First Joint Meeting on Natural Products Pharmacology
SIF-IUPHAR-IMGNPP

This well attended (260 present) and dynamic meeting was organised by the Italian Pharmacology Society, SIF (President Giorgio Racagni, President-elect Giuseppe Cirino), and marked the success of Giorgio’s IUPHAR/SIF initiative, taken up at the Kyoto WCP, to set up a Mediterranean regional grouping for natural products (NPs), as it is an area with a unique biodiversity and a rich NP research. The meeting was extremely well organised and Giorgio had set up two novel symposia of great interest:

• An opening session uniting two Italian ministries, IUPHAR, the federation of pharmaceutical companies, Pharmacognosy (SIPHAR), representatives for food supplements, agriculture, and also consumers.
• A session on reglementary aspects of health products from the EMA, companies, marketing, regulatory issues for medical devices, herbal products, and food supplements. This session underlined a position of real importance for pharmacologists. The EMA have made some remarkable changes in the positioning of Herbal Medicinal Products (HMP) and Traditional Herbal Medicinal Products (THMP) and substance-based medical devices versus Food Additives, as there are very little regulations for food supplements which can also be given to children over three. A major proposition from the EMA is to now establish mechanism of action! But without contact with IUPHAR or pharmacologists on the Herbal Medicinal Products Committee (MHPC)… Thirty years use of HMPs replaces need for clinical safety studies.
• Substantial changes have been announced by the Medical Device Coordination Group (MDCG) – this is very relevant as it covers any device associated with medicinal products or natural products, for delivery (skin patches, giving sets etc), including mechanistic issues and requiring pharmacology/PK.
• Thus, pharmacology must be associated to the new regulations.

Andreas Papapetropoulos, Athens (Sec Gen EPHAR), described the network for scientists for Greek compounds (NPs) in cardiovascular disease and cancer. 30M Insects 1M animals, 30M plants, Hotspots of biodiversity, Centre of excellence for natural products, isolating and generating libraries also Plant-UP research infrastructure. Example: NPs in olive oil; oleuropein is the main active precursor (major polyphenol in leaves) for the derivatives such tyrosol and hydroxytyrosol which occur mainly from hydrolysis of oleuropein. 10 and 20 mg/kg in rabbits is equivalent to human consumption of olive oil.  In a rabbit cardiac ischaemia model the infarct area versus area at risk showed a reduction from 48 to 18 in prevention dosing, less effective in cholesterol-loaded rabbits. Also effective post-infarct. Inhibitors of classic pathways (such as NO) did not block benefit, so unknown mechanism. Beneficial effects on lipid profile, and improves cardiac morphology after ischaemia. Increases fly longevity in drosophila.

Chios mastic gum comes from one Greek island, present in multiple products. Effective in reducing infarct size but not in cholesterol-fed rabbits.  Indigo and indorubin (red), (TCM) Danggui Longhui Wan antileukaemic activity due to indorubin (CDK inhibitors) and with inhibition of GSK3b, but Greek fractions poorly active.  6Br-indirubin 40 nM IC50 GSK3b! Big S/A leading to 6-BIO in ATP site. Scaffold changes gives different selectivity of tyrosine kinases.

Frequently the activity of a single compound does not mimic the effect of the mixture.

These are just some of the numerous examples of components present in plants, insects, and animals of the Mediterranean Area that had been the subject of discussion during the Naples Meeting. For many of these, the mechanisms of action underlying the reference pharmacological effect have been highlighted, thus supporting the possibility of bending the pharmacological activity in a more correct clinical use.

In summary, we can conclude that the Naples Meeting, the first of its kind, fully hit the targets set by the organizers. It:

• Made the Mediterranean regional group for natural products known to the world of Institutions as numerous authorities of the political world and institutions participated in the opening session and in the symposium on regulatory aspects.
• Identified a collaborative scientific community in the Mediterranean area with the mission of supporting and advancing the entire field of pharmacology of natural substances.
• Promoted rigorous research on the pharmacology of natural products, with particular reference to those of the Mediterranean area as resulted from oral communications and posters of a high level and characterized by methodological rigor and clear experimental schemes.
• Identified natural extracts of plants from the Mediterranean area that are of potential benefit to human health on which solid pharmacological bases are reported including the pharmacokinetics. For almost all of them, the description of the therapeutic effect at a preclinical level was accompanied by the description of a mechanism of action supported by scientific evidence conducted with in vivo, in vitro and ex vivo studies.
• Addressed the problem of pharmacovigilance of these products, an integrated surveillance system for adverse reactions due to food supplements. Pharmacovigilance was perceived as a necessity of the safety evaluation of extracts/medical devices based on natural substances in the post-registration period.
• Spread knowledge. The presence of a large number of young researchers who exchanged experimental, design and methodological ideas is the most relevant proof of the full achievement of this goal.
• Improved the quality control systems, as resulted from the session on phytochemistry which dealt with this very delicate issue.