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Pelargonium sidoides:
nuovo rimedio per le malattie da raffreddamento

Ha origini sudafricane il nuovo rimedio naturale per le affezioni tipiche della stagione invernale: il Pelargonium sidoides. Era anticamente conosciuta per l'utilizzo popolare contro la tubercolosi e oggi impiegata nel trattamento di affezioni dell'apparato respiratorio, come raffreddore ed influenza. Sembra che le propriet terapeutiche della pianta siano state scoperte solo alla fine del secolo scorso grazie alle vicende di un militare inglese, che contratta la tubercolosi in SudAfrica, venne curato con un decotto di Pelargonium. Sembra che rientrato in Europa nel 1897 il militare abbia presentato la nuova pianta che venne poi impiegata con successo in molti casi di tubercolosi. L'interesse del mondo scientifico verso questa pianta medicinale della tradizione popolare stato risvegliato dai riscontri sulle sue propriet antibatteriche e sulle sue potenzialit come rimedio efficace contro le patologie otorinolaringoiatriche quali per esempio tonsillite, bronchite, sinusite e rinofaringite. Infatti, anche alcuni studi di laboratorio condotti sulla pianta ne hanno confermato e dimostrato spiccate attivit come immunostimolante e moderate propriet antibatteriche ad ampio spettro. Dalla pianta di utilizzano gli estratti ottenuti dalle radici ricchi in fenoli semplici (principalmente l'acido gallico) e proantocianidine cui sono state associate le attivit antibatteriche, immunostimolanti e mucoregolatrici della pianta. Il rimedio impedisce la riproduzione dei germi patogeni impedendone la penetrazione nelle cellule della mucosa, aumenta le difese immunitarie impedendo l'adesione dei virus alle cellule della mucosa infine fluidifica il muco migliorando notevolmente la respirazione. Alla luce dei documentati benefici terapeutici del Pelargonium sidoides nel trattamento delle vie respiratorie, si deve notare che gli estratti della radice mediano significative attivit simili a quelle dell'interferone notoriamente implicato nei meccanismi fisiologici di immunostimolazione. Per quanto riguarda l'attivit antimicrobica della pianta studi di laboratorio hanno evidenziato che il rimedio moderatamente attivo contro una serie di batteri responsabili di diverse affezioni delle vie respiratorie; in particolare stata studiata l'azione del Pelargonium sidoides nei confronti di ceppi particolarmente resistenti di Staphylococcus aureus. Mentre molti antibiotici (ciproflloxacina, eritromicina, clindamicina, ossitetraciclina...) non hanno mostrato azione nei confronti di questi ceppi resistenti, il Pelargonium ha mostrato una migliore attivit antibatterica. Uno studio ha valutato l'efficacia dell'estratto di

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Pelargonium contro placebo in 143 bambini con faringotonsillite e ha concluso che il gruppo dei bambini trattati ha diminuito la severit dei sintomi della malattia e ridotto di circa due giorni la durata della malattia. Un altro studio condotto da 468 pazienti adulti affetti da bronchite acuta furono trattati con Pelargonium Sidoides a confronto con placebo; i risultati mostrarono che il rimedio riduce i sintomi di bronchite acuta in tre-sette giorni. Nonostante il sintomo della tosse possa persistere pi a lungo i pazienti sono comunque in grado di ritornare a lavoro prima rispetto al gruppo trattato con placebo. Attualmente sono in corso ulteriori studi sulla pianta per approfondire le sue modalit di azione e le sue applicazioni terapeutiche.

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Pelargonium
Scientific Name(s): Pelargonium sidoides DC., Pelargonium reniforme Curt. Family: Geraniaceae Common Name(s): African geranium , Umckaloaba (Zulu language, severe cough), kalwerbossie , Rabassamin , Zucol

Uses of Pelargonium
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.

Pelargonium 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.

Pelargonium Interactions
None well documented.

Pelargonium 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

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document allergic reactions associated with the use of Pelargonium extract.

Toxicology
No animal toxicology studies have been reported.

Botany
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

History
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.

