The Experts below are selected from a list of 648 Experts worldwide ranked by ideXlab platform

Robert Zaczek - One of the best experts on this subject based on the ideXlab platform.

  • 2-Fluoro-4-pyridinylmethyl analogues of Linopirdine as orally active acetylcholine release-enhancing agents with good efficacy and duration of action.
    Journal of medicinal chemistry, 1998
    Co-Authors: Richard A. Earl, C M Maciag, A R Logue, W J Tinker, S W Tam, Robert Zaczek, Christopher A. Teleha, B N Fisher, M E Marynowski, S M Huang
    Abstract:

    In an effort to improve the pharmacokinetic and pharmacodynamic properties of the cognition-enhancer Linopirdine (DuP 996), a number of core structure analogues were prepared in which the 4-pyridyl pendant group was systematically replaced with 2-fluoro-4-pyridyl. This strategy resulted in the discovery of several compounds with improved activity in acetylcholine (ACh) release-enhancing assays, in vitro and in vivo. The most effective compound resulting from these studies, 10, 10-bis[(2-fluoro-4-pyridinyl)methyl]-9(10H)-anthracenone (9), is between 10 and 20 times more potent than Linopirdine in increasing extracellular hippocampal ACh levels in the rat with a minimum effective dose of 1 mg/kg. In addition to superior potency, 9 possesses an improved pharmacokinetic profile compared to that of Linopirdine. The half-life of 9 (2 h) in rats is 4-fold greater than that of Linopirdine (0.5 h), and it showed a 6-fold improvement in brain-plasma distribution over Linopirdine. On the basis of its pharmacologic, pharmacokinetic, absorption, and distribution properties, 9 (DMP543) has been advanced for clinical evaluation as a potential palliative therapeutic for treatment of Alzheimer's disease.

  • Two New Potent Neurotransmitter Release Enhancers, 10,10-Bis(4-Pyridinylmethyl)-9(10H)-Anthracenone and 10,10-Bis(2-Fluoro-4-Pyridinylmethyl)-9(10H)-Anthracenone: Comparison to Linopirdine
    The Journal of pharmacology and experimental therapeutics, 1998
    Co-Authors: Robert Zaczek, C M Maciag, A R Logue, B N Fisher, R J Chorvat, J A Saye, M E Pierdomenico, D H Rominger, Richard A. Earl
    Abstract:

    Linopirdine (3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one, DUP996) is an extensively studied representative of a class of cognition enhancing compounds that increase the evoked release of neurotransmitters. Recent studies suggest that these agents act through the blockade of specific K+ channels. We have recently identified more potent anthracenone analogs of Linopirdine: 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE991) and 10,10-bis(2-fluoro-4-pyridinylmethyl)-9(10H)-anthracenone (DMP 543). Although Linopirdine possesses an EC50 of 4.2 microM for enhancement of [3H]ACh release from rat brain slices, XE991 and DMP 543 have EC50S of 490 and 700 nM, respectively. In addition to greater in vitro potency relative to Linopirdine, both compounds show greater in vivo potency and duration of action. Although 5 mg/kg (p.o.) Linopirdine does not lead to statistically significant increases in hippocampal extracellular acetylcholine levels, 5 mg/kg (p.o.) XE991 leads to increases (maximal effect > 90% over baseline) which are sustained for 60 min. Moreover, DMP 543 at 1 mg/kg causes more than a 100% increase in acetylcholine levels with the effect lasting more than 3 hr. At doses relevant to their release-enhancing properties, the only overt symptom consistently observed was tremor, possible via a cholinergic mechanism. These results suggest that XE991 and DMP 543 may prove to be superior to Linopirdine as Alzheimer's disease therapeutics. In addition, these agents should be useful pharmacological tools for probing the importance of particular ion channels in the control of neurotransmitter release.

  • Pharmacology of the Neurotransmitter Release Enhancer Linopirdine (DuP 996), and Insights into Its Mechanism of Action
    Advances in pharmacology (San Diego Calif.), 1996
    Co-Authors: Simon P. Aiken, Robert Zaczek, Barry S Brown
    Abstract:

    Publisher Summary Drugs that enhance the release of neurotransmitters, or that otherwise affect neurotransmission via a presynaptic action have potential use in a wide range of neurological diseases, including perhaps Alzheimer's disease, Parkinsonism, and depression. The discovery of Linopirdine [DuP 996]; 3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one; AVIVA TM offered a new approach to the improvement of cholinergic function, and the drug has subsequently been used in clinical trials in Alzheimer's patients. Linopirdine was found to increase the release of ACh and other neurotransmitters in response to a depolarizing stimulus. By facilitating neurotransmission only during neuronal firing, it might be expected that the functioning of impaired cholinergic pathways in the CNS could be improved. There is no reason to suppose that the cholinergic approach to the treatment of Alzheimer's disease would reverse the gross histological manifestations of the disease: the neurofibrillary tangles and neuritic (senile) plaques. Continued studies on the etiology of Alzheimer's are clearly of the utmost importance in determining new strategies for drug treatment, and possibly also for prevention. The nature of the disease causes it to severely impact the families of patients, as well as the patients themselves, and it is currently the fourth leading cause of death in the United States. Clinical management of Alzheimer's disease is handicapped by the heterogeneity of the illness, and by the difficulty of detecting it in the earlier stages. This chapter reviews the pharmacological actions of Linopirdine with a particular emphasis on understanding the mechanism by which these effects are achieved. It is hoped that a better understanding of Linopirdine's action can lead to new improved compounds, and perhaps can suggest new target sites for the treatment of Alzheimer's disease and other neurological disorders.

  • Acetylcholine release enhancers related to Linopirdine: A structure—activity relationship study. II*
    European Journal of Medicinal Chemistry, 1996
    Co-Authors: Wendell Wilkie Wilkerson, Richard A. Earl, Christopher A. Teleha, Jc Calabrese, S Drammond, Matthew E. Voss, Robert Zaczek
    Abstract:

    Summary Several series of α,α-disubstituted polycyclic compounds were found to enhance the stimulus-induced release of neurotransmitters, especially acetylcholine, in brain slices. This work resulted in the identification of Linopirdine [3,3-bis (4-pyridinylmethyl)-1, 3-dihydro-1-phenyl-2 H -indol-2-one] 1a which was tested clinically for the treatment of Alzheimer's disease. The structure-activity relationship (SAR) results suggest that the potency of the series was dependent on the nature of the pendent groups (R), the distance geometry produced by the pendant groups, and the hydrogen-bonding property of the core group.

  • acetylcholine release enhancers related to Linopirdine a structure activity relationship study ii
    European Journal of Medicinal Chemistry, 1996
    Co-Authors: Wendell Wilkie Wilkerson, Richard A. Earl, Christopher A. Teleha, Jc Calabrese, S Drammond, Matthew E. Voss, Robert Zaczek
    Abstract:

    Summary Several series of α,α-disubstituted polycyclic compounds were found to enhance the stimulus-induced release of neurotransmitters, especially acetylcholine, in brain slices. This work resulted in the identification of Linopirdine [3,3-bis (4-pyridinylmethyl)-1, 3-dihydro-1-phenyl-2 H -indol-2-one] 1a which was tested clinically for the treatment of Alzheimer's disease. The structure-activity relationship (SAR) results suggest that the potency of the series was dependent on the nature of the pendent groups (R), the distance geometry produced by the pendant groups, and the hydrogen-bonding property of the core group.

Barry S Brown - One of the best experts on this subject based on the ideXlab platform.

  • Multiple Channel Interactions Explain the Protection of Sympathetic Neurons from Apoptosis Induced by Nerve Growth Factor Deprivation
    The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002
    Co-Authors: Shuli Xia, Barry S Brown, Patricia A. Lampe, Mohanish Deshmukh, Aizhen Yang, Steve M. Rothman, Eugene M. Johnson
    Abstract:

    We investigated the neuroprotective properties of two M-type K+ channel blockers, Linopirdine and its analog XE991, in rat sympathetic neurons deprived of nerve growth factor (NGF). Linopirdine and XE991 promoted sympathetic neuronal survival 48-72 hr after NGF withdrawal in a concentration-dependent manner. Both drugs prevented neuronal apoptosis by blocking the pathway leading to the release of cytochrome c and development of "competence-to-die" after NGF deprivation. Fura-2 Ca2+ imaging showed no significant difference in intracellular free Ca2+ ([Ca2+]i) in the presence or absence of NGF; Linopirdine and XE991, on the other hand, caused membrane depolarization and increases in [Ca2+]i. Whole-cell recordings showed that Linopirdine and XE991 selectively blocked the M current at neuroprotective concentrations, although they additionally inhibited other K+ currents at high concentrations. Membrane depolarization and [Ca2+]i increases induced by Linopirdine and XE991 were blocked by the Na+ channel blocker tetrodotoxin (TTX) or by the L-type Ca2+ channel antagonist nifedipine. TTX and nifedipine also prevented the neuroprotection elicited by Linopirdine or XE991. We propose that Na+ channel activation amplifies the membrane depolarization produced by M channel blockade and is essential for subsequent Ca2+ entry via the L-type Ca2+ channel. The interaction of these three classes of ion channels highlights an integrated anti-apoptosis mechanism in sympathetic neurons.

