Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide1, 2. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis3, 4, 5, several of which are currently in clinical trials6, 7, 8. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis

Effects of intraoperative hypotension on postoperative renal function in arthroscopic shoulder surgery: a retrospective study

Abstract Background: Arthroscopic shoulder surgery tends to cause a drop in blood pressure due to the beach chair position used during the procedure, including activation of the Bezold-Jarisch reflex. We hypothesized that patients with low blood pressure undergoing arthroscopic shoulder surgery in the beach chair position would also have reduced renal function after surgery.Methods: The medical records of patients (N = 643) undergoing arthroscopic shoulder surgery in the beach chair position between July 2013 and May 2015 were examined. The vital signs were measured at 5-minute intervals, and the number of non-invasive blood pressure (NIBP) measurements in the upper arm dropping below a mean arterial pressure (MAP) of 50 mmHg (MAP50) or 60 mmHg (MAP60) were recorded. The primary outcome was change in creatinine immediately after surgery relative to the preoperative level (Cr post/pre). The factors affecting Cr post/pre were examined by correlation analysis.Results: A total of 597 patients were included in the analysis. Longer duration of hypotension during surgery (MAP50) was correlated with higher Cr post/pre (R = 0.107, P = 0.010). However, the correlation between MAP60 and Cr post/pre was not significant (R = 0.033, P = 0.431).Conclusions: It is necessary to ensure that the MAP does not fall below 50 mmHg to ensure sufficient renal function during general anesthesia for shoulder arthroscopy in a beach chair position.</jats:p