Chemistry
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

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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

Pelargonium Uses and Pharmacology

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

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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 tonsillopharyngitis. 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

Dosage
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 Children < 6 years of age Children 6 to 12 years of age > 12 years of age Dosage regimen 10 drops 3 times a day 20 drops 3 times a day 30 drops 3 times a day

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

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

Interactions

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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

Adverse Reactions
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

Toxicology
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 .

Bibliography
1. Kolodziej H. Fascinating metabolic pools of Pelargonium sidoides and Pelargonium reniforme , traditional and phytomedicinal sources of the herbal medicine Umckaloabo . Phytomedicine . 2007;14(suppl 6):9-17. 2. Kolodziej H, Berlin OK. Pelargonium sidoides DC.: Latest findings towards understanding the phytotherapeutic preparation Umckaloabo. Z Phytother . 1998;19:141-151. 3. Bladt S, Wagner H. From the Zulu medicine to the European phytomedicine Umckaloabo. Phytomedicine . 2007;14(suppl 6):2-4. 4. Lewu FB, Grierson DS, Afolayan AJ. Clonal propagation of Pelargonium sidoides : a threatened medicinal plant of South Africa. Afr J Biotechnol . 2006;5:123-125. 5. Kolodziej H. Traditionally used Pelargonium species: Chemistry and biological activity of umckaloabo extracts and their constituents. Curr Top Phytochem . 2000;3:77-93. 6. Patrick G, Hickner J. This obscure herb works for the common cold. J Fam Pract . 2008;57(3):157-161. 7. Seidel V, Taylor PW. In vitro activity of extracts and constituents of Pelargonium against rapidly growing mycobacteria. Int J Antimicrob Agents . 2004;23(6):613-619. 8. Kolodziej H, Burmeister A, Trun W, et al. Tannins and related compounds induce nitric oxide synthase and cytokines gene expressions in Leishmania major -infected macrophage-like RAW 264.7 cells. Bioorg Med Chem . 2005;13(23):6470-6476. 9. Schoetz K, Erdelmeier C, Germer S, Hauer H. A detailed view on the constituents of EPs 7630 . Planta Med . 2008;74(6):667-674. 10. Kayser O, Latte K, Kolodziej H, Hammerschmidt F. Composition of the essential oils of Pelargonium sidoides DC and Pelargonium reniforme Curt. Flavour Fragrance J . 1998;13(3):209-212. 11. Wagner H, Bladt S. Neue cumarine aus Pelargonium reniforme Curt.-wurzel. Tetrahedron Lett . 1974;43:3807-3808. 12. Wagner H, Bladt S. Cumarine aus Sdafrikanischen Pelargonium -arten. Phytochem . 1975;14:2061-2064. 13. Kayser O, Kolodziej H. Highly oxygenated coumarins from Pelargonium sidoides . Phytochemistry . 1995;39:1181-1185.
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14. Kolodziej H, Kayser O, Tan N. Novel coumarin sulfates from Pelargonium sidoides : isolation, structure and synthetic approach. Proc Phytochem Soc Eur . 2002;47:59-64. 15. Latt KP, Ferreira D, Venkatraman MS, Kolodziej H. O -galloyl- C -glycosylflavones from Pelargonium reniforme . Phytochemistry . 2002;59(4):419-424. 16. Goedecke T, Kaloga M, Kolodziej H. A phenol glucoside, uncommon coumarins and flavonoids from Pelargonium sidoides DC. Z Naturforsch B . 2005;60:677-682. 17. Kolodziej H, Schutz V. Umchaloabo-from traditional application to modern phytodrug. Independent Pharm J Sci Prac . 2003;12:9. 