An effective alternative to antibiotics in acute bronchitis?

By Ahmed Asiri

ABSTRACT:

Pelargonium sidoides DC is a perennial plant with tuberous rhizomes from the Geraniaceae. It is native to southern Africa, particularly the eastern coastal regions. P. sidoides has been used by indigenous people and traditional healers to treat indications such as diarrhoea, dysentery, cough, wounds, gastrointestinal diseases and tuberculosis (TB). Its activities are attributed to a combination of polyoxygenated compounds, such as coumarin derivatives, flavonoids, proanthocyanidins and gallic acids. The efficacy and safety of P. sidoides as a treatment of acute bronchitis and other respiratory tract infections has studied and confirmed by a considerable number of clinical trials, meta-analysis and systematic reviews. Currently, Umckaloabo® (Kaloba®) is a widely available licensed product to treat acute bronchitis and other respiratory tract infections in different European countries. Moreover, it can be consumed by adults and children over 6 years. However, it is not recommended to pregnant and lactating women due to lack of evidence to support its safety.

 

BOTANICAL CHARACTERISTICS and IDENTIFICATION:

Scientific name: Pelargonium sidoides DC. (Geraniaceae)

Related species: Pelargonium reniforme Curtis (also found in the trade)

Common Names: Umckaloabo, South Africa geranium, geranium root, Rabas (Ulbricht et al., 2010).

Geographical Origin: Eastern parts of South Africa, particularly Lesotho, Kwazulu-Natal and Eastern Cape.

Part used: The root of Pelargonium sidoides is used for several indications (Brendler and van Wyk, 2008).

 BOTANICAL CHARACTERISTICS and IDENTIFICATION:

sidoides is a small rosette-like perennial plant with tuberous rhizomes, and branched stems. The leaves are present as heart shaped and dark red to black small flowers (Brendler and van Wyk, 2008). It grows approximately to 25-50 cm in height, forming a helix of leaves around the base (Lewu et al., 2010). It is very similar morphologically and chemically to the related P. reniforme, but can be distinguished by its petals and sepals. P. sidoides has dark red petals rather than the pink of the P. reniforme. (Lewu et al., 2010). Moreover, the white margins of P. sidoides’ sepals contrast with the pink margins of P. reniforme (White, 2008). The leaves of P. sidoides are heart-shaped and cordate, while P. reniforme leaves are kidney -shaped (Bladt and Wagner, 2007).

In addition, it can be distinguished by the colour of the pollen (Bladt and Wagner, 2007). However, the botanical drugs derived from these species are very difficult to distinguish; therefore the most reliable method to do so is chemical analysis and identification. This can be applied by using chemical markers. P. sidoides has many unique compounds which can be used as markers, such as 7-Hydroxy-5, 6-dimethoxycoumarine (Umckalin) and 5, 6, 7-trimethoxycoumarin. While, reniformin, which is a novel diterpene found only in P. reniforme, is also a useful marker (Kolodziej, 2007). Other chemical similarities and differences will be discussed in the phytochemistry section.

 PLANT HISTORY AND ETYMOLOGY:

In 1897, Charles Henry Stevens, an English man from Birmingham, was diagnosed with tuberculosis. His doctor advised him to go to southern Africa, where the quality of air was considered to be better than in the UK. He travelled to southern Africa, where he met a traditional healer called Mike Kijitse, who prescribed him a decoction of – what was later identified as – P. sidoides. Stevens was ‘cured of TB’ after three months. In 1907, he established ’Stevens Co.’ to market the root, which he had brought from southern Africa. At that time, infectious diseases and TB spread dramatically and no treatment had been discovered yet. He sold it by the name ‘Stevens’ cure’. The medical establishment attempted to restrict illegal remedies such as Stevens’ cure. As a result, Stevens’ sales fell in the UK, so he tried to sell it abroad (Newsom, 2002).

A Swiss physician learned about Stevens’ product from a patient and began to treat TB patients with it. He collected information and documented all clinical follow-ups of his case studies. Many years later, Dr Adrien Sechehaye published his findings to demonstrate the efficacy of Stevens’cure. Stevens died in 1942; his son then sold his father’s business to a German drug company. In the 1970s, the plant was identified and the medicine’s mysterious ingredients unveiled by Dr Sabine Bladt (Bladt and Wagner, 2007). At this time, much interest and researches have done and the product developed. Stevens’ developed product was commercialised again to treat bronchitis and the common cold in the 1990s, while research continued. In 2005, P. sidoides (Umckaloabo® – EPs 7630) approved as a fully licensed herbal medicine in Germany and is listed in the European Pharmacopoeia (Brendler and van Wyk, 2008).

