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  • General, Applied and Systems Toxicology, 12/2009; , ISBN: 9780470744307
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    ABSTRACT: Herbal medicines have a long tradition of therapeutic use. However, they may occasionally cause dose-related (type A) or idiosyncratic (type B) toxicity and herb-drug interactions are also possible. Toxicity can arise as a result of misidentification or adulteration of the preparation. Legislation (the Directive on traditional herbal medicinal products 2004/24/EC) was enacted on 30 April 2004 to improve public health protection and promote the free movement of traditional medicinal products in the EU. It requires each Member State to set up a simplified registration scheme for manufactured traditional herbal medicines that are suitable for use without medical supervision. Evidence of 30 years of traditional use, at least 15 years of which should normally be within the EU, is required to permit minor claims, replacing the requirement to demonstrate efficacy. Safety is based on evidence in the published literature, although the regulator can also ask for more data if there are safety concerns. The pharmacovigilance requirements and quality standards are the same as for licensed medicines. Patient information is similar to that for any over-the-counter medicine, with an additional requirement for a statement on labels and in advertisements that the indication is based on traditional use. A European positive list of herbal substances will set out the indication, strength, dosing recommendations, route of administration and other information on safe use. Where a product complies with the list, the applicant will not need to demonstrate either the traditional use or the safety of the product. The list will be compiled by the recently established Committee on Herbal Medicinal Products at the European Medicines Agency. EU Member States were required to comply with the Directive by 30 October 2005. Traditional herbal medicinal products already on the market when the Directive became law need not comply with its provisions for 7 years after its coming into force. The public need to be aware that 'natural' does not necessarily mean 'safe' in all circumstances. They should be fully informed about all medicines they take. Consideration also needs to be given to effective regulation of herbal medicines practitioners, so that they are identifiable in law, are governed by professional codes of practice and have agreed standards of training and competency. There are many references to herbal medicines in Shakespeare's tragedy, Romeo and Juliet, which was written around 1595. A herbal medicine (distilled liquor) was almost certainly used to put Juliet into a deep sleep. A poison, possibly of herbal origin, was used by Romeo to take his own life when he thought his beloved Juliet was dead, rather than sleeping. While European herbal medicines regulation seeks to protect the public health by ensuring the necessary guarantees of quality, safety and efficacy, it was poor communication that appears to have triggered the chain of events leading to the death of Romeo and Juliet. Good communication between regulators, practitioners, patients and the public is necessary so that those who choose to take herbal medicines can do so with acceptable safety.
    Drug Safety 02/2008; 31(5):416-8.

