The Pharmaceutical Journal
Vol 272 No 7291 p358-359
20 March 2004

This article
Reprint
Photocopy

PDF* 80K

Searching for new anti-inflammatory and anti-infective products from plants

Plants have yielded many widely used drugs and the current treatment of inflammatory conditions as well as infectious diseases relies heavily on natural products and their derivatives (eg, aspirin, quinine, chloroquine). The search for novel anti-inflammatory and anti-infective agents of natural origin was the focus of this two-day meeting. Many of the speakers were drawn from an EU-sponsored consortium co-ordinated by Michael Heinrich, professor of pharmacognosy, University of London. The search for novel compounds and standardised extracts with an effect on the pro-inflammatory signalling cascade has been at the centre of the research and development activities of this consortium of seven academic institutions from Spain, Italy, Germany, Switzerland, Israel, the UK and Finland and a pharmaceutical company (GlaxoSmithKline UK).

Biochemical basis of inflammation

The promotion of inflammatory conditions and the initiation of the innate immune response requires the synthesis of many special effector proteins. Numerous signalling cascades have been elucidated, involving as one of the last steps the activation of inducible transcription factors that bind to the promoter regions of their respective genes. Such targets include the genes for adhesion molecules (chemokines) and cytokines (TNF-alpha, interleukins). Essential for the gene activation is a protein complex called Nuclear Factor-kappaB (NF-kB), which represents one of the final steps in the activation cascade of a large number of genes. NF-kB is one of the principle inducible transcription factors in mammals and has been shown to play a pivotal role in the mammalian innate immune response and chronic inflammatory conditions such as rheumatoid arthritis. The signalling mechanisms of NF-kB involve an integrated sequence of protein regulated steps and many are potential key targets for intervention in treating inflammatory conditions.

The AINP (Anti-inflammatory Natural Products) consortium contributes to the development of new anti-inflammatory drugs for clinical use in the EU by identifying medicinal plant extracts with NF-kB inhibitory activity or inhibitory effects on targets of the inflammatory cascade in peripheral and central nervous system tissues. These targets include, for example, IL(interleukin)-1b, TNF-alpha, prostaglandin-E2, and IL-6. A number of compounds mediating this inhibitory effect have already been isolated and their structure elucidated. The consortium has evaluated more than 1,100 extracts from 340 botanical drugs in a large set of targets related to the transcriptional activation of gene products of relevance for inflammatory, immunomodulatory and apoptotic activity. Select compounds are currently studied further in in vivo as well as in vitro systems. Pre-clinical and clinical development of lead compounds are expected. The species included in this project mainly come from Sardinia and south-eastern Spain, but some species from Panama and Kenya were also studied. This symposium was both an opportunity to highlight some of the preliminary results of the consortium’s research and to broaden the vision to other core areas of natural product biology, especially the search for anti-infective agents.

Novel anti-inflammatory medicines

In his keynote lecture, Giovanni Appendino, of the University of Piemonte Orientale in Italy, highlighted the potential role of compounds from plants commonly used in the kitchen and how much novel discoveries we can expect in widely known and commonly used plants: “The kitchen connection — anti-inflammatory natural products from food plants and spices”. Our rapidly expanding knowledge of targets in the pro-inflammatory signalling pathway allows us to reassess the biochemical-pharmacological effects of such commonly used kitchen herbs as capsicum (chilli). Key to these studies was the discovery of the vanilloid receptors, a class of ion channels involved in chemo-, mechano- and thermosensation as well as in neurogenic inflammation and pain. Importantly, the compounds have been modified semi-synthetically, yielding a series of unnatural derivatives and a more detailed understanding of the mechanism of action of these compounds.

Bernd Fiebich from the University Hospital in Freiburg, Germany, summarised recent findings on the pharmacological profile and clinical effectiveness of Devil’s Claw (Harpagophyti radix), which is a licensed phytomedicine in many continental European countries. Standardised extracts have been shown by his group to interfere with the TNF-alpha-signalling pathway. The drug was found to be safe and clinically superior to placebo.