Umckaloabo was the name Stevens gave to the herbal extract he used in his ‘Stevens’ cure’. Many attempts have been made to elucidate the origin of this name. An interpretation by Bladt claims that it is composed of two Zulu terms: umKhulane, which is a term of several diseases that may be accompanied by fever or cough, and the term uHlabo, which refers to breast pain (Bladt, 1974 cited in Brendler and van Wyk, 2008). Heinrich et al. (2017) stated that the Umckaloabo is a fusion of two Zulu terms (“Umkuhlune” = Coughing and fever, fused with “Uhlabo” = chest pains) and this means linked to being “useful for deep cough” in Zulu. Another attempt stated that the might have been invented by Stevens to keep this plant mysterious and secret (Brendler and van Wyk, 2008). Despite the number of attempts made to discover it, the name’s origin is still questionable.

 TRADITIONAL and CONTEMPORARY USES:

Species of the genus Pelargonium have been used for many purposes in southern Africa. More than 35 plants, of which no less than six were Pelargonium species, have been documented as having been used as traditional medicines for different indications in southern Africa between 1650 and 1800 (Scott and Hewett, 2008). The most well-known species used are Pelargonium sidoides and Pelargonium reniforme. P. sidoides is native mainly to the eastern cape of southern Africa and the Lesotho mountains (Bladt and Wagner,2007) where the indigenous people used it in herbal remedies to treat ailments, such as diarrhoea, dysentery, wounds, gastrointestinal diseases and TB (Brendler and van Wyk, 2008). Despite Stevens’ introduction of this plant to the UK in 1907 as a secret remedy to treat TB, it has taken a long time for it to develop into a phytopharmaceutical product.

While it started as a herbal remedy, many case studies, pharmacological experiments and clinical studies have confirmed its efficacy and investigated its underlying pharmacological mechanism and phytochemistry. As a result, P. sidoides became a fully licensed medicine first in Germany in 2005 under the name of Umckaloabo®. Nowadays, it is marketed through health shops and pharmacies to treat upper respiratory tract infections, particularly acute bronchitis in adults and children.

PHYTOCHEMISTRY:

The phytochemistry of P. sidoides has been investigated comprehensively. Kolodziej (2007) studied the chemical compounds of P. sidoides and P. reniforme and compared them to the ethanolic extract used commercially (EPs 7630). P. sidoides extract is rich in polyoxygenated compounds, such as coumarins, coumarin sulfate, coumarin glycosides, phenolic acids, proanthocyanidins, flavonoids and phenylpropanoid derivatives (Kolodziej, 2007). Umckalin, 5, 6, 7, 8-trimethoxycoumarin (Artelin), 7, 8-Dihydroxy-6-methoxycoumarine (fraxetin) and 5, 6, 7-trimethoxycoumarin, are found exclusively in P. sidoides (Kolodziej, 2007Hauer et al. (2009) identified 6-methoxy-7-(sulfooxy)-2H-1-benzopyran-2-one and 6, 8-Bis(sulfooxy)-7-methoxy-2H-1 benzopyran-2-one for the first time in P. sidoides.It is thought that the immunomodulatory effects of P. sidoides are attributed to the combination of the numerous coumarins and phenolic compounds, while the anti-viral and antibacterial activities are due to the gallic acid and phenolic constituents (Kayser and Kolodziej, 1995; Kolodziej, 2007; Colling et al., 2010).

PRECLINICAL AND PHARMACOLOGICAL STUDIES:

A considerable number of in-vivo and in-vitro studies have been done on P. sidoides (most of preclinical and clinical studies used the ethanolic root extract EPs 7630). These studies aimed to investigate the actions of this extract and to understand the mechanisms behind them. Most of these studies addressed the effect of P. sidoides on acute bronchitis. Thus, this monograph will focus on this indication. A comprehensive review by Moyo and van Staden (2014) confirmed the multi-activity of P. sidoides as an antiviral, antibacterial, antimycobacterial, antifungal, antiparasitic and immunomodulatory agent by using in-vitro methods. It also addressed antiviral activity using an in vivo approach. P. sidoides exerts its effects due to the combined effects on different therapeutic targets.

First, the antibacterial activity is thought to act through three proposed mechanisms: by stimulating phagocytosis –ingestion and digestion of the pathogen by specific cells- (Hansmann, 2005 cited in Brendler and van Wyk, 2008), inhibiting adhesion of bacteria to human epithelial cells, (Daschner et al., 2004 cited in Brendler and van Wyk, 2008) and protecting mucus membranes from bacteria by modulating epithelial cell interaction (Wittschier et al., 2007).

Second, immunomodulatory properties enable non-specific activation of the immune system, stimulating natural killer cells (Kayser et al., 2003).

Third, it stimulates the ciliary beat frequency of human nasal epithelium which is a crucial defensive mechanism (Neugebauer et al., 2005). It is clear that different activities and mechanisms contribute to the effectiveness of P. sidoides in acute bronchitis and another respiratory tract infections. However, the precise mechanisms of the actions and the active compounds responsible for the effectiveness is complex and still undefined.

