Characterizing Adversity of Lysosomal Accumulation in Nonclinical Toxicity Studies: Results from the 5th ESTP International Expert Workshop.

Lysosomes have a central role in cellular catabolism, trafficking, and processing of foreign particles. Accumulation of endogenous and exogenous materials in lysosomes represents a common finding in nonclinical toxicity studies. Histologically, these accumulations often lack distinctive features indicative of lysosomal or cellular dysfunction, making it difficult to consistently interpret and assign adverse dose levels. To help address this issue, the European Society of Toxicologic Pathology organized a workshop where representative types of lysosomal accumulation induced by pharmaceuticals and environmental chemicals were presented and discussed. The expert working group agreed that the diversity of lysosomal accumulations requires a case-by-case weight-of-evidence approach and outlined several factors to consider in the adversity assessment, including location and type of cell affected, lysosomal contents, severity of the accumulation, and related pathological effects as evidence of cellular or organ dysfunction. Lysosomal accumulations associated with cytotoxicity, inflammation, or fibrosis were generally considered to be adverse, while those found in isolation (without morphologic or functional consequences) were not. Workshop examples highlighted the importance of thoroughly characterizing the biological context of lysosomal effects, including mechanistic data and functional in vitro readouts if available. The information provided here should facilitate greater consistency and transparency in the interpretation of lysosomal effects.

Update of the management of venous thromboembolism.

Venous thromboembolism is the third most common cardiovascular disease. Its treatment is based in unfractionated heparin (UFH), but the advance of low molecular weight heparins, with clinical efficacy at least similar to UFH and better safety profile, have changed the therapeutic consensus. The highly relevant physiopathologic information has contributed to understand the paradoxical thrombotic mechanisms associated with heparin induced thrombocytopenia. New drugs, such as danaparoid sodium, lepirudin and argatroban, are an alternative to anticoagulation by heparin when this adverse reaction occurs. Another relevant progress was the determination of optimal duration of oral anticoagulation in order to prevent thromboembolic recurrences. In the meantime, other pharmacological approaches (thrombolytics and antiplatelet agents) have been assessed in several trials of limited value outcomes. Prophylactic measures like graduated compression stockings/intermittent external pneumatic compression and inferior vena cava filters have shown efficacy in primary and secondary prevention in patients with different risks of thromboembolic recurrence.