18. Kayser O, Kolodziej H. Antibacterial activity of extracts and constituents of Pelargonium sidoides and Pelargonium reniforme . Planta Med . 1997;63(6):508-510. 19. Kolodziej H, Kayser O, Radtke OA, Kiderlen AF, Koch E. Pharmacological profile of extracts of Pelargonium sidoides and their constituents. Phytomedicine . 2003;10(suppl 4):18-24. 20. Kayser O, Kolodziej H, Kiderlen AF. Immunomodulatory principles of Pelargonium sidoides . Phytother Res . 2001;15(2):122-126. 21. Koch E, Lanzendrfer-Goossens, Wohn C. Stimulation of interferon (IFN)--synthesis and natural killer (NK) cell activity by an aqueous-ethanolic extract from roots of Pelargonium sidoides (Umckaloabo). Naunyn-Schmiederberg's Arch Pharmacol . 2002;365(suppl 1):R75. 22. Mativanlela SP, Meyer JJ, Hussein AA, Lall N. Antitubercular activity of compounds isolated from Pelargonium sidoides . Pharm Biol . 2007;45(8):645-650. 23. Neugebauer P, Mickenhagen A, Siefer O, Walger M. A new approach to pharmacological effects on ciliary beat frequency in cell culturesexemplary measurements under Pelargonium sidoides extract ( EPs 7630 ). Phytomedicine . 2005;12(1-2):46-51. 24. Agbabiaka TB, Guo R, Ernst E. Pelargonium sidoides for acute bronchitis: a systematic review and meta-analysis. Phytomedicine . 2008;15(5):378-385. 25. Matthys H, Eisebitt R, Seith B, Heger M. Efficacy and safety of an extract of Pelargonium sidoides ( EPs 7630 ) in adults with acute bronchitis. A randomised, double-blind, placebocontrolled trial. Phytomedicine . 2003;10(suppl 4):7-17. 26. Chuchalin AG, Berman B, Lehmacher W. Treatment of acute bronchitis in adults with a Pelargonium sidoides preparation ( EPs 7630 ): a randomized, double-blind, placebo-controlled trial. Explore (NY) . 2005;1(6):437-445. 27. Haidvogl M, Graz R, Schuster M, Heger E. Acute bronchitis in childhood. Zeitschrift fur Phytotherapie . 1996;17(5):19. 28. Golovatiouk A, Chuchalin AG. Efficacy of an extract from Pelargonium sidoides (EPs 7630) compared to placebo in patients with acute bronchitis. Phytopharmaka VIII . 2002:3-12. 29. Matthys H, Heger M. EPs 7630 -solutionan effective therapeutic option in acute and exacerbating bronchitis. Phytomedicine . 2007;14(suppl 6):65-68. 30. Matthys H, Kamin W, Funk P, Heger M. Pelargonium sidoides preparation ( EPs 7630 ) in the treatment of acute bronchitis in adults and children. Phytomedicine . 2007;14(suppl 6):69-73. 31. Schulz V. Liquid herbal drug preparation from the root of Pelargonium sidoides is effective against acute bronchitis: results of a double-blind study with 124 patients. Phytomedicine . 2007;14(suppl 6):74-75. 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. 33. Heger M, Bereznoy VV. Non-streptococcal tonsillo-pharyngitis in children: Efficacy of an extract from Pelargonium sidoides ( EPs 7630 ) compared to placebo. Phytopharmaka VII Darmstadt: Steinkopff Verlag . 2002. 34. Beil W, Kilian P. EPs 7630 , an extract from Pelargonium sidoides roots inhibits adherence of Helicobacter pylori to gastric epithelial cells. Phytomedicine . 2007;14(suppl 6):5-8. 35. Wittschier N, Faller G, Hensel A. An extract of Pelargonium sidoides ( EPs 7630 ) inhibits in situ adhesion of Helicobacter pylori to human stomach. Phytomedicine . 2007;14(4):285-288.

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36. de Boer HJ, Hagemann U, Bate J, Meyboom RH. Allergic reactions to medicines derived from Pelargonium species. Drug Saf . 2007;30(8):677-680. 37. Koch E, Biber A. Treatment of rats with the Pelargonium sidoides extract EPs 7630 has no effect on blood coagulation parameters or on the pharmacokinetics of warfarin. Phytomedicine . 2007;14(suppl 6):40-45. Copyright 2009 Wolters Kluwer Health ;

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