 CLINICAL STUDIES:                

A significant number of clinical trials have been conducted and reviewed regarding the use of P. sidoides for acute respiratory tract infections. Most of them involve acute bronchitis and compare EPs 7630, which is found in the final product, Umckaloabo®, with a placebo. Most of the findings have been assessed in meta-analyses and systematic reviews. The first systematic review and meta-analysis of Umckaloabo® for acute bronchitis was by Agbabiaka (2008) in which a total of six randomised clinical trials (RCTs) with 297 participants were included in order to assess the effectiveness of Umckaloabo® against a placebo in different doses for seven days. This study concluded that P. sidoides is effective when compared to a placebo for acute bronchitis. More recently, ten randomised, double-blind and controlled trials involving 1,771 participants with acute respiratory tract infections were reviewed in the Cochrane Database of Systematic Reviews (Timmer et al., 2013). Six of these trials (746 patients) involved the efficacy of P. sidoides in liquid and tablet preparations on adults and children with acute bronchitis. The authors concluded that P. sidoides may alleviate symptoms of acute bronchitis in both adults and children.

DOSAGES:

Generally, doses depend on the preparation and existing evidence on a specific product. The optimal doses of natural products are not clear. There is no standardisation for the ethanolic root extract (EPs 7630).

TOXICITY and INTERACTIONS:

Umckaloabo® is considered to be save to use for acute bronchitis for short periods (7 to 14 days) for adults (Conrad et al., 2007 cited in Brendler and van Wyk, 2008). and children above the age of 12. Children aged 6-12 years should take a lower dose and it is not recommended in younger children and infants. Some theoretical risks and toxicity of Umckaloabo due to the presence of coumarins such as cytotoxicity, liver and kidney toxicity are not confirmed and negligible (Kolodziej, 2003). In 2012 the German Federal Institute for Drugs and Medical Devices (BfArM) advised people who are taking Pelargonium root extracts to stop using the drug, and consult a doctor, if they notice symptoms of liver problems. Also, it is not established that the coumarins in Umckaloabo interact with anticoagulants (Brendler and van Wyk, 2008).

 PREGNANCY and LACTATION:

Umckaloabo® is not recommended for pregnant and lactating women due to the lack of data.

 SIDE EFFECTS:

World Health Organisation have been recorded 34 case reports of allergic reactions due to using Umckaloabo (de Boer et al., 2007).

INTELLECTUAL PROPERTY AND INDIGENOUS RIGHTS ASPECT:

sidoides is endemic to South Africa and Lesotho and used locally as traditional medicine. There are local and international pharmaceutical companies which harvest it from the wild to manufacture various phytomedicines. There are two main regulatory issues facing trading this phytomedicine internationally:

– The intellectual property rights (IPR) of the preparation methods of the plant and

– The right to harvest the bio-sources and the resulting economic opportunities.

As regards the latter issue, an integrated value chain of P. sidoides is used by pharmaceutical companies which is accepted by local and international authorities and offers good quality products. However, based on a critique by van Niekerk and Wynberg (2012) weak bargaining power, social and economic barriers to market access, lack of infrastructure, insecure land tenure systems and limited access to capital, credit and technology are problems which are typically faced by local producers of the primary material. In order to solve these problems for the rural poor to enter into exchange relations with sophisticated international companies on more equal terms. (van Niekerk and Wynberg, 2012). Unregulated value chains, have, on the other hand given rise to serious concerns about poor quality and adulterated products (Booker and Heinrich 2017)

Regarding intellectual property rights, Schwabe had two patents granted, one for the ethanolic extraction methods and one for the activity as an antiviral and antibacterial agent, but these were challenged. In 2010, various stakeholders including the Masakhane community sought to protect their own indigenous knowledge through intellectual property rights and successfully forced Schwabe to withdraw a patent related to Pelargonium. However, the community cannot expect to have a Benefit Sharing Agreement with Schwabe according to current Intellectual Property Laws law (Msomi and Matthews, 2015).

CONCLUSION:

Umckaloabo is considered a good example of an ethnobotanical-driven discovery of a phytomedicine. The efficacy of Umckaloabo for treating upper respiratory tract infections, particularly acute bronchitis, is confirmed by clinical studies and systematic reviews. Generally, it has a good safety profile. However, there are controversial issues regarding IPR and the rights of the indigenous community.

Disclaimer:

In this essay, we do not intend to advise or recommend herbs for medicinal or health use. This information is for educational purposes only and should not be considered as a recommendation or an endorsement of any particular medical or health treatment. The use of any such product should be based on the appropriate advice of a health care professional or based on the information available in the patient information leaflets (i.e. for THR products). The information provided should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.

© Ahmed Asiri, 2017. All Rights Reserved.

Ahmed Asiri, MSc student (2016 – 2017) in Medicinal Natural Products and Phytochemistry at the UCL School of Pharmacy, University of London. Research Cluster ‘Biodiversity and Medicines’ / Centre for Pharmacognosy and Phytotherapy, UCL School of Pharmacy, Univ. London, 29 – 39 Brunswick Sq., London WC1N 1AX

 

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