfully introduced in modern phytotherapy (Umckaloabo®) for the treatment of upper respiratory tract infections. In principle, the claimed efficacy could be rationalized by antibacterial activities and/or stimulation of the non-specific immune system. Phenols, coumarins and tannins have been identified [12] and some of these constituents showed moderate direct antibacterial properties [21], which, however, cannot adequately explain the documented clinical efficacy of Umckaloabo® in the treatment of non-tuberculous respiratory infections. Significantly, anti-infectious capabilities may also well be due to indirect effects. Respective investigations have recently demonstrated a significant impact of EPs® 7630 on the ciliary system, phagocytosis, oxidative burst, and provided evidence for bacterial anti-adhesion activity [22], [23]. These multiple bacterial defence mechanisms may considerably contribute to the therapeutic anti-infective potential of EPs® 7630 and deserve to be studied in more detail in terms of similar antiviral effects and detection of the bioactive compounds. Conspicously, antimycobacterial experiments, following traditional treatments, are hitherto limited in number and to direct growth inhibition of Mycobacteria species, and have not yet provided significant potencies of samples [21], [22], [23], 24]. The little interest may be due to the advent of chemotherapy and the temporarily decreased incidence of the disease at this time.

Besides the noted antibacterial activities, extracts of P. sidoides and the related formulation EPs® 7630 have been found to significantly activate the non-specific immune system, as evidenced by the induction of NO and TNF release as well as IFN-like activities using standard in vitro functional assays [21]. The impact on the IFN system deserves to be explicitly mentioned, since respiratory tract infections are frequently caused by viruses. Inhibition of the cytopathic effect of murine encephalo-myocarditis virus on a sensitive fibroblast L929 cell line and the enhanced IFN-β production in human MG-63 osteosarcoma cells in a dose-dependent manner upon pre-treatment with a viral double-stranded RNA analogue strongly suggested an improved antiviral protection in afflicted patients treated with Umckaloabo® [25]. Clearly, further relevant pharmacological and clinical studies are needed to confirm the antiviral properties of this herbal medicine.

Independent support of anti-infective potencies of EPs® 7630 was available from an infection model in which macrophages were infected with obligate intracellular Leishmania parasites [21]. Pronounced antileishmanial effects were observed, while all samples exhibited no or only negligible host cell cytotoxicity. These findings clearly suggested activation of microbicidal effector mechanisms in macrophages induced by Pelargonium samples.

In a separate microbiological killing assay, human peripheral blood phagocytes were found to significantly reduce the number of surviving Candida albicans organisms [22]. Since EPs® 7630 showed no direct antifungal activity in this test system, the observed improved intracellular destruction of the test organisms was concluded to be due to enhanced phagocyte killing activity induced by EPs® 7630. The demonstrated efficient elimination of invading pathogens establishes once more the anti-infective potential of this herbal medicine.

Confirmatory evidence of macrophage activating potencies of EPs® 7630 as provided by functional assays was available from gene expression analyses. This special extract considerably enhanced the iNOS and cytokine (IL-1, IL-12, IL-18, TNF, IFN-γ) mRNA levels in parasitized macrophages when compared with those in non-infected cells [26]. That the observed and also prolonged up-regulations were distinctly expressed under infectious conditions may reflect that EPs® 7630 stimulates the non-specific immune system to react effectively when needed. This agrees well with similar notes reported for its NO- and TNF-inducing capabilities. Preliminary protein measurement (IFN-α) using sandwich ELISA and FACS analysis (IL-1, IL-12 TNF) verified the expression profiles.

Clinical Studies and Safety Evaluation

To obtain information about the efficacy and safety of Umckaloabo®, a series of clinical studies were performed including patients suffering from tonsillitis, tonsillopharyngitis and bronchitis, and these have been summarized in a recent overview [27]. Briefly, the treatment outcome was the change in specific symptoms by both physicians and patients on a rating scale. The studies showed a notable rate to remission and a clear improvement in most cases, shortening the severity and duration of the respiratory complaints. It should be noted that the methodology of some studies is facing criticism, but the results collectively imply that Umckaloabo® represents a valuable addition to the standard therapeutic concepts in these conditions. Significantly, the therapeutic value of antibiotic treatments in proven bacterial superinfections, e. g., with Streptococcus, is placed beyond doubt. On the other hand, the benefit of antibiotic treatments is limited, particularly in viral infections as encountered predominantly in the aetiology of upper respiratory tract infections. Taking into consideration the side effects of antibiotics, their prescription should be weighed up very carefully. The (co)treatment with Umckaloabo® may minimize the use of antibiotics and subsequently reduce the adverse events.

