Comparative Analysis of Pharmacodynamics in the C3HeB/FeJ Mouse Tuberculosis Model for DprE1 Inhibitors TBA-7371, PBTZ169, and OPC-167832.

Multiple drug discovery initiatives for tuberculosis are currently ongoing to identify and develop new potent drugs with novel targets in order to shorten treatment duration. One of the drug classes with a new mode of action is DprE1 inhibitors targeting an essential process in cell wall synthesis of Mycobacterium tuberculosis. In this investigation, three DprE1 inhibitors currently in clinical trials, TBA-7371, PBTZ169, and OPC-167832, were evaluated side-by-side as single agents in the C3HeB/FeJ mouse model presenting with caseous necrotic pulmonary lesions upon tuberculosis infection. The goal was to confirm the efficacy of the DprE1 inhibitors in a mouse tuberculosis model with advanced pulmonary pathology and perform comprehensive analysis of plasma, lung, and lesion-centric drug levels to establish pharmacokinetic-pharmacodynamic (PK-PD) parameters predicting efficacy at the site of infection. Results showed significant efficacy for all three DprE1 inhibitors in the C3HeB/FeJ mouse model after 2 months of treatment. Superior efficacy was observed for OPC-167832 even at low-dose levels, which can be attributed to its low MIC, favorable distribution, and sustained retention above the MIC throughout the dosing interval in caseous necrotic lesions, where the majority of bacteria reside in C3HeB/FeJ mice. These results support further progression of the three drug candidates through clinical development for tuberculosis treatment.

Reducing the Impact of Perfusion Medical Waste on the Environment.

The U.S. healthcare system generates more than five billion pounds of waste each year. Waste disposal has become a serious environmental problem facing healthcare institutions. The operating room is the second largest source of hospital waste, and no current standards exist regarding perfusion waste reuse or recycling. A typical perfusion circuit produces approximately 15 pounds of plastic that ends up incinerated once used. Contaminated perfusion circuits consisting primarily of polyvinyl chloride (PVC) and polycarbonate are difficult to sterilize, reuse, or recycle. A literature review of Internet-based and peer-reviewed publications was conducted to identify all resources that describe sterilizing, dechlorinating, reusing, and recycling of medical-grade disposable products. There are several chemical methods available to re-harvest PVC after it has been properly decontaminated and melted down. Dichlorination by near-critical methanol shows promise in the recovery of additives such as plasticizers, stabilizers, and lubricants. The reinjection of PVC may have ecological and economic advantages. Dechlorinated PVC also creates a less toxic by-product when incinerated. Although this process is not recycling, it lessens the impact of poisonous chlorine gas release into the atmosphere. Sterilizing, dechlorinating, and recycling the perfusion circuit may be a promising avenue for reducing the ecological impact of perfusion waste. Although an economically sensitive mode of reusing, reducing, and recycling a circuit does not currently exist, this presentation will explore the perfusion waste dilemma and present potential solutions in hopes of promoting future reuse and recycling opportunities.