Ultrastructural analysis in preclinical safety evaluation.

The first electron microscopic images of biological specimens were made in the 1940s, and the next 30 years comprised an era of descriptive ultrastructure during which transmission electron microscopy (TEM) was integral to an explosion in cellular and molecular biology. However, when questions could no longer be answered by ultrastructural information alone, the use of TEM in biological research declined. Innovative molecular techniques and newer imaging technologies such as confocal fluorescence microscopy filled the gap, providing faster answers with less rigorous training as a prerequisite to data collection.

The role of the toxicologic pathologist in the biopharmaceutical industry.

Toxicologic pathologists contribute significantly to the development of new biopharmaceuticals, yet there is often a lack of awareness of this specialized role. As the members of multidisciplinary teams, toxicologic pathologists participate in all aspects of the drug development process. This review is part of an initiative by the Society of Toxicologic Pathology to educate scientists about toxicologic pathology and to attract junior scientists, veterinary students, and veterinarians into the field.

Asymptomatic macrothrombocytopenia in a young pure-bred beagle dog: a case report.

During baseline evaluation prior to a preclinical safety study, a 10-month-old male pure-bred Beagle dog was found to have marked thrombocytopenia (6 × 10(3) platelets [PLT]/µL) associated with a mean platelet volume (MPV) of 17.9 fL. Tests for Rickettsia rickettsii, Ehrlichia canis, and Borrelia burgdorferi were negative.

A quantitation method for mass spectrometry imaging.

A new quantitation method for mass spectrometry imaging (MSI) with matrix-assisted laser desorption/ionization (MALDI) has been developed. In this method, drug concentrations were determined by tissue homogenization of five 10 µm tissue sections adjacent to those analyzed by MSI. Drug levels in tissue extracts were measured by liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS).

A rationale for determining, testing, and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity.

The synthesis of pharmaceutical products frequently involves the use of reactive reagents and the formation of intermediates and by-products. Low levels of some of these may be present in the final drug substance and drug product as impurities. Such chemically reactive impurities may have at the same time the potential for unwanted toxicities including genotoxicity and carcinogenicity and hence can have an impact on product risk assessment.

Isolated human hepatocytes in culture display markedly different gene expression patterns depending on attachment status.

In vitro human hepatocyte cultures are a key tool in the investigation of xenobiotic toxicity and metabolism. In most in vitro hepatocyte studies, the cells are allowed to adhere to an extracellular matrix, such as collagen. Unfortunately, the ability of freshly isolated hepatocytes to adhere to collagen varies from donor to donor.