Presentation Details
| Summary of an Innovative Approach for Mitigation of Postoperative Respiratory Depression: ENA-001 Robert B.Raffa1, 2, Joseph V.Pergolizzi Jr2, Thomas L.Miller2, George C.Dungan II3, Jeanette Mathews2, Krista Casazza4, William K Schmidt5. 1Temple University (Emeritus), Philadelphia, PA, USA.2Enalare Therapeutics, Mullica Hill, NJ, USA.3Dungan Research Associates, Denton, TX, USA.4K2D2 Consulting, Bonita, FL, USA.5NorthStar Consulting, Davis, CA, USA |
Abstract
BACKGROUND: The extent and negative impact of postoperative respiratory depression (PORD) is often under-recognized or reported. Anesthetics, opioids, and other central depressants administered during the perioperative period can lead to PORD or other pulmonary complications (PPCs). In addition, PPCs may lead to delayed (even 90-day) increases in morbidity and mortality. The opioid-receptor antagonist naloxone may reverse the opioid component of PORD, but it may also reverse analgesia, and it is not effective against non-opioid depressants. Recent research seeks an ‘agnostic’ reversal agent – and focuses on the carotid body as a target. We present such an agent, ENA-001, and its novel target: large-conductance Ca2+ and voltage-activated K+ (BK) channels in the carotid body.
PURPOSE: Data were accumulated from published literature and internal research on PORD and the carotid-body as target for respiratory stimulants. Past approaches (‘analeptics’) have primarily targeted the brain or sympathetic subdivision of the autonomic nervous system and have significant disadvantages when used in a postoperative setting.
RESULTS: ENA-001 works by antagonism of BK channels in type-I glomus cells in the carotid bodies. K+-channel chemoreceptors in the carotids detect changes in pO2, pCO2, and pH. These peripheral chemoreceptors send afferent impulses to the nucleus tractus solitarius (NTS) in the brainstem. The NTS, via links through the pontine respiratory group, connects to the pre-Bötzinger complex, which functions as an augmentable pacemaker for normal respiration. ENA-001 elicits dose-dependent increases in minute ventilation and the reversal of opioid- and non-opioid-induced respiratory depression.
CONCLUSIONS: The BK-channel antagonist ENA-001 restores ventilatory control, counteracting respiratory depressants. Unlike opioid receptor antagonists, ENA-001 does not compromise opioid-mediated analgesia, and it is ‘agnostic’ in that it also reverses respiratory depression evoked by non-opioids, including benzodiazepines and propofol.
No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.
PURPOSE: Data were accumulated from published literature and internal research on PORD and the carotid-body as target for respiratory stimulants. Past approaches (‘analeptics’) have primarily targeted the brain or sympathetic subdivision of the autonomic nervous system and have significant disadvantages when used in a postoperative setting.
RESULTS: ENA-001 works by antagonism of BK channels in type-I glomus cells in the carotid bodies. K+-channel chemoreceptors in the carotids detect changes in pO2, pCO2, and pH. These peripheral chemoreceptors send afferent impulses to the nucleus tractus solitarius (NTS) in the brainstem. The NTS, via links through the pontine respiratory group, connects to the pre-Bötzinger complex, which functions as an augmentable pacemaker for normal respiration. ENA-001 elicits dose-dependent increases in minute ventilation and the reversal of opioid- and non-opioid-induced respiratory depression.
CONCLUSIONS: The BK-channel antagonist ENA-001 restores ventilatory control, counteracting respiratory depressants. Unlike opioid receptor antagonists, ENA-001 does not compromise opioid-mediated analgesia, and it is ‘agnostic’ in that it also reverses respiratory depression evoked by non-opioids, including benzodiazepines and propofol.
No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.
Content Locked. Log into a registered attendee account to access this presentation.