H. P. T. Ammon Boswellic Acids in Chronic Inflammatory Diseases Review Abstract CHE: Cholinesterase Con A: Concanavalin A Oleogum resins from Boswellia species are usedin traditional COX1: Cyclooxygenase 1 medicine in India and African countries for the treatment of a COX2: Cyclooxygenase 2 variety of diseases. Animal experiments showed anti-inflamma- cPLA: Phospholipase A tory activity of the extract. The mechanism of this action is due to CRP: C-reactive protein some boswellic acids. It is different from that of NSAID and is EC50: Effective concentration 50 relatedto components of the immune system. The most evident ESR: Erythrocyte sedimentation rate action is the inhibition of 5-lipoxygenase. However, other factors FEV1: Forcedexpiratory volume in 1 sec (liters) such as cytokines (interleukins andTNF- a) andthe complement FLAP: 5-Lipoxygenase activating protein system are also candidates. Moreover, leukocyte elastase and fMLP: n-Formyl-methionyl-leucyl-phenylalanin oxygen radicals are targets. Clinical studies, so far with pilot FVC: Forcedvital capacity (liters) character, suggest efficacy in some autoimmune diseases includ- HAB: Homöopathisches Arzneibuch ing rheumatoidarthritis, Crohn's disease,ulcerative colitis and (German homeopathic pharmacopoeia) bronchial asthma. Side effects are not severe when compared to 5-HETE: 5-Hydroxyeicosatetraenoic acid modern drugs used for the treatment of these diseases. 12-HETE: 12-Hydroxyeicosatetraenoic acid 12-HHT: 12-Hydroxyheptadecatrienoic acid Key words HLE: Human leucocyte elastase Boswellic acids ´ anti-inflammatory actions ´ immune system ´ IC50: Inhibitory concentration 50 leukotrienes ´ chronic bowel diseases ´ arthritis ´ bronchial asth- 5-LO: 5-Lipoxygenase ma IKK: IkBa kinase IL-1: Interleukin-1 Abbreviations IL-2: Interleukin-2 AKBA: Acetyl-11-keto-b-boswellic acid KBA: 11-Keto-b-boswellic acid BA: Boswellic acid LPS: Lipopolysaccharide BE: Extract from oleogum resin of Boswellia serrata LTB4: Leukotriene B4 BS: Boswellia serrata LTC4: Leukotriene C4 BSA: Bovine serum albumin LTD4: Leukotriene D4 2+ This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. [Ca ]: Cytosolic calcium concentration LTE4: Leukotriene E4 Affiliation Dept. of Pharmacology, Institute of Pharmaceutical Sciences, University of Tuebingen, Tuebingen, Germany Dedication In memory of Prof. E. Reinhard Correspondence Prof. H. P. T. Ammon ´ Pharmakologie ´ Universität Tübingen ´ Auf der Morgenstelle 8 ´ 72076 Tuebingen ´ Germany ´ Phone: +49-7071-297-4675 ´ Fax: +49-7071-392-476 ´ E-mail: [email protected] Received April 24, 2006 ´ Accepted June 15, 2006 Bibliography Planta Med Georg Thieme Verlag KG Stuttgart ´ New York DOI 10.1055/s-2006-947227 ´ Publishedonline 2006 ISSN 0032-0943 MAPK: Mitogen activatedprotein kinase PHA: Phytohaemagglutinin MCH: Mean corpuscular haemoglobin PI3-K: Phosphatidylinositol 3-kinase MCHC: Mean corpuscular haemoglobin concentration PMNs: Polymorphonuclear neutrophils MCV: Mean corpuscular volume RAS: 21 kDA-GTP-binding protein MEK: Mitogen activatedprotein kinase kinase TA: Tirucallic acid NSAID: Non-steroidal anti-inflammatory drug TH1: T-Helper cells 1 P38: p38 kinase TH2: T-Helper cells 2 P42: p42 kinase TNFa: Tumor necrosis factor a PEFR: Peak expiratory flowrate PGF 1a: Prostaglandin F 1a nd th Review Introduction 2 century AD andin Astangahrdaya Samhita, 7 century AD). Medical preparations containing the bark or the oleogum resin In the last decade preparations from the oleogum resin of were used to treat a variety of diseases. These included diseases Boswellia serrata (BS) andother Boswellia species, also called of the respiratory tract like cough, other respiratory problems, as frankincense or olibanum, have become more andmore popular well as diarrhoea, constipation, flatulence, central nervous dis- in some European countries for the treatment of a variety of eases andothers (Table 1). chronic inflammatory diseases including rheumatoid arthritis, chronic bowel diseases, bronchial asthma, peritumoural brain Olibanum was still a remedy in the beginning of the 20th century oedema and others. This review summarises the present evi- in Europe. Thus, olibanum is mentionedin the supplement to the dence of pharmacological actions and clinical outcome of bos- 6th edition of the German Pharmacopoeia, which appeared in wellic preparations with special reference to the actions of bos- 1926. Thereafter, olibanum disappeared from medical treat- wellic acids. ments due to the lack of scientific evidence be it pharmacological or clinical. Scientists of the Regional Research Laboratory in Jam- mu (India) were the first to describe anti-inflammatory proper- Historical Background ties of an extract of the oleogum