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Title: Functional observational battery and motor activity in rats after single administration of two NHE 1 inhibitors

Abstract

Two tests, a functional observational battery (FOB) and measurement of motor activity, have been used to screen the two NHE inhibitors EMD 96785 and EMD 125021 for neurobehavioral effects. These two NHE inhibitors, which exhibit a marked selectivity for the NHE 1 isoform, are under development in the research laboratories of Merck KGaA. NHE inhibitors are developed for the treatment of acute myocardial infarction and chronic heart failure. In prior studies with EMD 96785 and EMD 125021, clinical symptoms, such as uncoordinated movements and weakness of the hindlimbs, were detected in rats. The aim of this study was the evaluation of clinical findings in more detail using a FOB and measurement of motor activity in 96 female rats. The time course and reversibility of the adverse effects were investigated. The animals were treated with EMD 96785 or EMD 125021 by intravenous injection at a single dose of 100 mg/kg and four different time points (2 h, 1 day, 7 days and 21 days after treatment) were chosen for the clinical examination. This neurobehavioral test battery clearly detected neurological activity and defined time-course characteristics after treatment with EMD 96785 or EMD 125021. The various clinical parameters were grouped into functional-related domainsmore » and most alterations were seen in the domains of central nervous system and neuromuscular system. The most prominent clinical findings were seen with the pharmacologically more potent NHE inhibitor EMD 125021 when compared to EMD 96785. The clinical symptoms were proven to be reversible by 7 days after the single treatment for both compounds.« less

Authors:
 [1];  [2];  [1];  [1];  [3]
  1. Merck KGaA, Institute of Toxicology, Frankfurter Strasse 250, Darmstadt, 64293 (Germany)
  2. Merck KGaA, Institute of Toxicology, Frankfurter Strasse 250, Darmstadt, 64293 (Germany). E-mail: barbara.gottschling@merck.de
  3. Tieraerztliche Hochschule Hannover, Institute of Pathology, Buenteweg 17, D-30559 Hannover (Germany)
Publication Date:
OSTI Identifier:
20722027
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 208; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2005.02.017; PII: S0041-008X(05)00112-2; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CENTRAL NERVOUS SYSTEM; ENZYME INHIBITORS; EVALUATION; HEART FAILURE; INHIBITION; INTRAVENOUS INJECTION; MYOCARDIAL INFARCTION; RATS; SINGLE INTAKE

Citation Formats

Huebler, Nicole, Gottschling, Barbara, Jacobs, Maren, Landenberg, Friedrich von, and Hewicker-Trautwein, Marion. Functional observational battery and motor activity in rats after single administration of two NHE 1 inhibitors. United States: N. p., 2005. Web. doi:10.1016/j.taap.2005.02.017.
Huebler, Nicole, Gottschling, Barbara, Jacobs, Maren, Landenberg, Friedrich von, & Hewicker-Trautwein, Marion. Functional observational battery and motor activity in rats after single administration of two NHE 1 inhibitors. United States. doi:10.1016/j.taap.2005.02.017.
Huebler, Nicole, Gottschling, Barbara, Jacobs, Maren, Landenberg, Friedrich von, and Hewicker-Trautwein, Marion. Tue . "Functional observational battery and motor activity in rats after single administration of two NHE 1 inhibitors". United States. doi:10.1016/j.taap.2005.02.017.
@article{osti_20722027,
title = {Functional observational battery and motor activity in rats after single administration of two NHE 1 inhibitors},
author = {Huebler, Nicole and Gottschling, Barbara and Jacobs, Maren and Landenberg, Friedrich von and Hewicker-Trautwein, Marion},
abstractNote = {Two tests, a functional observational battery (FOB) and measurement of motor activity, have been used to screen the two NHE inhibitors EMD 96785 and EMD 125021 for neurobehavioral effects. These two NHE inhibitors, which exhibit a marked selectivity for the NHE 1 isoform, are under development in the research laboratories of Merck KGaA. NHE inhibitors are developed for the treatment of acute myocardial infarction and chronic heart failure. In prior studies with EMD 96785 and EMD 125021, clinical symptoms, such as uncoordinated movements and weakness of the hindlimbs, were detected in rats. The aim of this study was the evaluation of clinical findings in more detail using a FOB and measurement of motor activity in 96 female rats. The time course and reversibility of the adverse effects were investigated. The animals were treated with EMD 96785 or EMD 125021 by intravenous injection at a single dose of 100 mg/kg and four different time points (2 h, 1 day, 7 days and 21 days after treatment) were chosen for the clinical examination. This neurobehavioral test battery clearly detected neurological activity and defined time-course characteristics after treatment with EMD 96785 or EMD 125021. The various clinical parameters were grouped into functional-related domains and most alterations were seen in the domains of central nervous system and neuromuscular system. The most prominent clinical findings were seen with the pharmacologically more potent NHE inhibitor EMD 125021 when compared to EMD 96785. The clinical symptoms were proven to be reversible by 7 days after the single treatment for both compounds.},
doi = {10.1016/j.taap.2005.02.017},
journal = {Toxicology and Applied Pharmacology},
number = 3,
volume = 208,
place = {United States},
year = {Tue Nov 01 00:00:00 EST 2005},
month = {Tue Nov 01 00:00:00 EST 2005}
}