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Synergistic effect of combining dual enkephalinase inhibitor PL37 and sumatriptan in a preclinical model of migraine.

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Title: Synergistic effect of combining dual enkephalinase inhibitor PL37 and sumatriptan in a preclinical model of migraine.
Authors: Rossignol, Jeanne, Ouimet, Tanja, Poras, Hervé, Dallel, Radhouane, Luccarini, Philippe
Source: Headache: The Journal of Head & Face Pain. Mar2024, Vol. 64 Issue 3, p243-252. 10p.
Subjects: Enkephalins, Isosorbide dinitrate (Drug), Sumatriptan, Research funding, Nitric oxide, Data analysis, Descriptive statistics, Drug efficacy, Animal experimentation, Narcotics, Analysis of variance, One-way analysis of variance, Statistics, Data analysis software, Confidence intervals, Migraine
Abstract: Objective: The aim of this study was to test whether a combination of sumatriptan with dual enkephalinase inhibitor PL37 would result in an additive or a synergistic effect. Background: Combination treatment is frequently used to improve the therapeutic efficacy of drugs. The co‐administration of two drugs may result in efficacy at lower doses than those needed for either drug alone, thus minimizing side effects. Here, we tested the effect of the co‐administration of two drugs on cutaneous mechanical hypersensitivity (MH), a symptom often affecting cephalic regions in patients with migraine: dual enkephalinase inhibitor PL37, a small molecule that protects enkephalins from rapid degradation, and sumatriptan, a serotonin 5‐HT1B/1D receptor agonist. Methods: We investigated the effects of oral administrations of sumatriptan, PL37, or their combination on changes in cutaneous mechanical sensitivity induced by a single intraperitoneal administration of the nitric oxide donor, isosorbide dinitrate (ISDN) in male rats. Mechanical sensitivity was assessed using von Frey filaments applied to the face of animals to determine pain thresholds. Isobolographic analysis was performed to determine the nature of the interaction between sumatriptan and PL37. Results: Sumatriptan as well as PL37 each produced a dose‐dependent inhibition of ISDN‐induced cephalic MH. Median effective dose (ED50) values were 0.3 and 1.1 mg/kg for sumatriptan and PL37, respectively. An isobolographic analysis of the effect of combined doses of sumatriptan and PL37 based on their calculated ED50 values demonstrated a synergistic effect of the combination on cephalic MH, with an interaction index of 0.14 ± 0.04. Conclusion: These results suggest that PL37 acts synergistically with sumatriptan to produce an anti‐allodynic effect in a rat model of migraine. Thus, combining PL37 and sumatriptan may be a useful therapeutic strategy in the management of migraine. Plain Language Summary: There have been many advances in migraine treatment, but we still need more options that are effective and have few side effects. Sumatriptan is one available drug for acute treatment of migraine, but it does not work for every patient and is not suitable for some people. We tested a new drug called PL37 (that blocks enkephalinases) together with sumatriptan and the combination minimized side effects and allowed lower doses of the drugs for effective migraine treatment in an animal model. [ABSTRACT FROM AUTHOR]
Copyright of Headache: The Journal of Head & Face Pain is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Synergistic effect of combining dual enkephalinase inhibitor PL37 and sumatriptan in a preclinical model of migraine.
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  Data: <searchLink fieldCode="AR" term="%22Rossignol%2C+Jeanne%22">Rossignol, Jeanne</searchLink><br /><searchLink fieldCode="AR" term="%22Ouimet%2C+Tanja%22">Ouimet, Tanja</searchLink><br /><searchLink fieldCode="AR" term="%22Poras%2C+Hervé%22">Poras, Hervé</searchLink><br /><searchLink fieldCode="AR" term="%22Dallel%2C+Radhouane%22">Dallel, Radhouane</searchLink><br /><searchLink fieldCode="AR" term="%22Luccarini%2C+Philippe%22">Luccarini, Philippe</searchLink>
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  Data: <searchLink fieldCode="JN" term="%22Headache%3A+The+Journal+of+Head+%26+Face+Pain%22">Headache: The Journal of Head & Face Pain</searchLink>. Mar2024, Vol. 64 Issue 3, p243-252. 10p.
