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Title: Improved preclinical cardiovascular therapeutic indices with long-term inhibition of norepinephrine reuptake using reboxetine

Abstract

Norepinephrine reuptake inhibitors (NRIs) acutely increase norepinephrine (NE) levels, but therapeutic antidepressant activity is only observed after weeks of treatment because central NE levels progressively increase during continued drug exposure. Similarly, while NRIs acutely increase blood pressure (BP) and heart rate (HR) due to enhanced sympathetic neurotransmission, chronic treatment changes the responsiveness of the central noradrenergic system and suppresses these effects via autonomic regulation. To better understand the relationship between NE increases and cardiovascular safety, we investigated acute and chronic effects of the NRI reboxetine on central NE release and on BP and HR and electrical alternans, a measure of arrhythmia liability, in guinea pigs. NE release was assessed by microdialysis in medial prefrontal cortex (mPFC) and hypothalamic paraventricular nucleus (PVN); BP and HR were measured by telemetry. Animals were treated for 28 days with 15 mg/kg/day of reboxetine or vehicle via an osmotic minipump and then challenged with acute intravenous doses of reboxetine. Animals chronically treated with reboxetine had 2-fold higher extracellular basal NE levels in mPFC and PVN compared to basal levels after chronic vehicle treatment. BP was significantly increased after the first day of treatment, and gradually returned to vehicle levels by day 21. These data indicatemore » that chronic NRI treatment may lead to an increase in central NE levels and a concomitant reduction in BP based on exposure–response curves compared to vehicle treatment, suggesting a larger separation between preclinical estimates of efficacy vs. safety compared to acute NRI treatment. -- Highlights: ► Acute RBX produces blood pressure increases acutely that decrease with chronic RBX ► Chronic RBX increases brain NE levels, a preclinical surrogate of improved efficacy ► Short-term screening of NRI often underestimates the chronic therapeutic index ► Chronic cardiovascular safety and efficacy more adequately address therapeutic index ► Similar paradigms may exist with other centrally and peripherally acting drugs.« less

Authors:
 [1];  [1]; ;  [2]; ; ; ;  [1]
  1. Department of Global Safety Pharmacology, Department of Pharmacokinetics, Dynamics and Metabolism, and Neuroscience, Pfizer Global Research and Development Eastern Point Road, Groton, CT 06340 (United States)
  2. Brains On-Line B.V., University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen (Netherlands)
Publication Date:
OSTI Identifier:
22215954
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 264; Journal Issue: 3; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BLOOD PRESSURE; BRAIN; GUINEA PIGS; HEART; INHIBITION; NORADRENALINE; SAFETY; TELEMETRY

Citation Formats

Fossa, Anthony A., E-mail: anthony.fossa@icardiac.com, Wisialowski, Todd A., Cremers, Thomas, Hart, Marieke van der, Tseng, Elaine, Deng, Shibing, Rollema, Hans, and Wang, Ellen Q. Improved preclinical cardiovascular therapeutic indices with long-term inhibition of norepinephrine reuptake using reboxetine. United States: N. p., 2012. Web. doi:10.1016/J.TAAP.2012.09.010.
Fossa, Anthony A., E-mail: anthony.fossa@icardiac.com, Wisialowski, Todd A., Cremers, Thomas, Hart, Marieke van der, Tseng, Elaine, Deng, Shibing, Rollema, Hans, & Wang, Ellen Q. Improved preclinical cardiovascular therapeutic indices with long-term inhibition of norepinephrine reuptake using reboxetine. United States. doi:10.1016/J.TAAP.2012.09.010.
Fossa, Anthony A., E-mail: anthony.fossa@icardiac.com, Wisialowski, Todd A., Cremers, Thomas, Hart, Marieke van der, Tseng, Elaine, Deng, Shibing, Rollema, Hans, and Wang, Ellen Q. Thu . "Improved preclinical cardiovascular therapeutic indices with long-term inhibition of norepinephrine reuptake using reboxetine". United States. doi:10.1016/J.TAAP.2012.09.010.
@article{osti_22215954,
title = {Improved preclinical cardiovascular therapeutic indices with long-term inhibition of norepinephrine reuptake using reboxetine},
author = {Fossa, Anthony A., E-mail: anthony.fossa@icardiac.com and Wisialowski, Todd A. and Cremers, Thomas and Hart, Marieke van der and Tseng, Elaine and Deng, Shibing and Rollema, Hans and Wang, Ellen Q.},
abstractNote = {Norepinephrine reuptake inhibitors (NRIs) acutely increase norepinephrine (NE) levels, but therapeutic antidepressant activity is only observed after weeks of treatment because central NE levels progressively increase during continued drug exposure. Similarly, while NRIs acutely increase blood pressure (BP) and heart rate (HR) due to enhanced sympathetic neurotransmission, chronic treatment changes the responsiveness of the central noradrenergic system and suppresses these effects via autonomic regulation. To better understand the relationship between NE increases and cardiovascular safety, we investigated acute and chronic effects of the NRI reboxetine on central NE release and on BP and HR and electrical alternans, a measure of arrhythmia liability, in guinea pigs. NE release was assessed by microdialysis in medial prefrontal cortex (mPFC) and hypothalamic paraventricular nucleus (PVN); BP and HR were measured by telemetry. Animals were treated for 28 days with 15 mg/kg/day of reboxetine or vehicle via an osmotic minipump and then challenged with acute intravenous doses of reboxetine. Animals chronically treated with reboxetine had 2-fold higher extracellular basal NE levels in mPFC and PVN compared to basal levels after chronic vehicle treatment. BP was significantly increased after the first day of treatment, and gradually returned to vehicle levels by day 21. These data indicate that chronic NRI treatment may lead to an increase in central NE levels and a concomitant reduction in BP based on exposure–response curves compared to vehicle treatment, suggesting a larger separation between preclinical estimates of efficacy vs. safety compared to acute NRI treatment. -- Highlights: ► Acute RBX produces blood pressure increases acutely that decrease with chronic RBX ► Chronic RBX increases brain NE levels, a preclinical surrogate of improved efficacy ► Short-term screening of NRI often underestimates the chronic therapeutic index ► Chronic cardiovascular safety and efficacy more adequately address therapeutic index ► Similar paradigms may exist with other centrally and peripherally acting drugs.},
doi = {10.1016/J.TAAP.2012.09.010},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 264,
place = {United States},
year = {2012},
month = {11}
}