resin of BS in animal models in the years up to 1986. After the detection of the inhibitory effects Incense was known to all the ancient civilisations andusedin ri- of the extract on leukotriene synthesis in 1991, the subject re- tuals andprayers to the gods.Frank (ªpureº) incense andmyrrh ceivedlarge interest in the scientific world. were the finest andmost scarce, producedonlyin a small area of the Arabian peninsula, Somalia andEthiopia. Because of their rarity andgreat cost, the gifts of the Magi were a sign of wealth and sacrifice. Beyond that, there is medical evidence that gold, Table 1 Therapeutic uses of Salai guggal in the traditional Indian Ayurvedic medicine (from [2]) frankincense andmyrrh were important for woundhealing, usedby many cultures andsocieties for thousandsof years. The Organs and functional systems Effects Babylonians, Hindus, Buddhists, Chinese, Shintoists, Greeks and Romans incorporatedthe use of incense in their ritualistic cere- Nervous system Analgesic monies. Mental tonic Stimulation Eye tonic The oldest written document, which mentions frankincense as a Cardiovascular system Cardiotonic drug is the papyrus Ebers. In 1873, the Professor of Egyptology, Gastrointestinal tract Regulating colour of stool Moritz Fritz Ebers receiveda more than 20 m long papyrus from Carminative, stomachic an Arab businessman. It hadbeen foundeleven years before be- Improving digestion, antidiarrhoeic Improving taste tween the legs of a mummy in Luxor. It containedpractical infor- Anthelmintic This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. mation for medical doctors regarding diagnosis and treatment of Urogenital system Diuretic internal diseases with about 900 prescription formulae. It was Aphrodisiac Improving menstruation probably written about 1500 BC at the time of Pharaoh Ameno- Fever Antipyretic phis I [1]. Skin Increases perspiration Wound cleaning Remedies containing preparations from frankincense (here Whole organism Anti-inflammatory Boswellia carterii Birdw.) were used by Hippocrates, Celcus, Gale- Antiseptic nus andDioskurides[1]. Main external uses of Boswellia carterii Reducing fat Haemostypic Birdw. preparations were treatment of tumours, carcinomas and Connecting tissue oedemas. Moreover, inflammatory diseases including diarrhoea Decreasing Kapha diseases and diseases of the respiratory tract were treated. (in Ayurvedic nomenclature) The use of the oleogum resin of Boswellia serrata (BS) salai gug- gal is described in Ayurvedic text books (Charaka Samhita, 1st - Ammon P. Boswellic Acids in¼ Planta Med Botanical Aspects thors reported marked differences in different species. A striking difference was observed in the content of the main active bos- Incense is the oleogum resin produced in the bark of different wellic acids AKBA and KBA. It is evident that the Indian sample Boswellia species belonging to the family of Burseraceae. Some containedquite similar amounts of AKBA andKBA whereas the of them are listedin Table 2. African samples containedless KBA than AKBA. Interestingly, as discussed later, in pharmacokinetic studies with extracts from The author is aware that the chapters dealing with the historical Boswellia serrata oleogum resin only little AKBA was foundin and botanical aspects are rather incomplete and, for details, the the plasma if comparedto KBA. A new pentacyclic triterpene study of special historical, botanical and phytochemical litera- from BS, i.e., 3a-acetyl-20(29)-lupene-24-oic acidwas recently ture [1] is suggested. identified by Beisner et al. [4]. Employing a commercial extract from BS (H 15 AyurmedicaTM), ~2.6 mg/100 mg KBA and ~2.8 mg/100 mg AKBA were detected on average in 11 different Composition of Oleogum Resins lots [5]. Ganzera et al. [6] studied 4 different commercial pro- ducts containing the oleogum resin of BS together with up to 10 Review More than 200 different compounds were identified in the oleo- other plant extracts. Considering the manufacturer's dosing re- gum resin of different Boswellia species. Main components are commendations, the daily intake of total boswellic acids varies volatile oil, pure resin andmucus. The content of these differs up to 6-fold(18.49 to 109.62 mg per day).Hamm et al. [7] tested from species to species, between different harvestings and differ- volatile andsemi-volatile terpenes from 6 differentolibanum ent locations. An approximate composition of some oleogum re- samples, i.e., B. carterii, B. sacra, B. serrata, B. papyfera and B. sins is listedin Table 3. The resins of Boswellia species contain frereana. The chemical composition was different in all species pentacyclic andtetracyclic triterpenes. Among the pentacyclic andallowedidentification of the taxonomic