Potentiation of the anticonvulsant efficacy of sodium channel inhibitors by an NK1-receptor antagonist in the rat

Mikhail Kalinichev, Andrea Bradford, Silvia Bison, Adam Lucas, Ilaria Sartori, Nicoletta Garbati, Filippo Andreetta, Simon Bate, Nigel E. Austin, Declan N. C. Jones, Kevin D. Read, Giuseppe Alvaro, Charles H. Large

    Research output: Contribution to journalArticle

    9 Citations (Scopus)

    Abstract

    P>Purpose:

    Many patients with epilepsy are refractory to anticonvulsant drugs or do not tolerate side effects associated with the high doses required to fully prevent seizures. Antagonists of neurokinin-1 (NK1) receptors have the potential to reduce seizure severity, although this potential has not been fully explored in animals or humans. The present study was designed to evaluate the efficacy of the NK1-receptor antagonist, vofopitant, alone and in combination with different anticonvulsant drugs.

    Methods:

    Studies were conducted in rats using a model of generalized seizure induced by electroshock. Drug concentrations in blood and brain were determined in parallel to distinguish pharmacodynamic from pharmacokinetic interactions.

    Results:

    The NK1-receptor antagonist, GR205171 (vofopitant) had no anticonvulsant efficacy by itself, but could potentiate the anticonvulsant efficacy of lamotrigine and other sodium channel blockers. However, GR205171 had no effect on the anticonvulsant potency of either valproate or gabapentin. GR205171 did not produce central nervous system (CNS) side effects at the doses tested, and it did not potentiate side effects induced by high doses of lamotrigine. The NK1-receptor inactive enantiomer of GR205171, GR226206 did not potentiate the efficacy of lamotrigine, suggesting that effects observed with GR205171 were mediated by NK1 receptors. Analysis of the dose-effect relationship for GR205171 indicated that a high (> 99%) occupancy of NK1 receptors is required for effect, consistent with previous behavioral and human clinical studies with this pharmacologic class.

    Discussion:

    These results suggest that there may be benefit in adding treatment with a suitable NK1-receptor antagonist to treatment with a sodium channel blocker in patients with refractory epilepsy.

    Original languageEnglish
    Pages (from-to)1543-1551
    Number of pages9
    JournalEpilepsia
    Volume51
    Issue number8
    DOIs
    Publication statusPublished - Aug 2010

    Cite this

    Kalinichev, M., Bradford, A., Bison, S., Lucas, A., Sartori, I., Garbati, N., ... Large, C. H. (2010). Potentiation of the anticonvulsant efficacy of sodium channel inhibitors by an NK1-receptor antagonist in the rat. Epilepsia, 51(8), 1543-1551. https://doi.org/10.1111/j.1528-1167.2009.02482.x
    Kalinichev, Mikhail ; Bradford, Andrea ; Bison, Silvia ; Lucas, Adam ; Sartori, Ilaria ; Garbati, Nicoletta ; Andreetta, Filippo ; Bate, Simon ; Austin, Nigel E. ; Jones, Declan N. C. ; Read, Kevin D. ; Alvaro, Giuseppe ; Large, Charles H. / Potentiation of the anticonvulsant efficacy of sodium channel inhibitors by an NK1-receptor antagonist in the rat. In: Epilepsia. 2010 ; Vol. 51, No. 8. pp. 1543-1551.
    @article{7fd869e80caa4dc1a080db87e1f01e57,
    title = "Potentiation of the anticonvulsant efficacy of sodium channel inhibitors by an NK1-receptor antagonist in the rat",
    abstract = "P>Purpose:Many patients with epilepsy are refractory to anticonvulsant drugs or do not tolerate side effects associated with the high doses required to fully prevent seizures. Antagonists of neurokinin-1 (NK1) receptors have the potential to reduce seizure severity, although this potential has not been fully explored in animals or humans. The present study was designed to evaluate the efficacy of the NK1-receptor antagonist, vofopitant, alone and in combination with different anticonvulsant drugs.Methods:Studies were conducted in rats using a model of generalized seizure induced by electroshock. Drug concentrations in blood and brain were determined in parallel to distinguish pharmacodynamic from pharmacokinetic interactions.Results:The NK1-receptor antagonist, GR205171 (vofopitant) had no anticonvulsant efficacy by itself, but could potentiate the anticonvulsant efficacy of lamotrigine and other sodium channel blockers. However, GR205171 had no effect on the anticonvulsant potency of either valproate or gabapentin. GR205171 did not produce central nervous system (CNS) side effects at the doses tested, and it did not potentiate side effects induced by high doses of lamotrigine. The NK1-receptor inactive enantiomer of GR205171, GR226206 did not potentiate the efficacy of lamotrigine, suggesting that effects observed with GR205171 were mediated by NK1 receptors. Analysis of the dose-effect relationship for GR205171 indicated that a high (> 99{\%}) occupancy of NK1 receptors is required for effect, consistent with previous behavioral and human clinical studies with this pharmacologic class.Discussion:These results suggest that there may be benefit in adding treatment with a suitable NK1-receptor antagonist to treatment with a sodium channel blocker in patients with refractory epilepsy.",
    author = "Mikhail Kalinichev and Andrea Bradford and Silvia Bison and Adam Lucas and Ilaria Sartori and Nicoletta Garbati and Filippo Andreetta and Simon Bate and Austin, {Nigel E.} and Jones, {Declan N. C.} and Read, {Kevin D.} and Giuseppe Alvaro and Large, {Charles H.}",
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    Kalinichev, M, Bradford, A, Bison, S, Lucas, A, Sartori, I, Garbati, N, Andreetta, F, Bate, S, Austin, NE, Jones, DNC, Read, KD, Alvaro, G & Large, CH 2010, 'Potentiation of the anticonvulsant efficacy of sodium channel inhibitors by an NK1-receptor antagonist in the rat', Epilepsia, vol. 51, no. 8, pp. 1543-1551. https://doi.org/10.1111/j.1528-1167.2009.02482.x

