Pharmacokinetic effects of endoscopic gastric decontamination for multidrug gastric pharmacobezoars.

Introduction: Intentional multiple drugs overdose is an often-encountered method of self-harm in adolescence. Treatments include supportive therapy, antidotes (when available) and decontamination techniques with the aim of reducing drugs absorption by the gastrointestinal system to minimize toxicity. Nevertheless, the decontamination techniques currently used, such as gastric lavage (GL), activated charcoal or whole-bowel irrigation, have a questionable effectiveness. Endoscopic gastric decontamination (EGD) treatment for massive ingestion of drugs or formation of pharmacobezoars is currently described only in anecdotal cases. Here we describe the management of an intentional drug overdose in an adolescent patient treated with EGD and the effects of this therapy on drugs pharmacokinetics. Case report: A 15-year-old boy was admitted in an unconscious state (Glasgow Coma Scale: 7-8) to the pediatric intensive care unit after assuming an unspecified amount of quetiapine, aspirin, bisoprolol, fluoxetine, furosemide, alprazolam, and pregabalin pills. Rapid sequence intubation was immediately performed and then the patient was treated with symptomatic therapy and GL with minimal removal of gastric material. Accounting for the type of drugs, the time elapsed from oral assumption and the unknown quantity assumed, EGD was attempted with aim of removing potential aggregate of the drugs. Serial blood samples were taken before and after EGD to measure the plasma level of the drugs. A pharmacobezoar was found and was immediately removed with EGD. The results of the drug monitoring showed that quetiapine exceeded the toxic level reported in literature indicating that it may have been the drug assumed in higher quantity by our patient. PICU stay was uneventful, and the patient was transferred to the psychiatric ward after extubation. Discussion: Our case shows how GL is not effective in mitigating multidrug absorption especially drugs potentially inducing pharmacobezoars. Furthermore, based on our plasma drug monitoring, we believe that early EGD should be considered in all cases of massive pill intake, prolonged release drugs that can form pharmacobezoars or in cases where a life-threatening dose cannot be excluded.

The molecular mechanisms responsible for resistance to ET-743 (Trabectidin; Yondelis) in the Ewing's sarcoma cell line, TC-71.

Identification of new active agents against sarcoma is considered an important challenge in medical oncology. ET-743 (Trabectidin; Yondelis) has recently emerged as the first active drug developed against sarcoma in the last two decades, with promising results especially against soft-tissue sarcoma and Ewing's sarcoma (ES). In this study, we analyzed the molecular mechanisms responsible for resistance to ET-743 in ES cells. Three resistant cell variants (TC/ET 3 nM, TC/ET 6 nM and TC/ET 12 nM) were obtained, showing 28-, 47- and 102-fold increase in ET-743 resistance. Cross-resistance to other drugs was analyzed. Comparative genomic hybridization and cDNA microarray technology were employed to characterize and compare the gene expression profile of two TC/ET variants with the parental cell line. TC/ET cells show a conventional multidrug resistance phenotype and P-glycoprotein overexpression was found to significantly contribute to ET-743 resistance. However, functional studies with the cyclosporine analogue, PSC-833, indicate that other mechanisms are involved in resistance to ET-743. The gene expression profile of TC/ET cells indicated, among up-regulated genes, an increase in expression of insulin-like growth factor receptor-I (IGF-IR) and one of its major intracellular mediators, insulin receptor substrate-1. Functional studies using a neutralizing antibody anti-IGF-IR confirmed involvement of this signaling pathway in resistance to ET-743. Simultaneous blockage of both P-glycoprotein and IGF-IR completely restored sensitivity to ET-743 in ES cells. Overall, these findings provide impetus for future studies testing the therapeutic value of new specific inhibitors of P-glycoprotein and IGF-IR, which could represent a concrete therapeutic option for ES patients refractory to conventional agents.

Impact of IGF-I/IGF-IR circuit on the angiogenetic properties of Ewing's sarcoma cells.

The insulin-like growth factor receptor I (IGF-I)-mediated circuit is a major autocrine loop for Ewing's sarcoma (ES) cells, and plays a role the pathogenesis and malignancy of this tumor. IGF-I receptor (IGF-IR) has emerged as a good therapeutic site for ES patients. In this study, we analyzed the impact of strategies targeting the IGF-IR on the regulation of VEGFs, which are of fundamental importance in angiogenesis, and TGFbeta, CTGF and Cyr61, which are factors primarily involved in skeletal growth control and angiogenesis. IGF-I increases expression of VEGF-A, TGFbeta, CTGF and Cyr61 mRNA. However, only the modulation of VEGF-A expression appears to be mediated by IGF-IR. Functional assays on endothelial cells indicate a strict correlation between survival and proliferation of HUVECs and VEGF-A levels, confirming a major role for this factor in angiogenesis. Blockage of IGF-IR functions by neutralizing antibody or antisense strategies significantly reduced the expression and secretion of VEGF-A by ES cells, and supernatants of treated cells were unable to sustain the survival and proliferation of HUVECs. Analysis of the signaling mechanisms involved in constitutive or IGF-induced expression and secretion of VEGF-A indicated that PI3-K and MAPK signaling pathways are both required for VEGF expression and production in ES cells. Selective inhibitors LY294002 or PD98059 were highly effective in reducing the ability of ES cells to produce VEGF-A and stimulate survival and proliferation of HUVECs. Taken together, these findings add a new activity to the IGF-I repertoire in ES and highlight how disruption of IGF-IR functions may constitute an effective tool for the control of neovascularization in this tumor.