  • Selectivity of Linopirdine (DuP 996), a Neurotransmitter Release Enhancer, in Blocking Voltage-Dependent and Calcium-Activated Potassium Currents in Hippocampal Neurons
    The Journal of pharmacology and experimental therapeutics, 1998
    Co-Authors: Michael E. Schnee, Barry S Brown
    Abstract:

    Linopirdine [DuP 996, 3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one], a putative cognition enhancing drug, increases acetylcholine release in rat brain tissue and improves performance in animal models of learning and memory. The mechanism whereby Linopirdine enhances acetylcholine release has been proposed to involve inhibition of the M-type K + current (I M ). Our study examines the selectivity of Linopirdine for I M by determining its effects on other ionic currents present in rat hippocampal CA 1 neurons using patch clamp techniques. Linopirdine was found to block voltage-gated, calcium-activated and leak K + currents in a dose-dependent manner. Of the seven currents measured, Linopirdine was most selective for I M with an IC 50 of 2.4 ± 0.4 μM, followed by I C (measured as a medium afterhyperpolarization tail current, I mAHP ) with an IC 50 of 16.3 ± 2.4 μM. Both I M and I C were completely suppressed by Linopirdine. At a concentration of 100 μM, Linopirdine weakly inhibited the K + leak current, I L , the transient outward current, I A , the delayed rectifier, I K , and the slow component of I AHP , by 28 ± 8, 37 ± 10, 36 ± 9 and 52 ± 10 percent, respectively. The mixed Na + /K + inward rectifying current, I Q , was essentially unaffected by Linopirdine (IC 50 >300 μM). These results indicate that Linopirdine selectively blocks I M at concentrations ≤ 3 μM, the approximate EC 50 for acetylcholine release enhancement. Inhibition of other voltage-gated and calcium-activated K + currents could also contribute to enhanced neurotransmitter release by Linopirdine at intermediate (I C ) and high (I L , I A , I K , I sAHP ) concentrations.

  • Linopirdine reduces stimulus intensity threshold for induction of long term potentiation in the schaffer collateral ca1 pathway in rat hippocampal slices
    Neuroscience Letters, 1997
    Co-Authors: Betty J Lampe, Jacqui L Gaskill, Susan C Keim, Barry S Brown
    Abstract:

    Abstract Linopirdine, a putative cognition enhancing agent, increases neurotransmitter release and blocks M-current in rat brain. Its effects on long-term potentiation (LTP) in the Schaffer collateral/CA1 pathway were investigated using standard, extracellular recording techniques in the rat hippocampal slice preparation. When using a half maximal stimulus intensity for tetanic stimulation, a 30 min exposure to 3 or 10 μ M Linopirdine exerted no significant effect on excitatory postsynaptic potential (EPSP) slope, post-tetanic potentiation or LTP. In contrast, when a weak stimulus was employed, Linopirdine enhanced the incidence and amplitude of LTP in a dose-dependent manner. These results indicate that Linopirdine reduced stimulus intensity threshold for induction of LTP, an effect which may be mediated by its ability to enhance presynaptic glutamate release and cause CA1 membrane depolarization.

  • Linopirdine reduces stimulus intensity threshold for induction of long-term potentiation in the Schaffer collateral/CA1 pathway in rat hippocampal slices.
    Neuroscience letters, 1997
    Co-Authors: Betty J Lampe, Jacqui L Gaskill, Susan C Keim, Barry S Brown
    Abstract:

    Abstract Linopirdine, a putative cognition enhancing agent, increases neurotransmitter release and blocks M-current in rat brain. Its effects on long-term potentiation (LTP) in the Schaffer collateral/CA1 pathway were investigated using standard, extracellular recording techniques in the rat hippocampal slice preparation. When using a half maximal stimulus intensity for tetanic stimulation, a 30 min exposure to 3 or 10 μ M Linopirdine exerted no significant effect on excitatory postsynaptic potential (EPSP) slope, post-tetanic potentiation or LTP. In contrast, when a weak stimulus was employed, Linopirdine enhanced the incidence and amplitude of LTP in a dose-dependent manner. These results indicate that Linopirdine reduced stimulus intensity threshold for induction of LTP, an effect which may be mediated by its ability to enhance presynaptic glutamate release and cause CA1 membrane depolarization.

