Identification by whole genome sequencing of genes associated with delayed postoperative hemorrhage in Scottish deerhounds.

Background: Delayed postoperative hemorrhage (DEPOH) is an important health concern for Scottish deerhounds.

Hypothesis/objectives: Identify genes associated with DEPOH in Scottish deerhounds.

Animals: Two hundred sixty-nine privately owned Scottish deerhounds.

Toxicity and toxicokinetic assessment of an anti-tubercular drug pretomanid in cynomolgus monkeys.

Pretomanid is a nitroimidazooxazine antimycobacterial drug that was approved in more than 10 countries as part of a three-drug, all oral regimen, consisting of bedaquiline, pretomanid, and linezolid (BPaL) for 6-months treatment of adults with pulmonary extensively drug-resistant tuberculosis (XDR-TB) or with complicated forms of multidrug-resistant tuberculosis (MDR-TB). The toxicological profile of pretomanid was thoroughly evaluated in repeat-dose oral toxicity studies up to 39 weeks long in cynomolgus monkeys. Exposures up to 10-fold higher than in humans at the approved pretomanid dose (200 mg) were achieved in acute studies allowing for characterization of dose-limiting toxicity.

Assessment of the Carcinogenic Potential of Pretomanid in Transgenic Tg.rasH2 Mice.

Pretomanid is a nitroimidazooxazine antimycobacterial drug that was approved as part of a three-drug oral regimen, consisting of bedaquiline, pretomanid, and linezolid, for 6-months treatment of adults with pulmonary extensively drug-resistant tuberculosis or with complicated forms of multidrug-resistant tuberculosis by the food and drug administration in the United States and regulatory bodies in over 10 other countries. Nitroaromatic compounds as a class carry a risk of genotoxicity and potential carcinogenicity based on reactive metabolite formation. A battery of good laboratory practice genotoxicity studies on pretomanid indicated that the compound was not genotoxic, however its hydroxy imidazole metabolite (M50) was genotoxic in the Ames assay.

Identification of 2,2-Dimethylbutanoic Acid (HST5040), a Clinical Development Candidate for the Treatment of Propionic Acidemia and Methylmalonic Acidemia.

Propionic acidemia (PA) and methylmalonic acidemia (MMA) are rare autosomal recessive disorders of propionyl-CoA (P-CoA) catabolism, caused by a deficiency in the enzymes P-CoA carboxylase and methylmalonyl-CoA (M-CoA) mutase, respectively. PA and MMA are classified as intoxication-type inborn errors of metabolism because the intramitochondrial accumulation of P-CoA, M-CoA, and other metabolites results in secondary inhibition of multiple pathways of intermediary metabolism, leading to organ dysfunction and failure. Herein, we describe the structure-activity relationships of a series of short-chain carboxylic acids which reduce disease-related metabolites in PA and MMA primary hepatocyte disease models.

Acute Histopathologic Findings Related to Needle Puncture Trauma during Subcutaneous Injection in the Sprague-Dawley Rat Model.

It is important to detect injection site reactions during the nonclinical phases of drug development. However, differentiating between normal changes following needle trauma and changes due to the toxicity of injected drugs can be challenging. Therefore, we used the Sprague-Dawley rat model to evaluate the pathological findings expected following a single subcutaneous injection of normal saline.