Pelargonium

March 2009

Pelargonium sidoides DC., Pelargonium reniforme Curt. Family: Geraniaceae

African geranium , Umckaloaba (Zulu language, severe cough), kalwerbossie , Rabassamin , Zucol

Uses

P. sidoides and P. reniforme are marketed as Umckaloaba or Zucol for bronchitis and pharyngitis. The plant species has also been investigated for use in treating gastritis. Despite a murky beginning in early 20th century herbal promotions, there appears to be some evidence for efficacy in treating bronchitis due to Pelargonium's direct antibiotic effect and host immune stimulation.

Dosing

Clinical trials have used doses of extract corresponding to 1.2 g of plant material daily without adverse reactions. Manufacturer dosage guidelines for Zucol suggest 3 lozenges every day for 6 days, even if symptoms are reduced.

Contraindications

Avoid use with hypersensitivity to any of the components in EPs 7630 or Pelargonium species. Avoid use in patients with serious kidney or liver diseases.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. One report recommends caution if used during pregnancy.

Interactions

None well documented.

Adverse Reactions

Clinical trials enrolling nearly 2,500 adults and children document mostly allergic reactions or GI complaints (eg, gastric pain, heartburn, nausea, diarrhea). In Germany, pharmacovigilance studies document allergic reactions associated with the use of Pelargonium extract.

Toxicology

No animal toxicology studies have been reported.

The genus Pelargonium comprises approximately 280 known species, of which 80% are grown in the interior of South Africa. ¹ Both of the title plant species are distinguished by the color of the flowers, the shape of the leaves, and the pollen color. P. sidoides is a small geranium-like plant that grows in a rosette from thick and very dark brown underground roots that grow up to 15 cm in length. Sparsely branched stems grow from the base and display deep red to black flowers, and the species is distinguished by the cordate or heart-shaped leaves. The pollen of the plant species is yellow. In contrast, P. reniforme has magenta red to black flowers, kidney-shaped leaves, and white to green pollen. ^2, , ^3, Both plant species may be found along the seacoast and interior portions of South Africa. Because of poor seed viability, a clonal method of propagation has been developed to reduce pressure on natural populations. ⁴

The plant species indigenous to areas of South Africa are widely used by traditional healers of the Zulu, Basuto, Xhosa, and Mfengi tribes to treat dysentery, diarrhea, hepatic complaints, wounds, colds, fatigue, fevers, generalized weakness, and infections of the respiratory tract including tuberculosis. ^4, , ⁵ Western use of the P. sidoides and P. reniforme species to treat tuberculosis is traced back to the Englishman Major Charles Stevens in 1897 when he was treated by a tribal healer with an extract from the roots of Pelargonium species. ²

Originally, the plant source of the drug was identified as P. reniforme ; however, further botanical investigations discovered the closely related species P. sidoides , which is now predominately used for therapeutic purposes. ²

P. sidoides has been marketed under the brand name Umckaloaba and has been widely used in Europe since the 1980s. Economically, annual sales for the product in 2002 were $55 million or 4.1 million packages. ⁶ The product is marketed as Zucol in the United States and is widely available. EPs 7630 is an ethanolic extract of the roots of P. sidoides , which is marketed by ISO-Arzneimittel under license from Schwabe.

Chemical analyses have led to characterization of about 65 metabolites including phenolic and cinnamic acids, tannins, flavonoids, and coumarins in both plant species. ^5, , ^7, , ⁸ Extracts of P. sidoides are composed of 6 main components that account for 70% to 80% of the total weight: substituted and unsubstituted oligomeric prodelphinidins, monomeric and oligomeric carbohydrates, minerals, peptides, purine derivatives, and highly substituted benzopyranones. ^9, Nearly 230 components have been detected in each of the plant species' essential oils, with sesquiterpenes the most abundant. ¹⁰

Coumarin, 5,6-dimethoxy,7-hydroxy-coumarin, and several related ethers, glycosides, and sulfates have been isolated from both species of Pelargonium . ^11, , ^12, , ^13, , ¹⁴ Many of these coumarins also are found in the roots of other South African Pelargonium species. ¹² A series of galloyl C-glycosidic flavones, along with related nongalloyl flavones, have been isolated from P. reniforme aerial parts. ¹⁵ P. sidoides contains similar flavonoids and phenolics. ^16, The high tannin content (about 9%) may justify the plant's use in GI complaints in cases of bacterial toxin-induced secretory diarrhea. The broad spectrum of activity against viruses and bacteria may be caused by the coumarins and phenolic acids. ^1, , ²

Numerous in vitro, animal, and clinical studies document the plant's antibacterial activity. Several fairly large clinical trials examine the plant's efficacy in treating acute bronchitis, common cold, and pharyngitis or sore throat. ¹⁷

Antibacterial activity

In vitro data The extracts of both Pelargonium species have modest direct antibacterial activity, with isolated coumarins and phenolics having minimum inhibitory concentration values from 200 to 1,000 mcg/mL in agar dilution assays versus common test bacteria. ^18, Unsaturated fatty acids from the roots, especially linoleic acid, had antimycobacterial activity at 2 mcg/mL in vitro. ⁷

Immune stimulation of the host is a potential course for antimycobacterial activity. Immune stimulation by P. sidoides extracts, coumarins, and phenolics has been documented in a variety of functional assays, ^19, , ^20, including enhancement of interferon-beta synthesis and activation of natural killer cell activity. ^21, Tannins from the plant induced nitric oxide synthase and cytokine gene expression in a macrophage-like cell line. ^8, The butanol root extract has antimycobacterial activity. ²²

Ciliary beat frequency increased in a model system after exposure to EPs 7630 extract. ²³ The effect was reversible and may be relevant in diverse lung and airway infections because cilia are important in removal of bacteria and foreign particulates.

