Chemical Proteomics-Based Analysis of Off-target Binding Profiles for Rosiglitazone and Pioglitazone: Clues for Assessing Potential for Cardiotoxicity

Drugs exert desired and undesired effects based on their binding interactions with protein target(s) and off-target(s), providing evidence for drug efficacy and toxicity. Pioglitazone and rosiglitazone possess a common functional core, glitazone, which is considered a privileged scaffold upon which to build a drug selective for a given target—in this case, PPARγ. Herein, we report a retrospective analysis of two variants of the glitazone scaffold, pioglitazone and rosiglitazone, in an effort to identify off-target binding events in the rat heart to explain recently reported cardiovascular risk associated with these drugs. Our results suggest that glitazone has affinity for dehydrogenases, consistent with known binding preferences for related rhodanine cores. Both drugs bound ion channels and modulators, with implications in congestive heart failure, arrhythmia, and peripheral edema. Additional proteins involved in glucose homeostasis, synaptic transduction, and mitochondrial energy production were detected and potentially contribute to drug efficacy and cardiotoxicity

Effects of L-NAME and timolol on aqueous IL-1 beta, IL-6 IL-8, TNF-alpha and NO levels after Nd : YAG laser iridotomy in rabbits

PURPOSE. Pro-inflammatory cytokines are produced by tissues and play a vital role in the host inflammatory response and uveitis. Nitric oxide (NO) can be produced in large amounts as a response to experimentally-induced uveitis or cytokines. In this study, we measured the levels of pro-inflammatory cytokines such as interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor (TNF)-alpha and free-radical in aqueous humor after Nd:YAG laser iridotomy in rabbits, and investigated whether timolol maleate an anti-glaucoma drug, or a NO synthase inhibitor, NG-nitro-L-arginine methyl esther (L-NAME) had an inhibitory effect on these molecules, since L-NAME is a known anti-inflammatory agent in rabbits

The levels of cytokines and nitric oxide in rabbit vitreous humor after retinal laser photocoagulation

OBJECTIVE: To determine the levels of nitric oxide (NO) and cytokines such as interleukin 1-beta (IL-1 beta), interleukin G (IL-6), interleukin 8 (IL-8), and tumor necrosis factor-alpha (TNF-alpha) on vitreous humor following retinal laser photocoagulation