Pharmacokinetic Scaling of Anticancer Drugs in Dogs

Anticancer drugs are characterized by a narrow therapeutic index and wide inter-individual variability in therapeutic outcome, disposition, and toxicity. The accurate calculation and administration of anticancer drugs from the initiation of treatment is necessary to attain a good therapeutic outcome. Currently, the doses of anticancer drugs are calculated based on the body surface area approach, which requires prior dose escalation studies to establish the maximum tolerated dose. In addition, several studies have questioned the ability of standard dosing methods to adequately normalize drug exposure for several anticancer drugs. As with most drugs, the efficacy of anticancer drugs correlates best with total drug exposure, or the area under the plasma concentration versus time curve. If the clearance of a drug is accurately known, then the dose required to produce a desired total drug exposure can be calculated accordingly. Therefore, it is important to understand the factors that influence the clearance of aVeterinary Pathobiolog

Development and evaluation of a mechanical ventilator-sharing system

BackgroundDuring the COVID-19 pandemic surge in the hospitalization of critically ill patients and the global demand for mechanical ventilators, alternative strategies for device sharing were explored. We developed and assessed the performance of a system for shared ventilation that uses clinically available components to individualize tidal volumes under a variety of clinically relevant conditions. The feasibility of remote monitoring of ventilators was also assessed.MethodsBy using existing resources and off-the-shelf components, a ventilator-sharing system (VSS) that ventilates 2 patients simultaneously with a single device, and a ventilator monitoring system (VMS) that remotely monitors pulmonary mechanics were developed. The feasibility and effectiveness of VSS and VMS were evaluated in benchtop testing using 2 test lungs on a single ventilator, and then performance was assessed in translational swine models of normal and impaired lung function.ResultsIn benchtop testing, VSS and VMS delivered the set individualized parameters with minimal % errors in test lungs under pressure- and volume-regulated ventilation modes, suggesting the highest precision and accuracy. In animal studies, the VSS and VMS successfully delivered the individualized mechanical ventilation parameters within clinically acceptable limits. Further, we found no statistically significant difference between the target and measured values.ConclusionThe VSS adequately ventilated 2 test lungs or animals with variable lung conditions. The VMS accurately displayed mechanical ventilation settings, parameters, and alarms. Both of these systems could be rapidly assembled for scaling up to ventilate several critically ill patients in a pandemic or mass casualty disaster situations by leveraging off-the-shelf and custom 3D printed components

How Do Patients Who Fail First-Line TB Treatment but Who Are Not Placed on an MDR-TB Regimen Fare in South India?

SETTING: Seven districts in Andhra Pradesh, South India. OBJECTIVES: To a) determine treatment outcomes of patients who fail first line anti-TB treatment and are not placed on an multi-drug resistant TB (MDR-TB) regimen, and b) relate the treatment outcomes to culture and drug susceptibility patterns (C&DST). DESIGN: Retrospective cohort study using routine programme data and Mycobacterium TB Culture C&DST between July 2008 and December 2009. RESULTS: There were 202 individuals given a re-treatment regimen and included in the study. Overall treatment outcomes were: 68 (34%) with treatment success, 84 (42%) failed, 36 (18%) died, 13 (6.5%) defaulted and 1 transferred out. Treatment success for category I and II failures was low at 37%. In those with positive cultures, 81 had pan-sensitive strains with 31 (38%) showing treatment success, while 61 had drug-resistance strains with 9 (15%) showing treatment success. In 58 patients with negative cultures, 28 (48%) showed treatment success. CONCLUSION: Treatment outcomes of patients who fail a first-line anti-TB treatment and who are not placed on an MDR-TB regimen are unacceptably poor. The worst outcomes are seen among category II failures and those with negative cultures or drug-resistance. There are important programmatic implications which need to be addressed

TRPA1 and CGRP antagonists counteract vesicant-induced skin injury and inflammation