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  Data: <searchLink fieldCode="DE" term="%22Enkephalins%22">Enkephalins</searchLink><br /><searchLink fieldCode="DE" term="%22Isosorbide+dinitrate+%28Drug%29%22">Isosorbide dinitrate (Drug)</searchLink><br /><searchLink fieldCode="DE" term="%22Sumatriptan%22">Sumatriptan</searchLink><br /><searchLink fieldCode="DE" term="%22Research+funding%22">Research funding</searchLink><br /><searchLink fieldCode="DE" term="%22Nitric+oxide%22">Nitric oxide</searchLink><br /><searchLink fieldCode="DE" term="%22Data+analysis%22">Data analysis</searchLink><br /><searchLink fieldCode="DE" term="%22Descriptive+statistics%22">Descriptive statistics</searchLink><br /><searchLink fieldCode="DE" term="%22Drug+efficacy%22">Drug efficacy</searchLink><br /><searchLink fieldCode="DE" term="%22Animal+experimentation%22">Animal experimentation</searchLink><br /><searchLink fieldCode="DE" term="%22Narcotics%22">Narcotics</searchLink><br /><searchLink fieldCode="DE" term="%22Analysis+of+variance%22">Analysis of variance</searchLink><br /><searchLink fieldCode="DE" term="%22One-way+analysis+of+variance%22">One-way analysis of variance</searchLink><br /><searchLink fieldCode="DE" term="%22Statistics%22">Statistics</searchLink><br /><searchLink fieldCode="DE" term="%22Data+analysis+software%22">Data analysis software</searchLink><br /><searchLink fieldCode="DE" term="%22Confidence+intervals%22">Confidence intervals</searchLink><br /><searchLink fieldCode="DE" term="%22Migraine%22">Migraine</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Objective: The aim of this study was to test whether a combination of sumatriptan with dual enkephalinase inhibitor PL37 would result in an additive or a synergistic effect. Background: Combination treatment is frequently used to improve the therapeutic efficacy of drugs. The co‐administration of two drugs may result in efficacy at lower doses than those needed for either drug alone, thus minimizing side effects. Here, we tested the effect of the co‐administration of two drugs on cutaneous mechanical hypersensitivity (MH), a symptom often affecting cephalic regions in patients with migraine: dual enkephalinase inhibitor PL37, a small molecule that protects enkephalins from rapid degradation, and sumatriptan, a serotonin 5‐HT1B/1D receptor agonist. Methods: We investigated the effects of oral administrations of sumatriptan, PL37, or their combination on changes in cutaneous mechanical sensitivity induced by a single intraperitoneal administration of the nitric oxide donor, isosorbide dinitrate (ISDN) in male rats. Mechanical sensitivity was assessed using von Frey filaments applied to the face of animals to determine pain thresholds. Isobolographic analysis was performed to determine the nature of the interaction between sumatriptan and PL37. Results: Sumatriptan as well as PL37 each produced a dose‐dependent inhibition of ISDN‐induced cephalic MH. Median effective dose (ED50) values were 0.3 and 1.1 mg/kg for sumatriptan and PL37, respectively. An isobolographic analysis of the effect of combined doses of sumatriptan and PL37 based on their calculated ED50 values demonstrated a synergistic effect of the combination on cephalic MH, with an interaction index of 0.14 ± 0.04. Conclusion: These results suggest that PL37 acts synergistically with sumatriptan to produce an anti‐allodynic effect in a rat model of migraine. Thus, combining PL37 and sumatriptan may be a useful therapeutic strategy in the management of migraine. Plain Language Summary: There have been many advances in migraine treatment, but we still need more options that are effective and have few side effects. Sumatriptan is one available drug for acute treatment of migraine, but it does not work for every patient and is not suitable for some people. We tested a new drug called PL37 (that blocks enkephalinases) together with sumatriptan and the combination minimized side effects and allowed lower doses of the drugs for effective migraine treatment in an animal model. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
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  Data: <i>Copyright of Headache: The Journal of Head & Face Pain is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1111/head.14681
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 10
        StartPage: 243
    Subjects:
      – SubjectFull: Enkephalins
        Type: general
      – SubjectFull: Isosorbide dinitrate (Drug)
        Type: general
      – SubjectFull: Sumatriptan
        Type: general
      – SubjectFull: Research funding
        Type: general
      – SubjectFull: Nitric oxide
        Type: general
      – SubjectFull: Data analysis
        Type: general
      – SubjectFull: Descriptive statistics
        Type: general
      – SubjectFull: Drug efficacy
        Type: general
      – SubjectFull: Animal experimentation
        Type: general
      – SubjectFull: Narcotics
        Type: general
      – SubjectFull: Analysis of variance
        Type: general
      – SubjectFull: One-way analysis of variance
        Type: general
      – SubjectFull: Statistics
        Type: general
      – SubjectFull: Data analysis software
        Type: general
      – SubjectFull: Confidence intervals
        Type: general
      – SubjectFull: Migraine
        Type: general
    Titles:
      – TitleFull: Synergistic effect of combining dual enkephalinase inhibitor PL37 and sumatriptan in a preclinical model of migraine.
        Type: main
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          Name:
            NameFull: Rossignol, Jeanne
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            NameFull: Ouimet, Tanja
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            NameFull: Poras, Hervé
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            NameFull: Dallel, Radhouane
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            – D: 01
              M: 03
              Text: Mar2024
              Type: published
              Y: 2024
          Identifiers:
            – Type: issn-print
              Value: 00178748
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              Value: 64
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              Value: 3
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            – TitleFull: Headache: The Journal of Head & Face Pain
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