  • Pharmacology of the Neurotransmitter Release Enhancer Linopirdine (DuP 996), and Insights into Its Mechanism of Action
    Advances in pharmacology (San Diego Calif.), 1996
    Co-Authors: Simon P. Aiken, Robert Zaczek, Barry S Brown
    Abstract:

    Publisher Summary Drugs that enhance the release of neurotransmitters, or that otherwise affect neurotransmission via a presynaptic action have potential use in a wide range of neurological diseases, including perhaps Alzheimer's disease, Parkinsonism, and depression. The discovery of Linopirdine [DuP 996]; 3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one; AVIVA TM offered a new approach to the improvement of cholinergic function, and the drug has subsequently been used in clinical trials in Alzheimer's patients. Linopirdine was found to increase the release of ACh and other neurotransmitters in response to a depolarizing stimulus. By facilitating neurotransmission only during neuronal firing, it might be expected that the functioning of impaired cholinergic pathways in the CNS could be improved. There is no reason to suppose that the cholinergic approach to the treatment of Alzheimer's disease would reverse the gross histological manifestations of the disease: the neurofibrillary tangles and neuritic (senile) plaques. Continued studies on the etiology of Alzheimer's are clearly of the utmost importance in determining new strategies for drug treatment, and possibly also for prevention. The nature of the disease causes it to severely impact the families of patients, as well as the patients themselves, and it is currently the fourth leading cause of death in the United States. Clinical management of Alzheimer's disease is handicapped by the heterogeneity of the illness, and by the difficulty of detecting it in the earlier stages. This chapter reviews the pharmacological actions of Linopirdine with a particular emphasis on understanding the mechanism by which these effects are achieved. It is hoped that a better understanding of Linopirdine's action can lead to new improved compounds, and perhaps can suggest new target sites for the treatment of Alzheimer's disease and other neurological disorders.

Robert Martz - One of the best experts on this subject based on the ideXlab platform.

  • single dose pharmacokinetics safety and tolerance of Linopirdine dup 996 in healthy young adults and elderly volunteers
    The Journal of Clinical Pharmacology, 1995
    Co-Authors: Henry J Pieniaszek, William D Fiske, Timothy D Saxton, Yong S Kim, Dennis M Garner, Mikis Xilinas, Robert Martz
    Abstract:

    The pharmacokinetics, safety, and tolerance of linopiridine ([3,3-bis(4-pyridinylmethyl)-1-phenylindolin2-one]; DuPO 996) a potential therapeutic agent of Alzheimer's disease, were assessed in double-blind, placebo-controlled, randomized studies in which single oral doses were given to 64 healthy young or elderly males. Young subjects received escalating doses of 0.5 to 55 mg, whereas elderly subjects were given doses of 20 to 45 mg. Linopiridine plasma and urine samples were quantified after liquid extraction by a specific HPLC method using UV detection. In both groups, linopridine disposition was characterized by rapid absorption (mean T max , <1 hr) and elimination (mean t 1/2 , 0.4-3.2 hr). Urinary excretion of unchanged drug was negligible. The pharmacokinetic parameters showed large inter- and intrasubject variability. Linopirdine was well-tolerated in both young and elderly volunteers. The most frequently reported adverse event was headache. The subjects who received Linopirdine did not experience clinically important changes in vital signs, electrocardiograms (ECGs), electroencephalograms (EEGs), or clinical laboratory evaluations

  • Single‐Dose Pharmacokinetics, Safety, and Tolerance of Linopirdine (DuP 996) in Healthy Young Adults and Elderly Volunteers
    Journal of clinical pharmacology, 1995
    Co-Authors: Henry J Pieniaszek, William D Fiske, Timothy D Saxton, Yong S Kim, Dennis M Garner, Mikis Xilinas, Robert Martz
    Abstract:

    The pharmacokinetics, safety, and tolerance of linopiridine ([3,3-bis(4-pyridinylmethyl)-1-phenylindolin2-one]; DuPO 996) a potential therapeutic agent of Alzheimer's disease, were assessed in double-blind, placebo-controlled, randomized studies in which single oral doses were given to 64 healthy young or elderly males. Young subjects received escalating doses of 0.5 to 55 mg, whereas elderly subjects were given doses of 20 to 45 mg. Linopiridine plasma and urine samples were quantified after liquid extraction by a specific HPLC method using UV detection. In both groups, linopridine disposition was characterized by rapid absorption (mean T max ,

Kenneth L. Byron - One of the best experts on this subject based on the ideXlab platform.