Bronchitis A meta-analysis of 4 randomized clinical trials, including 1,647 patients, supported the plant's efficacy in reducing bronchitis symptoms. The mechanism of action is associated with EPs 7630 antagonism of bacterial adhesion to intact epithelia, leading to protection from bacteria colonization and infection in the upper respiratory tract. ²⁴

Clinical data Clinical trials of EPs 7630 in acute bronchitis have been conducted in children and adults. ^25, , ^26, , ^27, , ^28, , ^29, , ^30, , ³¹ The primary outcome or review of efficacy for most of the trials are changes in the Bronchitis Severity Score (ie, coughing, expectoration, chest pain, dyspnea, wheezing) from baseline versus the last observation (ie, final observation typically within 1 week). Inclusion criteria involved patients diagnosed with acute bronchitis within 48 hours who were not receiving antibiotic therapy, and who had no obvious contraindications to therapy. Dosage regimens included either EPs 7630 solution (30 to 90 drops per day) or tablets (10 to 30 mg per day), or placebo for 7 days. Results document the efficacy of EPs 7630 versus placebo in reducing severity of symptoms, improving quality of life, and shortening the duration of sick leave by nearly 2 days. The therapy was well tolerated, with no serious adverse reactions during the trials examined.

Pharyngitis The mechanism of action may be associated with EPs 7630 antagonizing bacteria and virus adhesion to the tonsil surface or site of infection. ³²

Clinical data In 2 multicenter, prospective, randomized clinical trials, EPs 7630 was more effective than placebo in the initial treatment of children (6 to 10 years of age) with acute nonstreptococcal tonsillo-pharyngitis. Patients treated with EPs 7630 had reduced severity of symptoms and shortened duration of illness by at least 2 days. The therapy also protected against complications. The treatment regimen consisted of 20 drops 3 times a day (3 mL per day), 30 minutes before or after meals for a maximum period of 6 days. No serious adverse reactions were reported. ^32, , ³³

Other pharmacological activity

Gastritis EPs 7630 inhibited Helicobacter pylori growth and reduced bacterial adherence to gastric epithelial adrenogenital syndrome cells. EPs 7630 suppressed H. pylori growth in brain-heart infusion broth at a concentration of 100 mcg/mL and reduced H. pylori adherence at concentrations of 50 mcg/mL or more. The mechanism of action is primarily related to its antiadhesion activity. ^34, , ³⁵

EPs 7630 is an 11% aqueous ethanolic extract in which 100 g of finished product corresponds to 8 g of extracted plant material. One clinical trial administered 4.5 mL 3 times daily for 7 days, corresponding to a total daily dose of plant material of approximately 1.2 g. ^25, A second trial used the same dosing schedule. ^26, Other dosage regimens used in clinical trials include the following ¹⁷ :

Other Dosage Regimens Used in Clinical Trials
Age	Dosage regimen
Children < 6 years of age	10 drops 3 times a day
Children 6 to 12 years of age	20 drops 3 times a day
> 12 years of age	30 drops 3 times a day

Manufacturer dosage guidelines for Zucol suggest 3 lozenges every day for 6 days, even if symptoms are reduced.

Information regarding safety and efficacy in pregnancy and lactation is lacking. One report recommends caution if used during pregnancy. ³⁶

An interaction may be possible when patients are receiving anticoagulant medications (eg, warfarin) or antiplatelet drugs (eg, aspirin). However, a study in rats documented no pharmacokinetic or pharmacodynamic interactions between EPs 7630 and warfarin. ^36, , ³⁷

Clinical trials enrolling nearly 2,500 adults and children document mostly allergic reactions or GI complaints (eg, gastric pain, heart burn, nausea, diarrhea). In Germany, pharmacovigilance studies found case reports of allergic reactions associated with the use of Pelargonium extract. ^36, Additional surveillance studies document similar results. ²⁸

No reports on toxic effects of EPs 7630 are available. One investigation noted weak cytotoxic effects on coumarins in 2 human cell lines (lung carcinoma GLC4 and colorectal cancer cells COLO 320). Similar results were observed in a Salmonella reversion test. The toxic potential was classified as safe according to results from an assay on Artemia salina (brine shrimp) using extracts of EPs 7630 .

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32. Bereznoy VV, Riley DS, Wassmer G, Heger M. Efficacy of extract of Pelargonium sidoides in children with acute non-group A beta-hemolytic streptococcus tonsillopharyngitis: a randomized, double-blind, placebo-controlled trial. Altern Ther Health Med . 2003;9(5):68-79. PubMed

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