In December 2005, Umckaloabo® was approved as a drug by the German Medical Regulatory Authorities as a herbal medicine for treating acute bronchitis, giving much credence to its efficacy. This was only possible through a systematic preclinical and clinical research programme, in which efficacy and tolerability of the phytopharmaceutical could be convincingly demonstrated in accordance with all the criteria of modern clinical research. In clinical studies on over 9,200 adults and children suffering from such diseases have since been conducted [28], [29], [30], [31]. Of these, more than 3,800 cases have been included in controlled double-blind studies. This impressive clinical study programme demonstrates not only good tolerability but also a significantly more rapid relief from symptoms in acute bronchitis, sinusitis and tonsillitis as well as a reduction in time spent off work or school for more than 2 days. This is all the more significant in view of the fact that antibiotics are still prescribed far too often for these infections, which are of viral origin in up to 90 % of the cases. On the one hand antibiotics have been shown to be ineffective in these cases and on the other they have a wide spectrum of side effects, in addition to the increasingly threatening global problem of bacterial resistance. The positive assessment by the regulatory authorities should disprove unscientific comments that have been released in the press and in other sources.

The adverse effects most commonly reported included minor gastrointestinal complaints, assumed to be related to the presence of polyphenols. As for coumarins, there have been discussions about an increased risk of bleeding and a possible impact on concomitant treatments with coumarin-type anticoagulants. To date, no case has been recorded in all the clinical studies that definitely proved any increased bleeding tendency to be attributed to the treatment with Umckaloabo®. A close look at the coumarin structures readily shows that the minimal structural requirements for this particular biological activity, e. g., a 4-OH and a lipophilic residue at C-3, are missing which has apparently been broadly ignored. Consistent with the above, experiments did not show any effects on coagulation parameters or on the pharmacokinetics of warfarin in rats and proved the suspicion of an increased tendency to haemorrhage in patients after intake of Umckaloabo® highly unlikely [32]. Another concern referred to the ethanol content associated with the treatment of children. However, the recommended daily dosage is considered to be harmless, with a quantity below that of a glass of natural apple juice, and found its support by the licensed use for children as young as one year.

Conclusion

Medicinal plants of the genus Pelargonium have been successfully used for centuries in African folk medicine for the treatment of infectious diseases and gastrointestinal disorders. Towards the end of the 19^th century this ethnomedical utilization was an advantage to Major Charles Henry Stevens, whose tuberculosis was cured by the powdered root of a then unknown Pelargonium species during treatment by a Zulu medicine man. This successful self-healing moved Stevens to establish a ”secret medicine” in Europe as ”Stevens’ Consumption Cure” under the name ”Umckaloabo” as a medication for this pulmonary disease, which in those days was widespread.

At that time, the analytical methods to identify the crude drug were rather limited, so that for many decades only few scientific findings were available about this natural remedy. Scientific progress has since advanced to the point where Umckaloabo® has firmly established itself for over 30 years as a proven pharmaceutical product for the treatment of respiratory tract infections. As a consequence there is now clarity that P. sidoides DC forms the botanical origin of the crude drug material, with highly oxygenated coumarins, phenolics and a complex mixture of proanthocyanidins as the principal constituents. Current data on the coumarin profile suggest the occurrence of coumarin sulfates and coumarin glycosides to be apparently confined to P. sidoides, while the presence of umckalin in reasonable amounts serves as a useful chemical marker. However, the chemical composition has not yet been elucidated in detail, as is common for many herbal medicines. This is also true for the mode of action, but intensive and committed research over the past years has enabled us to establish a well-supported conception. According to this, the extract has antiviral and antibacterial properties which act both directly and indirectly. The indirect mechanisms are thought to function by modulating immune cell activities and influencing the interactions between pathogens and host cells. In addition, the phytopharmaceutical induces a marked increase in secretomotor action comparable to that of synthetic expectorants. These modes of action may explain the excellent anti-infectious effects in clinical studies of respiratory tract diseases.

But research into this natural remedy is by no means at an end. In addition to further clinical and preclinical study programmes, intensive research into the mechanisms of action and their underlying active principle(s) is being performed in the experimental field. For the latter, in particular, projects to provide clarification at the molecular level are already on the drawing board.