  • Effects of the Kv7 voltage‐activated potassium channel inhibitor Linopirdine in rat models of haemorrhagic shock
    Clinical and experimental pharmacology & physiology, 2018
    Co-Authors: Sean P. Nassoiy, Kenneth L. Byron, Favin S Babu, Heather M. Laporte, Matthias Majetschak
    Abstract:

    Recently, we demonstrated that Kv7 voltage-activated potassium channel inhibitors reduce fluid resuscitation requirements in short-term rat models of haemorrhagic shock. The aim of the present study was to further delineate the therapeutic potential and side effect profile of the Kv7 channel blocker Linopirdine in various rat models of severe haemorrhagic shock over clinically relevant time periods. Intravenous administration of Linopirdine, either before (1 or 3 mg/kg) or after (3 mg/kg) a 40% blood volume haemorrhage, did not affect blood pressure and survival in lethal haemorrhage models without fluid resuscitation. A single bolus of Linopirdine (3 mg/kg) at the beginning of fluid resuscitation after haemorrhagic shock transiently reduced early fluid requirements in spontaneously breathing animals that were resuscitated for 3.5 hours. When mechanically ventilated rats were resuscitated after haemorrhagic shock with normal saline (NS) or with Linopirdine-supplemented (10, 25 or 50 μg/mL) NS for 4.5 hours, Linopirdine significantly and dose-dependently reduced fluid requirements by 14%, 45% and 55%, respectively. Lung and colon wet/dry weight ratios were reduced with Linopirdine (25/50 μg/mL). There was no evidence for toxicity or adverse effects based on measurements of routine laboratory parameters and inflammation markers in plasma and tissue homogenates. Our findings support the concept that Linopirdine-supplementation of resuscitation fluids is a safe and effective approach to reduce fluid requirements and tissue oedema formation during resuscitation from haemorrhagic shock.

  • effects of the kv7 voltage activated potassium channel inhibitor Linopirdine in rat models of haemorrhagic shock
    Clinical and Experimental Pharmacology and Physiology, 2018
    Co-Authors: Sean P. Nassoiy, Kenneth L. Byron, Favin S Babu, Heather M. Laporte, Matthias Majetschak
    Abstract:

    Recently, we demonstrated that Kv7 voltage-activated potassium channel inhibitors reduce fluid resuscitation requirements in short-term rat models of haemorrhagic shock. The aim of the present study was to further delineate the therapeutic potential and side effect profile of the Kv7 channel blocker Linopirdine in various rat models of severe haemorrhagic shock over clinically relevant time periods. Intravenous administration of Linopirdine, either before (1 or 3 mg/kg) or after (3 mg/kg) a 40% blood volume haemorrhage, did not affect blood pressure and survival in lethal haemorrhage models without fluid resuscitation. A single bolus of Linopirdine (3 mg/kg) at the beginning of fluid resuscitation after haemorrhagic shock transiently reduced early fluid requirements in spontaneously breathing animals that were resuscitated for 3.5 hours. When mechanically ventilated rats were resuscitated after haemorrhagic shock with normal saline (NS) or with Linopirdine-supplemented (10, 25 or 50 μg/mL) NS for 4.5 hours, Linopirdine significantly and dose-dependently reduced fluid requirements by 14%, 45% and 55%, respectively. Lung and colon wet/dry weight ratios were reduced with Linopirdine (25/50 μg/mL). There was no evidence for toxicity or adverse effects based on measurements of routine laboratory parameters and inflammation markers in plasma and tissue homogenates. Our findings support the concept that Linopirdine-supplementation of resuscitation fluids is a safe and effective approach to reduce fluid requirements and tissue oedema formation during resuscitation from haemorrhagic shock.

  • Kv7 voltage-activated potassium channel inhibitors reduce fluid resuscitation requirements after hemorrhagic shock in rats
    Journal of Biomedical Science, 2017
    Co-Authors: Sean P. Nassoiy, Kenneth L. Byron, Matthias Majetschak
    Abstract:

