Conditioning-based therapeutics for aneurysmal subarachnoid hemorrhage - A critical review.

Aneurysmal subarachnoid hemorrhage (SAH) carries significant mortality and morbidity, with nearly half of SAH survivors having major cognitive dysfunction that impairs their functional status, emotional health, and quality of life. Apart from the initial hemorrhage severity, secondary brain injury due to early brain injury and delayed cerebral ischemia plays a leading role in patient outcome after SAH. While many strategies to combat secondary brain injury have been developed in preclinical studies and tested in late phase clinical trials, only one (nimodipine) has proven efficacious for improving long-term functional outcome. The causes of these failures are likely multitude, but include use of therapies targeting only one element of what has proven to be multifactorial brain injury process. Conditioning is a therapeutic strategy that leverages endogenous protective mechanisms to exert powerful and remarkably pleiotropic protective effects against injury to all major cell types of the CNS. The aim of this article is to review the current body of evidence for the use of conditioning agents in SAH, summarize the underlying neuroprotective mechanisms, and identify gaps in the current literature to guide future investigation with the long-term goal of identifying a conditioning-based therapeutic that significantly improves functional and cognitive outcomes for SAH patients.

Tetrodotoxin-bupivacaine-epinephrine combinations for prolonged local anesthesia.

Currently available local anesthetics have analgesic durations in humans generally less than 12 hours. Prolonged-duration local anesthetics will be useful for postoperative analgesia. Previous studies showed that in rats, combinations of tetrodotoxin (TTX) with bupivacaine had supra-additive effects on sciatic block durations. In those studies, epinephrine combined with TTX prolonged blocks more than 10-fold, while reducing systemic toxicity. TTX, formulated as Tectin, is in phase III clinical trials as an injectable systemic analgesic for chronic cancer pain. Here, we examine dose-duration relationships and sciatic nerve histology following local nerve blocks with combinations of Tectin with bupivacaine 0.25% (2.5 mg/mL) solutions, with or without epinephrine 5 µg/mL (1:200,000) in rats. Percutaneous sciatic blockade was performed in Sprague-Dawley rats, and intensity and duration of sensory blockade was tested blindly with different Tectin-bupivacaine-epinephrine combinations. Between-group comparisons were analyzed using ANOVA and post-hoc Sidak tests. Nerves were examined blindly for signs of injury. Blocks containing bupivacaine 0.25% with Tectin 10 µM and epinephrine 5 µg/mL were prolonged by roughly 3-fold compared to blocks with bupivacaine 0.25% plain (P < 0.001) or bupivacaine 0.25% with epinephrine 5 µg/mL (P < 0.001). Nerve histology was benign for all groups. Combinations of Tectin in bupivacaine 0.25% with epinephrine 5 µg/mL appear promising for prolonged duration of local anesthesia.