Demonstrating the statistical and pharmacological sensitivity of nonclinical QTc analysis using a dofetilide dose-response in nonhuman primates.

Nonclinical QTc studies can augment clinical QTc assessments in regulatory submissions provided they are of sufficient quality and sensitivity. Both the statistical performance and species translation play a role in determining the sensitivity of the model. The current analyses examine the effects of dofetilide or vehicle on the QT interval in nonhuman primate (NHP; n = 16) using a one-step estimated marginal means method where both treatment and animal ID are used in regression models to avoid a separate rate correction step, in comparison to other commonly utilized methods.

S-adenosyl-L-methionine is the unexpected methyl donor for the methylation of mercury by the membrane-associated HgcAB complex.

Mercury (Hg) is a heavy metal that exhibits high biological toxicity. Monomethylmercury and dimethylmercury are neurotoxins and a significant environmental concern as they bioaccumulate and biomagnify within the aquatic food web. Microbial Hg methylation involves two proteins, HgcA and HgcB.

New insights into thallium(I) behaviors at birnessite surfaces: Effects of an organic buffer and goethite.

Understanding the environmental behavior of thallium (Tl) is crucial due to its high toxicity and increasing anthropogenic presence. This study investigated the adsorption and redox behaviors of Tl(I) with acid birnessite (AcBi) in the presence of 1,4-piperazine-diethanesulfonic acid (PIPES) and goethite under diffusion-limited conditions using Donnan reactors in aerobic and anaerobic environments. Our findings indicate that Tl(I) preferentially adsorbs onto AcBi, with capacities 20 to 100 times higher than onto goethite, even when AcBi is partial reduced by PIPES.

A "one-step" approach to heart rate correction and statistical analysis applied to conscious dog QTc studies.

A "one-step" method which combined the heart rate correction and statistical analysis for conscious nonhuman primate (NHP) QTc assessment was recently published. The principles of this method are applicable to other species. In the current analysis, we demonstrate the utility of the technique in conscious dog QTc studies.

Reevaluating safety pharmacology respiratory studies within the ICH S7A core battery: A multi-company evaluation of preclinical utility and clinical translation.

Optimization of ICH safety guideline studies for inclusion into regulatory submissions is critical for resource conservation, animal use reduction, and efficient drug development. The ICH S7A guidance for Safety Pharmacology (SP) studies adopted in 2001 identified the core battery of studies to evaluate the acute safety of putative pharmaceutical molecules prior to First in Human (FIH) trials. To assess the utility of respiratory studies in predicting clinical AE's, seven pharmaceutical companies pooled preclinical and clinical respiratory findings.