    Background Recent evidence suggests that drugs targeting Kv7 channels could be used to modulate vascular function and blood pressure. Here, we studied whether Kv7 channel inhibitors can be utilized to stabilize hemodynamics and reduce resuscitation fluid requirements after hemorrhagic shock. Methods Anesthetized male Sprague-Dawley rats were instrumented with arterial and venous catheters for blood pressure monitoring, hemorrhage and fluid resuscitation. Series 1: Linopirdine (Kv7 channel blocker, 0.1–6 mg/kg) or retigabine (Kv7 channel activator, 0.1–12 mg/kg) were administered to normal animals. Series 2: Animals were hemorrhaged to a MAP of 25 mmHg for 30 min, followed by fluid resuscitation with normal saline (NS) to a MAP of 70 mmHg until t = 75 min. Animals were treated with single bolus injections of vehicle, Linopirdine (1–6 mg/kg), XE-991 (structural analogue of Linopirdine with higher potency for channel blockade, 1 mg/kg) prior to fluid resuscitation. Series 3: Animals were resuscitated with NS alone or NS supplemented with Linopirdine (1.25–200 μg/mL). Data were analyzed with 2-way ANOVA/Bonferroni post-hoc testing. Results Series 1: Linopirdine transiently (10–15 min) and dose-dependently increased MAP by up to 15%. Retigabine dose-dependently reduced MAP by up to 60%, which could be reverted with Linopirdine. Series 2: Fluid requirements to maintain MAP at 70 mmHg were 65 ± 34 mL/kg with vehicle, and 57 ± 13 mL/kg, 22 ± 8 mL/kg and 22 ± 11 mL/kg with intravenous bolus injection of 1, 3 and 6 mg/kg Linopirdine, respectively. XE-991 (1 mg/kg), reduced resuscitation requirements comparable to 3 mg/kg Linopirdine. Series 3: When resuscitation was performed with Linopirdine-supplemented normal saline (NS), fluid requirements to stabilize MAP were 73 ± 12 mL/kg with NS alone and 72 ± 24, 61 ± 20, 36 ± 9 and 31 ± 9 mL/kg with NS supplemented with 1.25, 6.25, 12.5 and 200 μg/mL Linopirdine, respectively. Conclusions Our data suggest that Kv7 channel blockers could be used to stabilize blood pressure and reduce fluid resuscitation requirements after hemorrhagic shock.

  • Kv7 voltage-activated potassium channel inhibitors reduce fluid resuscitation requirements after hemorrhagic shock in rats
    Journal of biomedical science, 2017
    Co-Authors: Sean P. Nassoiy, Kenneth L. Byron, Matthias Majetschak
    Abstract:

    Recent evidence suggests that drugs targeting Kv7 channels could be used to modulate vascular function and blood pressure. Here, we studied whether Kv7 channel inhibitors can be utilized to stabilize hemodynamics and reduce resuscitation fluid requirements after hemorrhagic shock. Anesthetized male Sprague-Dawley rats were instrumented with arterial and venous catheters for blood pressure monitoring, hemorrhage and fluid resuscitation. Series 1: Linopirdine (Kv7 channel blocker, 0.1–6 mg/kg) or retigabine (Kv7 channel activator, 0.1–12 mg/kg) were administered to normal animals. Series 2: Animals were hemorrhaged to a MAP of 25 mmHg for 30 min, followed by fluid resuscitation with normal saline (NS) to a MAP of 70 mmHg until t = 75 min. Animals were treated with single bolus injections of vehicle, Linopirdine (1–6 mg/kg), XE-991 (structural analogue of Linopirdine with higher potency for channel blockade, 1 mg/kg) prior to fluid resuscitation. Series 3: Animals were resuscitated with NS alone or NS supplemented with Linopirdine (1.25–200 μg/mL). Data were analyzed with 2-way ANOVA/Bonferroni post-hoc testing. Series 1: Linopirdine transiently (10–15 min) and dose-dependently increased MAP by up to 15%. Retigabine dose-dependently reduced MAP by up to 60%, which could be reverted with Linopirdine. Series 2: Fluid requirements to maintain MAP at 70 mmHg were 65 ± 34 mL/kg with vehicle, and 57 ± 13 mL/kg, 22 ± 8 mL/kg and 22 ± 11 mL/kg with intravenous bolus injection of 1, 3 and 6 mg/kg Linopirdine, respectively. XE-991 (1 mg/kg), reduced resuscitation requirements comparable to 3 mg/kg Linopirdine. Series 3: When resuscitation was performed with Linopirdine-supplemented normal saline (NS), fluid requirements to stabilize MAP were 73 ± 12 mL/kg with NS alone and 72 ± 24, 61 ± 20, 36 ± 9 and 31 ± 9 mL/kg with NS supplemented with 1.25, 6.25, 12.5 and 200 μg/mL Linopirdine, respectively. Our data suggest that Kv7 channel blockers could be used to stabilize blood pressure and reduce fluid resuscitation requirements after hemorrhagic shock.

  • Reply to Chadha et al.
    British Journal of Pharmacology, 2011
    Co-Authors: Bharath K. Mani, Lioubov I. Brueggemann, Kenneth L. Byron
    Abstract:

    To the editor: The letter from Drs Chadha, Greenwood, Zhong and Cole correctly points out that the drug XE991, which is commonly used as a specific inhibitor of Kv7 channels, may also inhibit other subtypes of voltage-activated K+ (Kv) channels. In an article published in 2011 in this same journal (Ng et al., 2011), Dr Greenwood and colleagues state: ‘XE991 and Linopirdine block all Kv7 channels with IC50 values ∼3 µmol·L−1 (Wang et al., 2000) and at concentrations

Matthias Majetschak - One of the best experts on this subject based on the ideXlab platform.

