Planta Medica Journal of Medicinal Plant and Natural Product Research
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www.thieme.de/fz/plantamedica l www.thieme-connect.com/ejournals Planta Medica Journal of Medicinal Plant and Natural Product Research Editor-in-Chief Advisory Board Publishers Luc Pieters, Antwerp, Belgium John T. Arnason, Ottawa, Canada Georg Thieme Verlag KG Yoshinori Asakawa, Tokushima, Japan Stuttgart · New York Lars Bohlin, Uppsala, Sweden Rüdigerstraße 14 Senior Editor Mark S. Butler, S. Lucia, Australia D-70469 Stuttgart Adolf Nahrstedt, Münster, Germany João Batista Calixto, Florianopolis, Brazil Postfach 30 11 20 Claus Cornett, Copenhagen, Denmark D-70451 Stuttgart Hartmut Derendorf, Gainesville, USA Review Editor Alfonso Garcia-Piñeres, Frederick MD, USA Thieme Publishers Matthias Hamburger, Basel, Switzerland Jürg Gertsch, Zürich, Switzerland 333 Seventh Avenue Simon Gibbons, London, UK New York, NY 10001, USA De-An Guo, Shanghai, China www.thieme.com Editors Andreas Hensel, Münster, Germany Rudolf Bauer, Graz, Austria Kurt Hostettmann, Geneva, Switzerland Veronika Butterweck, Muttenz, Peter J. Houghton, London, UK Switzerland Ikhlas Khan, Oxford MS, USA Reprint Thomas Efferth, Mainz, Germany Jinwoong Kim, Seoul, Korea Irmgard Merfort, Freiburg, Germany Wolfgang Kreis, Erlangen, Germany © Georg Thieme Verlag KG Hermann Stuppner, Innsbruck, Austria Roberto Maffei Facino, Milan, Italy Stuttgart·New York Yang-Chang Wu, Taichung, Taiwan Andrew Marston, Bloemfontein, Reprint with the permission South Africa of the publishers only Matthias Melzig, Berlin, Germany Editorial Offices Eduardo Munoz, Cordoba, Spain Claudia Schärer, Basel, Switzerland Nicolas Oberlies, Greensboro NC, USA Tess De Bruyne, Antwerp, Belgium Nigel B. Perry, Dunedin, New Zealand Joseph Pfeilschifter, Frankfurt, Germany Peter Proksch, Düsseldorf, Germany Jose-Luis Rios, Valencia, Spain Kurt Schmidt, Graz, Austria Thomas Schmidt, Münster, Germany Thomas Simmet, Ulm, Germany Leandros Skaltsounis, Athens, Greece Han-Dong Sun, Kunming, China Ping-Jyun Sung, Pingtung, Taiwan Deniz Tasdemir, London, UK Arnold Vlietinck, Antwerp, Belgium Günther Vollmer, Dresden, Germany Heikki Vuorela, Helsinki, Finland Jean-Luc Wolfender, Geneva, Switzerland bYang Ye, Shanghai, China 260 Original Papers In Vitro Permeation of Mesembrine Alkaloids from Sceletium tortuosum across Porcine Buccal, Sublingual, and Intestinal Mucosa Authors Emmanuel A. Shikanga1, Josias H. Hamman2,3, Weiyang Chen 2, Sandra Combrinck 1, Nigel Gericke4, Alvaro M. Viljoen2 Affiliations 1 Department of Chemistry, Tshwane University of Technology, Pretoria, South Africa 2 Department of Pharmaceutical Sciences, Tshwane University of Technology, Pretoria, South Africa 3 Unit for Drug Research and Development, North-West University, Potchefstroom, South Africa 4 Medical & Scientific Affairs, HG&H Pharmaceuticals (Pty) Ltd., Bryanston, South Africa Key words Abstract as well as in the form of crude extracts. The intes- l" apparent permeability ! tinal permeability of mesembranol was similar to coefficient Sceletium tortuosum is an indigenous South Afri- that of caffeine, while those of mesembrenol and l" in vitro transport can plant that has traditionally been used for its mesembrenone were lower than that of caffeine, l" mesembrine alkaloids mood-enhancing properties. Recently, products but much higher than that of the poorly perme- l" Sceletium tortuosum l" Mesembryanthemaceae containing S. tortuosum have become increasingly able reference compound atenolol (which served l" Sweetana‑Grass diffusion popular and are commonly administered as tab- as a negative control for membrane permeabili- lets, capsules, teas, decoctions, or tinctures, while ty). In general, the permeabilities of the alkaloids traditionally the dried plant material has been were lower across the sublingual and the buccal masticated. This study evaluated the in vitro per- tissues than across the intestinal tissue. However, s personal reprint s personal reprint ʼ ʼ meability of the four major S. tortuosum alkaloids comparing the transport of the alkaloids with that (i.e., mesembrine, mesembrenone, mesembrenol, of the reference compounds, there are indications and mesembranol) across porcine intestinal, sub- that transport across the membranes of the oral lingual, and buccal tissues in their pure form and cavity may contribute considerably to the overall in the form of three different crude plant extracts, bioavailability of the alkaloids, depending on pre- namely water, methanol, and an acid-base alka- systemic metabolism, when the plant material is loid-enriched extract. The permeability of me- chewed and kept in the mouth for prolonged pe- sembrine across intestinal tissue was higher than riods. The results from this study confirmed the that of the highly