Principles of antiepileptic drug treatment of epilepsy

For the successful treatment of epilepsy, accurate diagnosis of epilepsy and epileptic seizures, and proper selection of antiepileptic drugs (AED) according to the classification of epileptic syndromes are fundamentally important. Efficacy of AED treatment, however, depends not only on its pharmacological action but also on its efficient use, namely a rationally thinking tailor-made treatment considering the characteristics of each patients, i.e. individual differences in pharmacokinetics, factors influencing AED concentrations, AED interactions, and comprehensively their life style and psychosocial factors.     

Intravascular haemolysis in a patient on ceftriaxone with demonstration of anticeftriaxone antibodies

Drug-induced haemolytic anaemia can be life threatening. We report a case of ceftriaxone-induced severe haemolytic anaemia in a previously healthy 68-year-old woman. The patient had a positive direct antiglobulin test (anti-C3d positive, anti-immunoglobulin G negative). Serological tests showed ceftriaxone-specific antibodies. The patient recovered after cessation of the drug. This complication may cause milder anaemia and thus be poorly recognized.     

TGF-β isoforms and TGF-β receptors in drug-induced and hereditary gingival overgrowth

Drug therapy and hereditary factors are two of the main causes of gingival overgrowth (GO). Both of these forms of GO are associated with increased extracellular matrix production by fibroblasts. Transforming growth factor beta (TGF-beta) is an important mediator of wound healing and tissue regeneration, which stimulates fibroblasts to produce extracellular matrix materials. The aim of this immunohistochemical study was to determine whether there is any altered expression of TGF-beta isoforms or its receptors in tissue from patients with drug-induced GO (DIGO; n=10) and hereditary gingival fibromatosis (n=10) when compared to non-overgrowth tissue (n=10). Compared to control tissues, significantly more fibroblasts expressed TGF-beta1 in both DIGO and hereditary gingival fibromatosis tissues (P<0.03). Cells expressing TGF-beta2 were present at control levels in DIGO but were significantly reduced in hereditary gingival fibromatosis (P<0.02). By contrast, the number of TGF-beta3-positive cells was the same in overgrowth tissues and controls. However, because of differences in total fibroblast densities between groups, there was a proportional increase in TGF-beta3 as well as TGF-beta1 expressing cells within both overgrowth populations (P<0.0001). Furthermore, representation of the TGF-beta2-positive phenotype was reduced in hereditary gingival fibromatosis (P<0.01) but increased in DIGO (P<0.005) compared to controls. Absorbance measurements of the positive cell populations showed that the level of expression was significantly higher for TGF-beta1 in hereditary gingival fibromatosis (P<0.002) and significantly lower for TGF-beta3 in DIGO (P<0.03). No significant differences in the numbers of TGF-betaRI- or RII-positive cells were detected between overgrowth tissues and controls. However, there were increases in the proportion of receptor-positive cells in the total cell population analysed in overgrowth tissues (P<0.0001). These results indicate qualitative and quantitative differences in TGF-beta isoform and receptor expression by fibroblasts in gingival overgrowth that may contribute to disease pathogenesis.     

Corticosteroid-induced exophthalmos

We describe twenty-one patients on sustained corticosteroid therapy who presented with exophthalmos. Each patient received a complete ophthalmologic examination and further tests were conducted to rule out other causes of exophthalmos. Our data suggest that corticosteroid-induced exophthalmos is an entity more common than has been previously recognized.     

Cell based approaches for evaluation of drug-induced liver injury

An improved understanding of mechanisms that underlie drug-induced liver injury (DILI) is required to enable design of drugs that have minimal potential to cause this adverse reaction in man. Available evidence suggests DILI arises in susceptible patients because of an imbalance between chemical insults (which are an inherent property of certain drugs and/or their metabolites) and the ability of the liver to mount compensatory/adaptive responses. In vivo safety testing in pre-clinical species ensures that drugs which enter clinical trials do not cause reproducible and dose-dependent liver injury in man, but is of limited value for exploration of underlying mechanisms and does not assess potential to cause rare idiosyncratic DILI. This review highlights the value that can be gained from in vitro studies using cultured hepatocytes and also hepatocyte-derived cell lines transfected with individual human cytochrome P450 (CYP450) isoforms. We have evaluated a range of mechanisms and endpoints (cell necrosis, mitochondrial injury, inhibition of biliary transporters and metabolite-mediated toxicity) using these model systems. Our data indicate that multiple mechanisms are likely to be involved in development of idiosyncratic DILI in man caused by numerous drugs, e.g. the anticonvulsant chlorpromazine.     

Greater curvature antral flattening: A radiologic sign of NSAID-related gastropathy

We have occasionally encountered patients on nonsteroidal antiinflammatory drugs (NSAIDs) in whom double contrast barium studies revealed persistent flattening and stiffening of the distal greater curvature of the stomach. We therefore performed a study to determine the frequency of this finding in patients with NSAID-related gastropathy. Twenty-one cases of erosive gastritis, gastric ulcers, and/or gastric scarring associated with a known history of NSAID use were reviewed by two radiologists who made a joint decision regarding the presence or absence of greater curvature antral flattening. This finding was seen radiographically in five of the 21 patients (24%). Four of the five patients with antral flattening had associated erosions or ulcers in the gastric antrum. The remaining patient had antral flattening as an isolated finding. Our experience suggests that flattening of the greater curvature of the distal antrum, particularly if associated with erosive gastritis or gastric ulcers, is a useful radiologic sign of NSAID-related gastropathy.