Anna Jäger, of the Danish School of Pharmaceutical Sciences, reported on her research on plants used by the Zulu in South Africa and the species’ effects on cyclo-oxygenase 1 and 2 explaining that in many cases more than one class of compounds makes important contributions to the pharmacological effects. Core to her interest has been to develop these local resources so that they can be properly characterised and studied. Thus the main goal is to further the local usage and not to search for novel treatments for our medical systems.

Paul Bremner and Michael Heinrich, of the Centre for Pharmacognosy and Phytotherapy, School of Pharmacy, University of London, assessed our current understanding of the use of such plants and natural products isolated from them in terms of their action specifically against the ubiquitous transcription factor, NF-kB. A large number of isoprenoids, notably kaurene diterpenoids and the class of sesquiterpene lactones with an exomethylene group next to the lactone function as well as several phenolics, including curcumin, and several flavonoids like silybin, are currently known as NF-kB modulators. This presentation focused on the structural diversity of the known inhibitors and some of the outcomes of the AINP consortium’s effort.

Biochemical pharmacological connection

The pharmacologist Eduardo Muñoz, of the University of Cordoba, Spain, provided an overview on the cell cycle and its potential for novel targets in the development of chemotherapeutic agents like anti-mitotics. Several kinases, most notably the cyclin dependent kinases and the vanilloid receptors are crucial targets and his presentation highlighted the potential of the class of capsaicins (from chilli) as novel leads.

Two experts in the NF-kB-pathway, Lienhard Schmitz of the University of Bern, Switzerland, and Yinon Ben-Neriah, of the Hadassah University Medical Centre, Jerusalem, Israel, discussed various aspects of this pathway and their potential for assessing the biological activities of drug candidates. Dr Ben-Neriah presented new data on the link between the NF-kB pathway and cancer, especially hepatocellular carcinoma and highlighted the complexity of the NF-kB dependent signalling pathway. Dr Schmitz on the other hand focused on novel targets in the search for anti-inflammatory agents. He stressed the role of protein kinases especially PKC’s isotype theta (q), which is essential for the response in T cells.

Anti-inflammatory effects of cannabis

Raphael Mechoulam, of Jerusalem, Israel, presented the second keynote lecture on “Cannabinoids in chronic inflammatory conditions”. Since the earliest written records preparations derived from Cannabis sativa have been used as medicines throughout Europe and Asia, especially in the treatment of pain and inflammation. Cannabis already has a high rate of acceptance and interest throughout the general population, making research into this species and its use as a new medicine one of the most promising current research areas. He provided an overview of his 40-year relationship with this topic from the original identification of the various cannabinoids in the early 1960s to his most recent interest in synthetic derivatives for use as anti-inflammatory and immunosuppressive agents. D9-Tetrahydrocannabinol isolated by his group in 1964 is, of course, the core compound responsible for the hallucinogenic effect, but seems to be of little relevance for the extract’s anti-inflammatory effects. His later research led to the identification of the cannabinoid receptors and the endogenous transmitter anandamide. In his view cannabis holds great potential for developing novel non- psychoactive, anti-inflammatory medicines.

Anti-infective natural products

Simon Gibbons, of the School of Pharmacy, University of London, summarised his recent research on plants as sources of bacterial resistance modulators and anti-infective agents. Several polyacetylenes and diterpenes were shown to be active in efflux systems in multidrug resistant bacterial strains.

Colin Wright, of the University of Bradford, focused on antimalarial agents, most notably cryptolepine and its derivatives, as well as of phytomedicines from Artemisia annua currently developed specifically as locally available resources in order to control this devastating illness in the worst affected regions of Africa.

Conclusion

The conference demonstrated the enormous potential of natural product research, as well as the urgency to start multidisciplinary projects on natural products. The health status of people in many regions of the world is fast deteriorating, the biomedical armament against many infectious diseases is losing its strengths and the European population is more and more suffering from chronic, ageing-related diseases like rheumatoid arthritis. Both high quality phytomedicines and pure natural products are potential drug leads to be explored.