permeable reference compound ability of the alkaloids of S. tortuosum in purified caffeine (which served as a positive control for or crude extract form to permeate across intesti- membrane permeability) both in its pure form, nal, buccal, and sublingual mucosal tissues. received June 30, 2011 revised October 17, 2011 This is a copy of the author This is a copy of theaccepted author October 25, 2011 Introduction to regulating the balance of neurochemicals in b! the brain [5,6]. Phosphodiesterase (PDE4) inhibi- Bibliography Sceletium tortuosum (L.) N.E. Br (Mesembryan- tion has been reported for an extract of S. tortuo- DOI http://dx.doi.org/ themaceae) is a succulent plant indigenous to sum [7], and of the mesembrine alkaloids tested 10.1055/s-0031-1280367 Published online November 21, South Africa that has traditionally been used as a for PDE4 inhibitory activity, mesembrenone was 2011 masticatory and as a remedy to treat ailments af- found to be the most potent [8], while mesem- Planta Med 2012; 78: 260–268 fecting the central nervous system [1,2]. The psy- brine-HCl was found to be a relatively weak inhib- © Georg Thieme Verlag KG choactive properties are ascribed to the four ma- itor of the enzyme [5]. There is strong in vivo ex- Stuttgart · New York · ISSN 0032‑0943 jor alkaloids: mesembrine, mesembrenone, me- perimental evidence that PDE4 inhibitors can re- sembrenol, and mesembranol, collectively re- verse depression, improve cognition and alleviate Correspondence ferred to as the mesembrine alkaloids [3]. The anxiety [9,10]. Sceletium tortuosum plants and Prof. Alvaro M. Viljoen (PhD) Department of Pharmaceutical plant and its products have been prescribed for extracts with relatively high mesembrenone con- Sciences the management of psychiatric and psychological tent, and isolated mesembrenone, can thus act as Tshwane University of conditions including depression, anxiety [4], drug dual serotonin reuptake inhibitors and PDE4 in- Technology Private Bag X680 dependence, bulimia, and obsessive-compulsive hibitors, while plant material relatively high in Pretoria 0001 disorder [3]. The potential for mesembrine alka- mesembrine and isolated mesembrine can act as South Africa loids to treat central nervous system disorders highly selective serotonin reuptake inhibitors. Phone: + 27123826360 Fax: + 27123826243 has been attributed to their capacity to act as se- The therapeutic advantages of dual inhibition of [email protected] rotonin reuptake inhibitors, thereby contributing serotonin reuptake and PDE4 inhibition include Shikanga EA et al. In Vitro Permeation… Planta Med 2012; 78: 260–268 Original Papers 261 the possibility of using a lower dose to achieve enhanced efficacy, Pharmaceutical Sciences (Tshwane University of Technology, Pre- with a reduced side effect profile [11]. toria, South Africa). Krebs Ringer bicarbonate buffer was pur- Sceletium tortuosum has also been found to improve relaxation chased from Sigma Aldrich. Medical oxygen was obtained from and social interaction [1], in addition to the treatment of insom- Afrox Ltd. nia and digestive problems in both children and adults [1,12]. Although clinical in vivo studies [4,13] and in vitro experiments Preparation of extracts [5] confirmed the pharmacological effects of S. tortuosum and its Three crude extracts of S. tortuosum (aerial parts) were prepared alkaloid constituents, reports on bioavailability studies of these by utilising different solvents. For the MeOH extract, 20 g of dry compounds are lacking, and no information is available on the plant powder (≤ 0.5 mm particle size, Endecotts test sieve from permeability of mesembrine alkaloids across intestinal, buccal, Protea Holdings Ltd.; 600 W Salton Elite blender) was extracted and sublingual mucosal tissues. thrice with 60 mL of MeOH. The plant-MeOH mixture was shaken Traditionally, the aerial parts of S. tortuosum were consumed as a for 10 min at 200 rpm using a Labcon platform shaking incubator masticatory, and in the form of decoctions, teas, and tinctures [1, (Laboratory Marketing Services CC). The resulting filtered ex- 4], but the dry plant material has also been smoked and powdered tracts (Whatman no. 4 filter paper; Macherey-Nagel) were com- plant material inhaled as a snuff [14]. Currently, S. tortuosum bined and concentrated under reduced pressure (Buchi rotavapor products are commercially available as tablets, capsules, teas, R-200); whereafter they were dried in a vacuum oven (Vismara sprays, extracts, and tinctures [15]. The increase in the demand srl Scientific Equipment-Technical service, Model Vo 65) at 40 °C for and the consumption of S. tortuosum products are evident by under 0.2 bar pressure. the rapid rise in the establishment of commercial plantations and The water extract was prepared by adding 60 mL of water to 20 g companies