The skin is highly sensitive to the chemical warfare agent in mustard gas, sulfur mustard (SM) that initiates a delayed injury response characterized by erythema, inflammation and severe vesication (blistering). Although SM poses a continuing threat, used as recently as in the Syrian conflict, no mechanism-based antidotes against SM are available. Recent studies demonstrated that Transient Receptor Potential Ankyrin 1 (TRPA1), a chemosensory cation channel in sensory nerves innervating the skin, is activated by SM and 2‐chloroethyl ethyl sulfide (CEES), an SM analog, in vitro, suggesting it may promote vesicant injury. Here, we investigated the effects of TRPA1 inhibitors, and an inhibitor of Calcitonin Gene Related Peptide (CGRP), a neurogenic inflammatory peptide released upon TRPA1 activation, in a CEES-induced mouse ear vesicant model (CEES-MEVM). TRPA1 inhibitors (HC-030031 and A-967079) and a CGRP inhibitor (MK-8825) reduced skin edema, pro-inflammatory cytokines (IL-1β, CXCL1/KC), MMP-9, a protease implicated in skin damage, and improved histopathological outcomes. These findings suggest that TRPA1 and neurogenic inflammation contribute to the deleterious effects of vesicants in vivo, activated either directly by alkylation, or indirectly, by reactive intermediates or pro-inflammatory mediators. TRPA1 and CGRP inhibitors represent new leads that could be considered for validation and further development in other vesicant injury models

Oxidized Phospholipid OxPAPC Activates TRPA1 and Contributes to Chronic Inflammatory Pain in Mice.

Oxidation products of the naturally occurring phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycerol-3-phosphatidylcholine (PAPC), which are known as OxPAPC, accumulate in atherosclerotic lesions and at other sites of inflammation in conditions such as septic inflammation and acute lung injury to exert pro- or anti-inflammatory effects. It is currently unknown whether OxPAPC also contributes to inflammatory pain and peripheral neuronal excitability in these conditions. Here, we observed that OxPAPC dose-dependently and selectively activated human TRPA1 nociceptive ion channels expressed in HEK293 cells in vitro, without any effect on other TRP channels, including TRPV1, TRPV4 and TRPM8. OxPAPC agonist activity was dependent on essential cysteine and lysine residues within the N-terminus of the TRPA1 channel protein. OxPAPC activated calcium influx into a subset of mouse sensory neurons which were also sensitive to the TRPA1 agonist mustard oil. Neuronal OxPAPC responses were largely abolished in neurons isolated from TRPA1-deficient mice. Intraplantar injection of OxPAPC into the mouse hind paw induced acute pain and persistent mechanical hyperalgesia and this effect was attenuated by the TRPA1 inhibitor, HC-030031. More importantly, we found levels of OxPAPC to be significantly increased in inflamed tissue in a mouse model of chronic inflammatory pain, identified by the binding of an OxPAPC-specific antibody. These findings suggest that TRPA1 is a molecular target for OxPAPC and OxPAPC may contribute to chronic inflammatory pain through TRPA1 activation. Targeting against OxPAPC and TRPA1 signaling pathway may be promising in inflammatory pain treatment

Epidemiology and interaction of diabetes mellitus and tuberculosis and challenges for care: a review [Review article]

Supported by the TB Union/MSF Operational Research Cours

Detection of OxPAPC in the inflamed plantar skin of mice after establishment of chronic pain in the CFA model.

<p>(A) Representative immunofluorescence images of EO6 antibody staining of OxPAPC in plantar tissue of mice from vehicle (Veh)-, CFA-treated groups and no 1^st antibody added control (No 1^st Ab Contl) group. Tissues were collected 7 days after CFA or vehicle injection. Areas staining positive for EO6 antibody are shown in green. Nuclei were labeled with DAPI (blue). (B) Summary of the % increase in fluorescence of EO6 staining as shown in (A). n = 5 mice/group, **p < 0.01 <i>vs</i>. No 1^st Ab Contl group, ^##p < 0.01 <i>vs</i>. Veh group, NS: no significance.</p