Evaluation of growth and antioxidant responses of freshwater microalgae Chlorella sorokiniana and Scenedesmus dimorphus under exposure of moxifloxacin.

As one of the fourth-generation fluoroquinolone antibiotics, moxifloxacin (MOX) has been frequently released to the aquatic environment, threatening local organisms. However, researches on its ecotoxicity to aquatic organisms are still limited. This study analyzed effects of MOX on the growth, photosynthesis and oxidative stress of two common types of freshwater microalgae, Chlorella sorokiniana and Scenedesmus dimorphus. The 96 h-EC50 values of MOX for C. sorokiniana and S. dimorphus were 28.42 and 26.37 mg/L, respectively. Although variations of specific indicators for photosynthetic fluorescence intensity were different, photosystems of two types of microalgae were irreversibly damaged. The malondialdehyde content and superoxide dismutase of C. sorokiniana and S. dimorphus evidently increased, indicating that the exposure of MOX caused serious oxidative stress. Chlorophyll a, b and carotenoids contents of C. sorokiniana increased, probably resulting from the resistance to oxidative stress, whereas they were inhibited due to oxidation damage as for S. dimorphus. Risk quotients (RQs) of MOX for C. sorokiniana and S. dimorphus in wastewater were 7.882 and 8.495, respectively, which demonstrated that MOX had a considerable risk to aquatic environment, especially in the context of its increasing use in practice.

Comparative corneal endothelial cell toxicity of differing intracameral moxifloxacin doses after phacoemulsification.

PURPOSE: To determine whether intracameral moxifloxacin 500 µg is noninferior to 250 µg for central endothelial cell loss (ECL) after phacoemulsification. SETTING: Aravind Eye Care System. DESIGN: Prospective masked randomized study. METHODS: Eyes with bilateral nuclear cataracts, central endothelial cell density (ECD) of more than 2000 cells/mm, and ECD not differing between eyes by more than 200 cells/mm underwent phacoemulsification at least 14 days apart. Intraoperatively, the first eye was randomized to receive either a 500 or 250 µg dose of moxifloxacin intracamerally and received the other dose for the second-eye surgery. Postoperative course was monitored at 1 day, 1 week, 1 month, and 3 months. Preoperative and 30-day and 90-day postoperative central ECD was determined by a reading center for a masked analysis of ECL at 3 months postoperatively. RESULTS: Fifty eyes of 25 patients (aged 48 to 69 years) underwent uneventful surgery and had normal postoperative courses. The point estimate (PE) and 95% CI for the mean difference in % ECL between the 500 µg and 250 µg doses at 3 months postoperatively was 0.8% (-5.8%, 7.4%). Upon identifying and removing 2 outliers, noninferiority was proven with a mean difference of the PE, -2.2% (CI, -6.5%, 2.1%). CONCLUSIONS: Clinical and corneal endothelial cell were comparable in this study population for the 250 µg and 500 µg doses of intracameral moxifloxacin. Both doses were well tolerated clinically, supporting the use of the higher dose for improved antimicrobial coverage for the prevention of postoperative endophthalmitis.

Clinical Trial in a Dish: Personalized Stem Cell-Derived Cardiomyocyte Assay Compared With Clinical Trial Results for Two QT-Prolonging Drugs.

Induced pluripotent stem cells (iPSCs) have shown promise in investigating donor-specific phenotypes and pathologies. The iPSC-derived cardiomyocytes (iPSC-CMs) could potentially be utilized in personalized cardiotoxicity studies, assessing individual proarrhythmic risk. However, it is unclear how closely iPSC-CMs derived from healthy subjects can recapitulate a range of responses to drugs. It is well known that QT-prolonging drugs induce subject-specific clinical response and that all healthy subjects do not necessarily develop arrhythmias or exhibit similar amounts of QT prolongation. We previously reported this variability in a study of four human ether-a-go-go-related gene (hERG) potassium channel-blocking drugs in which each subject underwent intensive pharmacokinetic and pharmacodynamic sampling such that subjects had 15 time-matched plasma drug concentration and electrocardiogram measurements throughout 24 hours after dosing in a phase I clinical research unit. In this study, iPSC-CMs were generated from those subjects. Their drug-concentration-dependent QT prolongation response from the clinic was compared with in vitro drug-concentration-dependent action potential duration (APD) prolongation response to the same two hERG-blocking drugs, dofetilide and moxifloxacin. Comparative results showed no significant correlation between the subject-specific APD response slopes and clinical QT response slopes to either moxifloxacin (P = 0.75) or dofetilide (P = 0.69). Similarly, no significant correlation was found between baseline QT and baseline APD measurements (P = 0.93). This result advances our current understanding of subject-specific iPSC-CMs and facilitates discussion into factors obscuring correlation and considerations for future studies of subject-specific phenotypes in iPSC-CMs.

Towards Bridging Translational Gap in Cardiotoxicity Prediction: an Application of Progressive Cardiac Risk Assessment Strategy in TdP Risk Assessment of Moxifloxacin.

Drug-induced cardiac arrhythmia, especially occurrence of torsade de pointes (TdP), has been a leading cause of attrition and post-approval re-labeling and withdrawal of many drugs. TdP is a multifactorial event, reflecting more than just drug-induced cardiac ion channel inhibition and QT interval prolongation. This presents a translational gap in extrapolating pre-clinical and clinical cardiac safety assessment to estimate TdP risk reliably, especially when the drug of interest is used in combination with other QT-prolonging drugs for treatment of diseases such as tuberculosis. A multi-scale mechanistic modeling framework consisting of physiologically based pharmacokinetics (PBPK) simulations of clinically relevant drug exposures combined with Quantitative Systems Toxicology (QST) models of cardiac electro-physiology could bridge this gap. We illustrate this PBPK-QST approach in cardiac risk assessment as exemplified by moxifloxacin, an anti-tuberculosis drug with abundant clinical cardiac safety data. PBPK simulations of moxifloxacin concentrations (systemic circulation and estimated in heart tissue) were linked with in vitro measurements of cardiac ion channel inhibition to predict the magnitude of QT prolongation in healthy individuals. Predictions closely reproduced the clinically observed QT interval prolongation, but no arrhythmia was observed, even at ×10 exposure. However, the same exposure levels in presence of physiological risk factors, e.g., hypokalemia and tachycardia, led to arrhythmic event in simulations, consistent with reported moxifloxacin-related TdP events. Application of a progressive PBPK-QST cardiac risk assessment paradigm starting in early development could guide drug development decisions and later define a clinical "safe space" for post-approval risk management to identify high-risk clinical scenarios.