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In the European Union, traditional herbal medicines that are regarded as "acceptably safe, albeit not having a recognized level of efficacy" fit into a special category of drugs ("traditional herbal medicine products") for which requirements of non-clinical and clinical studies are less rigorous. A regulation proposal published by the Brazilian National Health Surveillance (Anvisa) defines a similar drug category ("traditional phytotherapeutic products") for registration purposes. Regarding herbal medicines, both agencies seem to be lenient regarding proof of efficacy, and consider long-standing folk use as evidence of safety and a waiver of a thorough toxicological evaluation. Nonetheless, several herbal products and constituents with a long history of folk usage are suspected carcinogenic and/or hepatotoxic. Herbal products have also been shown to inhibit and/or induce drug-metabolizing enzymes. Since herbal medicines are often used in conjunction with conventional drugs, kinetic and clinical interactions are a cause for concern. A demonstration of the safety of herbal medicines for registration purposes should include at least in vitro and in vivo genotoxicity assays, long-term rodent carcinogenicity tests (for drugs intended to be continuously used for > 3 months or intermittently for > 6 months), reproductive and developmental toxicity studies (for drugs used by women of childbearing age), and investigation of the effects on drug-metabolizing enzymes.

This paper describes a biochemical and pharmacological characterization of BpirPLA(2)-I, the first acidic Asp49-PLA(2) isolated from Bothrops pirajai. BpirPLA(2)-I caused hypotension in vivo, presented phospholipolytic activity upon artificial substrates and inhibitory effects on platelet aggregation in vitro. Moreover, a synthetic peptide of BpirPLA(2)-I, comprising residues of the C-terminal region, reproduced the antiplatelet activity of the intact protein. A cDNA fragment of 366 bp encompassing the mature form of BpirPLA(2)-I was cloned by reverse transcriptase-PCR of B. pirajai venom gland total RNA. A Bayesian phylogenetic analysis indicated that BpirPLA(2)-I forms a clade with other acid Asp49-PLA(2) enzymes from the Bothrops genus, which are characterized by the high catalytic activity associated with anticoagulant or hypotensive activity or both. Comparison of the electrostatic potential (EP) on the molecular surfaces calculated from a BpirPLA(2)-I homology model and from the crystallographic models of a group of close homologues revealed that the greatest number of charge inversions occurred on the face opposite to the active site entrance, particularly in the Ca(2+) ion binding loop. This observation suggests a possible relationship between the basic or acid character of PLA(2) enzymes and the functionality of the Ca(2+) ion binding loop.

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