  • Effects of the Kv7 voltage‐activated potassium channel inhibitor Linopirdine in rat models of haemorrhagic shock
    Clinical and experimental pharmacology & physiology, 2018
    Co-Authors: Sean P. Nassoiy, Kenneth L. Byron, Favin S Babu, Heather M. Laporte, Matthias Majetschak
    Abstract:

    Recently, we demonstrated that Kv7 voltage-activated potassium channel inhibitors reduce fluid resuscitation requirements in short-term rat models of haemorrhagic shock. The aim of the present study was to further delineate the therapeutic potential and side effect profile of the Kv7 channel blocker Linopirdine in various rat models of severe haemorrhagic shock over clinically relevant time periods. Intravenous administration of Linopirdine, either before (1 or 3 mg/kg) or after (3 mg/kg) a 40% blood volume haemorrhage, did not affect blood pressure and survival in lethal haemorrhage models without fluid resuscitation. A single bolus of Linopirdine (3 mg/kg) at the beginning of fluid resuscitation after haemorrhagic shock transiently reduced early fluid requirements in spontaneously breathing animals that were resuscitated for 3.5 hours. When mechanically ventilated rats were resuscitated after haemorrhagic shock with normal saline (NS) or with Linopirdine-supplemented (10, 25 or 50 μg/mL) NS for 4.5 hours, Linopirdine significantly and dose-dependently reduced fluid requirements by 14%, 45% and 55%, respectively. Lung and colon wet/dry weight ratios were reduced with Linopirdine (25/50 μg/mL). There was no evidence for toxicity or adverse effects based on measurements of routine laboratory parameters and inflammation markers in plasma and tissue homogenates. Our findings support the concept that Linopirdine-supplementation of resuscitation fluids is a safe and effective approach to reduce fluid requirements and tissue oedema formation during resuscitation from haemorrhagic shock.

  • effects of the kv7 voltage activated potassium channel inhibitor Linopirdine in rat models of haemorrhagic shock
    Clinical and Experimental Pharmacology and Physiology, 2018
    Co-Authors: Sean P. Nassoiy, Kenneth L. Byron, Favin S Babu, Heather M. Laporte, Matthias Majetschak
    Abstract:

    Recently, we demonstrated that Kv7 voltage-activated potassium channel inhibitors reduce fluid resuscitation requirements in short-term rat models of haemorrhagic shock. The aim of the present study was to further delineate the therapeutic potential and side effect profile of the Kv7 channel blocker Linopirdine in various rat models of severe haemorrhagic shock over clinically relevant time periods. Intravenous administration of Linopirdine, either before (1 or 3 mg/kg) or after (3 mg/kg) a 40% blood volume haemorrhage, did not affect blood pressure and survival in lethal haemorrhage models without fluid resuscitation. A single bolus of Linopirdine (3 mg/kg) at the beginning of fluid resuscitation after haemorrhagic shock transiently reduced early fluid requirements in spontaneously breathing animals that were resuscitated for 3.5 hours. When mechanically ventilated rats were resuscitated after haemorrhagic shock with normal saline (NS) or with Linopirdine-supplemented (10, 25 or 50 μg/mL) NS for 4.5 hours, Linopirdine significantly and dose-dependently reduced fluid requirements by 14%, 45% and 55%, respectively. Lung and colon wet/dry weight ratios were reduced with Linopirdine (25/50 μg/mL). There was no evidence for toxicity or adverse effects based on measurements of routine laboratory parameters and inflammation markers in plasma and tissue homogenates. Our findings support the concept that Linopirdine-supplementation of resuscitation fluids is a safe and effective approach to reduce fluid requirements and tissue oedema formation during resuscitation from haemorrhagic shock.