    Potentiation of the anticonvulsant efficacy of sodium channel inhibitors by an NK1-receptor antagonist in the rat. / Kalinichev, Mikhail; Bradford, Andrea; Bison, Silvia; Lucas, Adam; Sartori, Ilaria; Garbati, Nicoletta; Andreetta, Filippo; Bate, Simon; Austin, Nigel E.; Jones, Declan N. C.; Read, Kevin D.; Alvaro, Giuseppe; Large, Charles H.

    In: Epilepsia, Vol. 51, No. 8, 08.2010, p. 1543-1551.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Potentiation of the anticonvulsant efficacy of sodium channel inhibitors by an NK1-receptor antagonist in the rat

    AU - Kalinichev, Mikhail

    AU - Bradford, Andrea

    AU - Bison, Silvia

    AU - Lucas, Adam

    AU - Sartori, Ilaria

    AU - Garbati, Nicoletta

    AU - Andreetta, Filippo

    AU - Bate, Simon

    AU - Austin, Nigel E.

    AU - Jones, Declan N. C.

    AU - Read, Kevin D.

    AU - Alvaro, Giuseppe

    AU - Large, Charles H.

    PY - 2010/8

    Y1 - 2010/8

    N2 - P>Purpose:Many patients with epilepsy are refractory to anticonvulsant drugs or do not tolerate side effects associated with the high doses required to fully prevent seizures. Antagonists of neurokinin-1 (NK1) receptors have the potential to reduce seizure severity, although this potential has not been fully explored in animals or humans. The present study was designed to evaluate the efficacy of the NK1-receptor antagonist, vofopitant, alone and in combination with different anticonvulsant drugs.Methods:Studies were conducted in rats using a model of generalized seizure induced by electroshock. Drug concentrations in blood and brain were determined in parallel to distinguish pharmacodynamic from pharmacokinetic interactions.Results:The NK1-receptor antagonist, GR205171 (vofopitant) had no anticonvulsant efficacy by itself, but could potentiate the anticonvulsant efficacy of lamotrigine and other sodium channel blockers. However, GR205171 had no effect on the anticonvulsant potency of either valproate or gabapentin. GR205171 did not produce central nervous system (CNS) side effects at the doses tested, and it did not potentiate side effects induced by high doses of lamotrigine. The NK1-receptor inactive enantiomer of GR205171, GR226206 did not potentiate the efficacy of lamotrigine, suggesting that effects observed with GR205171 were mediated by NK1 receptors. Analysis of the dose-effect relationship for GR205171 indicated that a high (> 99%) occupancy of NK1 receptors is required for effect, consistent with previous behavioral and human clinical studies with this pharmacologic class.Discussion:These results suggest that there may be benefit in adding treatment with a suitable NK1-receptor antagonist to treatment with a sodium channel blocker in patients with refractory epilepsy.

    AB - P>Purpose:Many patients with epilepsy are refractory to anticonvulsant drugs or do not tolerate side effects associated with the high doses required to fully prevent seizures. Antagonists of neurokinin-1 (NK1) receptors have the potential to reduce seizure severity, although this potential has not been fully explored in animals or humans. The present study was designed to evaluate the efficacy of the NK1-receptor antagonist, vofopitant, alone and in combination with different anticonvulsant drugs.Methods:Studies were conducted in rats using a model of generalized seizure induced by electroshock. Drug concentrations in blood and brain were determined in parallel to distinguish pharmacodynamic from pharmacokinetic interactions.Results:The NK1-receptor antagonist, GR205171 (vofopitant) had no anticonvulsant efficacy by itself, but could potentiate the anticonvulsant efficacy of lamotrigine and other sodium channel blockers. However, GR205171 had no effect on the anticonvulsant potency of either valproate or gabapentin. GR205171 did not produce central nervous system (CNS) side effects at the doses tested, and it did not potentiate side effects induced by high doses of lamotrigine. The NK1-receptor inactive enantiomer of GR205171, GR226206 did not potentiate the efficacy of lamotrigine, suggesting that effects observed with GR205171 were mediated by NK1 receptors. Analysis of the dose-effect relationship for GR205171 indicated that a high (> 99%) occupancy of NK1 receptors is required for effect, consistent with previous behavioral and human clinical studies with this pharmacologic class.Discussion:These results suggest that there may be benefit in adding treatment with a suitable NK1-receptor antagonist to treatment with a sodium channel blocker in patients with refractory epilepsy.

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    DO - 10.1111/j.1528-1167.2009.02482.x

    M3 - Article

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    SP - 1543

    EP - 1551

    JO - Epilepsia

    JF - Epilepsia

    SN - 0013-9580

    IS - 8

    ER -