  • Toxicology 11/2007; 240(3):146-147. DOI:10.1016/j.tox.2007.06.030

  • 11th European Meeting on Complement in Human Disease; 09/2007

  • Molecular Immunology 09/2007; 44(16):3955-3955. DOI:10.1016/j.molimm.2007.06.109
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    ABSTRACT: The venom of the spider Loxosceles can cause both local and systemic effects including disseminated intravascular coagulation. The aim of this study was to investigate the effects of the venom of Loxosceles intermedia (L. intermedia) and the purified Sphingomyelinase D (SMaseD) toxin upon the Protein C (PC) natural anticoagulant pathway. Both the venom and e purified SMaseD reduced the cell surface expression of thrombomodulin (TM) and Endothelial PC Receptor on endothelial cells in culture. The reduction of cell surface expression was caused by cleavage from the cell surface mediated by activation of an endogenous metalloproteinase. Reduction of TM and Endothelial PC Receptor on the surface of these cells resulted in an impaired ability of the cells to assist in the thrombin-induced activation of PC. This novel observation gives further insight into the mechanisms of the pathology induced by venom from Loxosceles spiders and may aid the development of a suitable therapy.
    Journal of Thrombosis and Haemostasis 06/2007; 5(5):989-95. DOI:10.1111/j.1538-7836.2007.02382.x
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    ABSTRACT: There are many controversies surrounding the biological activities of native C-reactive protein (nCRP) and its various modified forms such as monomerized and biotinylated CRP (mCRP and bCRP). No simple methods have been described to distinguish among these forms. By adapting established electrophoresis methods, we have developed a useful quality control method with which we have investigated the structural and functional characteristics of these forms of CRP. Under all electrophoresis conditions, biotinylation altered the electrophoretic mobility of CRP. nCRP was sensitive to sodium dodecyl sulphate (SDS)-induced monomerization, and only mCRP was susceptible to digestion by trypsin or neutrophil-derived serine proteases. bCRP and mCRP but not nCRP bound to cells, suggesting that chemical modification by biotin and denaturation had altered the structural integrity of CRP. Neither nCRP nor mCRP had the ability to induce secretion of chemokines, nor did they increase intracellular adhesion molecule 1 (ICAM-1) expression in endothelial cells.
    Immunology 04/2007; 120(3):404-11. DOI:10.1111/j.1365-2567.2006.02516.x
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    ABSTRACT: Complement (C) activation is thought to contribute to the initiation and progression of atherosclerosis. Proliferation of smooth muscle cells plays an important role in atherosclerotic plaque formation. Our aim was to investigate the suitability of the rat aortic smooth muscle cell line A7r5 as an in vitro model to study C-induced events in smooth muscle cells. A7r5 cells abundantly expressed membrane bound C-regulators (CReg) Crry and CD59 as assessed by flow-cytometry, but no DAF or MCP was detected. Using RT-PCR in addition to Crry and CD59, also mRNA for rat DAF but not for MCP was detected. Flow-cytometry of cells removed by EDTA instead of trypsin demonstrated that A7r5 did express cell surface DAF. Upon prolonged culturing under either logarithmic growing conditions or under conditions where cells were kept over-confluent, two different sub cell lines were obtained, one which had lost the expression of CD59, while the other showed increased expression of DAF and Crry. The change in expression of these CReg resulted in a change in C-susceptibility. Incubation of the A7r5 cells with human serum induced membrane attack complex dependent proliferation. Transfection with human CD59 efficiently protected the cells from C-mediated killing and C-induced cell proliferation. Our results show that A7r5 cells can be used as an in vitro model for C-induced events, but care has to be taken to use the cells at an early stage of passaging as they readily change their phenotype.
    Molecular Immunology 02/2007; 44(4):608-14. DOI:10.1016/j.molimm.2006.01.014
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    ABSTRACT: Variable compliance with antiepileptic drugs (AEDs) is a potentially preventable cause of sudden unexplained death in epilepsy (SUDEP). Hair AED concentrations provide a retrospective insight into AED intake variability. We compared hair AED concentration variability in patients with SUDEP (n = 16), non-SUDEP epilepsy related deaths (n = 9), epilepsy outpatients (n = 31), and epilepsy inpatients (n = 38). AED concentrations were measured in 1 cm hair segments using high performance liquid chromatography. Individual patient hair AED concentration profiles were corrected for "washout" using linear regression analysis. The coefficient of variation (CV) of the corrected mean hair AED concentration provided an index of variability of an individual's AED taking behaviour. Hair sample numbers varied between subjects, and so weighted regression estimates of the CV were derived for each group. The CV regression estimates for each group were: SUDEP 20.5% (standard error 1.9), non-SUDEP 15.0% (3.9), outpatients 9.6% (1.4), and inpatients 6.2% (2.7). The SUDEP group therefore showed greater hair AED concentration variability than either the outpatient or the inpatient groups (p<0.0001). Observed variability of hair AED concentrations, reflecting variable AED ingestion over time, is greater in patients dying from SUDEP than in either epilepsy outpatients or inpatients. SUDEP, at least in a proportion of cases, appears preventable.
    Journal of Neurology Neurosurgery & Psychiatry 04/2006; 77(4):481-4. DOI:10.1136/jnnp.2005.067777
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    Clinical Chemistry 01/2006; 51(12):2385-7. DOI:10.1373/clinchem.2005.056499
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