  • Kv7 voltage-activated potassium channel inhibitors reduce fluid resuscitation requirements after hemorrhagic shock in rats
    Journal of Biomedical Science, 2017
    Co-Authors: Sean P. Nassoiy, Kenneth L. Byron, Matthias Majetschak
    Abstract:

    Background Recent evidence suggests that drugs targeting Kv7 channels could be used to modulate vascular function and blood pressure. Here, we studied whether Kv7 channel inhibitors can be utilized to stabilize hemodynamics and reduce resuscitation fluid requirements after hemorrhagic shock. Methods Anesthetized male Sprague-Dawley rats were instrumented with arterial and venous catheters for blood pressure monitoring, hemorrhage and fluid resuscitation. Series 1: Linopirdine (Kv7 channel blocker, 0.1–6 mg/kg) or retigabine (Kv7 channel activator, 0.1–12 mg/kg) were administered to normal animals. Series 2: Animals were hemorrhaged to a MAP of 25 mmHg for 30 min, followed by fluid resuscitation with normal saline (NS) to a MAP of 70 mmHg until t = 75 min. Animals were treated with single bolus injections of vehicle, Linopirdine (1–6 mg/kg), XE-991 (structural analogue of Linopirdine with higher potency for channel blockade, 1 mg/kg) prior to fluid resuscitation. Series 3: Animals were resuscitated with NS alone or NS supplemented with Linopirdine (1.25–200 μg/mL). Data were analyzed with 2-way ANOVA/Bonferroni post-hoc testing. Results Series 1: Linopirdine transiently (10–15 min) and dose-dependently increased MAP by up to 15%. Retigabine dose-dependently reduced MAP by up to 60%, which could be reverted with Linopirdine. Series 2: Fluid requirements to maintain MAP at 70 mmHg were 65 ± 34 mL/kg with vehicle, and 57 ± 13 mL/kg, 22 ± 8 mL/kg and 22 ± 11 mL/kg with intravenous bolus injection of 1, 3 and 6 mg/kg Linopirdine, respectively. XE-991 (1 mg/kg), reduced resuscitation requirements comparable to 3 mg/kg Linopirdine. Series 3: When resuscitation was performed with Linopirdine-supplemented normal saline (NS), fluid requirements to stabilize MAP were 73 ± 12 mL/kg with NS alone and 72 ± 24, 61 ± 20, 36 ± 9 and 31 ± 9 mL/kg with NS supplemented with 1.25, 6.25, 12.5 and 200 μg/mL Linopirdine, respectively. Conclusions Our data suggest that Kv7 channel blockers could be used to stabilize blood pressure and reduce fluid resuscitation requirements after hemorrhagic shock.

  • Kv7 voltage-activated potassium channel inhibitors reduce fluid resuscitation requirements after hemorrhagic shock in rats
    Journal of biomedical science, 2017
    Co-Authors: Sean P. Nassoiy, Kenneth L. Byron, Matthias Majetschak
    Abstract:

    Recent evidence suggests that drugs targeting Kv7 channels could be used to modulate vascular function and blood pressure. Here, we studied whether Kv7 channel inhibitors can be utilized to stabilize hemodynamics and reduce resuscitation fluid requirements after hemorrhagic shock. Anesthetized male Sprague-Dawley rats were instrumented with arterial and venous catheters for blood pressure monitoring, hemorrhage and fluid resuscitation. Series 1: Linopirdine (Kv7 channel blocker, 0.1–6 mg/kg) or retigabine (Kv7 channel activator, 0.1–12 mg/kg) were administered to normal animals. Series 2: Animals were hemorrhaged to a MAP of 25 mmHg for 30 min, followed by fluid resuscitation with normal saline (NS) to a MAP of 70 mmHg until t = 75 min. Animals were treated with single bolus injections of vehicle, Linopirdine (1–6 mg/kg), XE-991 (structural analogue of Linopirdine with higher potency for channel blockade, 1 mg/kg) prior to fluid resuscitation. Series 3: Animals were resuscitated with NS alone or NS supplemented with Linopirdine (1.25–200 μg/mL). Data were analyzed with 2-way ANOVA/Bonferroni post-hoc testing. Series 1: Linopirdine transiently (10–15 min) and dose-dependently increased MAP by up to 15%. Retigabine dose-dependently reduced MAP by up to 60%, which could be reverted with Linopirdine. Series 2: Fluid requirements to maintain MAP at 70 mmHg were 65 ± 34 mL/kg with vehicle, and 57 ± 13 mL/kg, 22 ± 8 mL/kg and 22 ± 11 mL/kg with intravenous bolus injection of 1, 3 and 6 mg/kg Linopirdine, respectively. XE-991 (1 mg/kg), reduced resuscitation requirements comparable to 3 mg/kg Linopirdine. Series 3: When resuscitation was performed with Linopirdine-supplemented normal saline (NS), fluid requirements to stabilize MAP were 73 ± 12 mL/kg with NS alone and 72 ± 24, 61 ± 20, 36 ± 9 and 31 ± 9 mL/kg with NS supplemented with 1.25, 6.25, 12.5 and 200 μg/mL Linopirdine, respectively. Our data suggest that Kv7 channel blockers could be used to stabilize blood pressure and reduce fluid resuscitation requirements after hemorrhagic shock.