References

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Herbert Kolodziej

Institute of Pharmacy

Pharmaceutical Biology

Freie Universität Berlin

Königin-Luise-Str. 2 + 4

14195 Berlin

Germany

Phone: +49-30-8385-3731

Fax: +49-30-8385-3729

Email: kolpharm@zedat.fu-berlin.de

References

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  PubMedSearch in Google Scholar
• 2 Van der Walt J JA, Voster P J. Pelargoniums of Southern Africa, Vol. 3. Kirstebosch; National Botanic Gardens 1988
  Search in Google Scholar
• 3 Watt C, Breyer-Brandwyk M G. Medicinal and poisonous plants of Southern and Eastern Africa. Edinburgh/London; Livingstone 1962: 449-55
  Search in Google Scholar
• 4 Hutchings A. Zulu medicinal plants. Pietermaritzburg; Natal University Press 1996
  Search in Google Scholar
• 5 Helmstädter A. Umckaloabo - Late vindication of a secret remedy.  Pharm Historian. 1996;  26 2-4
  PubMedSearch in Google Scholar
• 6 Newsom S WB. Stevens’ cure: a secret remedy.  J R Soc Med. 2002;  95 463-7
  CrossrefPubMedSearch in Google Scholar
• 7 Taylor P, Maalim S, Coleman S. The strange story of umckaloabo.  Pharm J. 2005;  275 790-2
  PubMedSearch in Google Scholar
• 8 Sechehaye A. The treatment of tuberculosis with Umckaloabo (Stevens’ Cure). London; Fraser & Co 1931
  Search in Google Scholar
• 9 Sechehaye A. Die Behandlung der organischen und chirurgischen Tuberkulose durch Umckaloabo. Freiburg; Selbstverlag 1933
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• 10 Sechehaye A, Balzli J. Umckaloabo in der inneren Behandlung der Tuberkulose. Reutlingen; Kommissionsverlag Knödler 1951
  Search in Google Scholar
• 11 Bladt S. Zur Chemie der Inhaltsstoffe der Pelargonium reniforme CURT.-Wurzel (Umckaloabo) [dissertation]. München; Ludwig-Maximilian-Universität 1974
  Search in Google Scholar
• 12 Kolodziej H. Fascinating metabolic pools of Pelargonium sidoides and Pelargonium reniforme, traditional and phytomedicinal sources of the herbal medicine Umckaloabo®.  Phytomedicine. 2007;  14 9-17 (Suppl. IV)
  Search in Google Scholar
• 13 Lattè K P, Kayser O, Tan N, Kaloga M, Kolodziej H. Unusual coumarin patterns of Pelargonium species forming the origin of the traditional herbal medicine umckaloabo.  Z Naturforsch. 2000;  55c 528-33
  PubMedSearch in Google Scholar
• 14 Kolodziej H, Kayser O, Gutman M. Arzneilich verwendete Pelargonien aus Südafrika.  Dtsch Apoth Ztg. 1995;  135 853-64
  PubMedSearch in Google Scholar
• 15 Kolodziej H. Pelargonium reniforme and Pelargonium sidoides: their botany, chemistry and medicinal use. In: Lis-Balchin M, editor Geranium and Pelargonium. London; Taylor & Francis 2002: 262-90
  Search in Google Scholar
• 16 Harvey W H, Sonder O W. Flora Capensis: Systematic description of the plants of Cape Colony, Caffraria and Port Natal. Dublin; Hodges, Smith & Co 1859: 1
  Search in Google Scholar
• 17 Knuth R. Geraniaceae. In: Engler A, editor Das Pflanzenreich. Leipzig; Engelmann 1912: IV
  Search in Google Scholar
• 18 Wettstein R. Handbuch der systematischen Botanik. Leipzig; Deiticke 1935
  Search in Google Scholar
• 19 Miller D. The taxonomy of Pelargonium species and cultivars, their origins and growth in the wild. In: Lis-Balchin M, editor Geranium and Pelargonium. London; Taylor & Francis 2002: 49-79
  Search in Google Scholar
• 20 Wagner H, Bladt S, Abraham D D, Lotter H. Neue Cumarine aus Pelargonium reniforme Curt.-Wurzel.  Tetrahedron Lett. 1974;  43 3807-8
  PubMedSearch in Google Scholar
• 21 Kolodziej H, Kiderlen A F. In vitro evaluation of antibacterial and immunomodulatory activities of Pelargonium sidoides and the related herbal drug preparation EPs® 7630.  Phytomedicine. 2007;  14 18-26 (Suppl. IV)
  Search in Google Scholar
• 22 Conrad A, Hansman C, Engels I, Daschner F D, Frank U. Extract of Pelargonium sidoides (EPs® 7630) improves phagocytosis, oxidative burst, and intracellular killing of human peripheral blood phagocytes in vitro. .  Phytomedicine. 2007;  14 46-51 (Suppl. VI)
  PubMedSearch in Google Scholar
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  PubMedSearch in Google Scholar
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  PubMedSearch in Google Scholar
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Herbert Kolodziej

Institute of Pharmacy

Pharmaceutical Biology

Freie Universität Berlin

Königin-Luise-Str. 2 + 4

14195 Berlin

Germany

Phone: +49-30-8385-3731

Fax: +49-30-8385-3729

Email: kolpharm@zedat.fu-berlin.de