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Martin Canis - One of the best experts on this subject based on the ideXlab platform.

  • role of capillary pericytes and precapillary arterioles in the vascular mechanism of Betahistine in a guinea pig inner ear model
    Life Sciences, 2017
    Co-Authors: Mattis Bertlich, Michael Strupp, Bernhard G. Weiss, Friedrich Ihler, Saskia Freytag, Mark Jakob, Martin Canis
    Abstract:

    Betahistine is a histamine analogue that is used for the treatment of Meniere's disease. Animal studies showed that it increases local blood flow in the stria vascularis. In terms of its mode of action, recent studies have prompted discussion of whether Betahistine actively affects cochlear microcirculation by dilations of pericytes or of precapillary arterioles or by mere downstream effects. Hence, we investigated the effects of Betahistine on cochlear capillary pericytes and precapillary arterioles.The stria vascularis was visualized in 12 guinea pigs by in vivo fluorescence microscopy. In these, 152 pericytes were stained and local diameter at sites of pericyte somas and downstream controls as well as intravascular blood flow were measured before and after Betahistine application. Moreover, in two guinea pigs the precapillary arterioles were visualized by 2-photon-microscopy before and after Betahistine application.There was no significant change in capillary diameter at sites of pericyte somas after Betahistine application compared to controls, baseline or downstream controls, even though cochlear blood flow increased significantly. The two-photon measurements indicated an active dilation of precapillary arterioles.Since we found no evidence that Betahistine affects cochlear microcirculation by cochlear pericytes, its main mode of action is evidently active dilation of pre-capillary arterioles. These findings are in line with similar effects reported in the central nervous system and indicate an active effect on cochlear microcirculation.

  • Betahistine Exerts a Dose-Dependent Effect on Cochlear Stria Vascularis Blood Flow in Guinea Pigs In Vivo
    2016
    Co-Authors: Fritz Ihler, Mattis Bertlich, Kariem Sharaf, Sebastian Strieth, Martin Canis
    Abstract:

    Objective: Betahistine is a histamine H1-receptor agonist and H3-receptor antagonist that is administered to treat Menière’s disease. Despite widespread use, its pharmacological mode of action has not been entirely elucidated. This study investigated the effect of Betahistine on guinea pigs at dosages corresponding to clinically used doses for cochlear microcirculation. Methods: Thirty healthy Dunkin-Hartley guinea pigs were randomly assigned to five groups to receive Betahistine dihydrochloride in a dose of 1,000 mg/kg b. w. (milligram per kilogram body weight), 0.100 mg/kg b. w., 0.010 mg/kg b. w., 0.001 mg/kg b. w. in NaCl 0.9 % or NaCl 0.9 % alone as placebo. Cochlear blood flow and mean arterial pressure were continuously monitored by intravital fluorescence microscopy and invasive blood pressure measurements 3 minutes before and 15 minutes after administration of Betahistine. Results: When Betahistine was administered in a dose of 1.000 mg/kg b. w. cochlear blood flow was increased to a peak value of 1.340 arbitrary units (SD: 0.246; range: 0.933–1.546 arb. units) compared to baseline (p,0.05; Two Way Repeated Measures ANOVA/Bonferroni t-test). The lowest dosage of 0.001 mg/kg b. w. Betahistine or NaCl 0.9 % had the same effect as placebo. Nonlinear regression revealed that there was a sigmoid correlation between increase in blood flow and dosages. Conclusions: Betahistine has a dose-dependent effect on the increase of blood flow in cochlear capillaries. The effects of th

  • Betahistine metabolites, Aminoethylpyridine, and Hydroxyethylpyridine increase cochlear blood flow in guinea pigs in vivo
    International journal of audiology, 2014
    Co-Authors: Mattis Bertlich, Fritz Ihler, Kariem Sharaf, Michael Strupp, Bernhard G. Weiss, Martin Canis
    Abstract:

    AbstractObjective: Betahistine is a histamine-like drug that is used in the treatment of Meniere's disease. It is commonly believed that Betahistine increases cochlear blood flow and thus decreases the endolymphatic hydrops that is the cause of Meniere's. Despite common clinical use, there is little understanding of the kinetics or effects of its metabolites. This study investigated the effect of the Betahistine metabolites aminoethylpyridine, hydroxyethylpyridine, and pyridylacetic acid on cochlear microcirculation. Design: Guinea pigs were randomly assigned to one of the groups: placebo, Betahistine, or equimolar amounts of aminoethylpyridine, hydroxyethylpyridine, or pyridylacetic acid. Cochlear blood flow and mean arterial pressure were recorded for three minutes before and 15 minutes after treatment. Study sample: Thirty Dunkin-Hartley guinea pigs assigned to one of five groups with six guinea pigs per group. Results: Betahistine, aminoethylpyridine, and hydroxyethylpyridine caused a significant incr...

  • Betahistine exerts a dose dependent effect on cochlear stria vascularis blood flow in guinea pigs in vivo
    PLOS ONE, 2012
    Co-Authors: Fritz Ihler, Mattis Bertlich, Kariem Sharaf, Sebastian Strieth, Michael Strupp, Martin Canis
    Abstract:

    Objective Betahistine is a histamine H1-receptor agonist and H3-receptor antagonist that is administered to treat Meniere’s disease. Despite widespread use, its pharmacological mode of action has not been entirely elucidated. This study investigated the effect of Betahistine on guinea pigs at dosages corresponding to clinically used doses for cochlear microcirculation. Methods Thirty healthy Dunkin-Hartley guinea pigs were randomly assigned to five groups to receive Betahistine dihydrochloride in a dose of 1,000 mg/kg b. w. (milligram per kilogram body weight), 0.100 mg/kg b. w., 0.010 mg/kg b. w., 0.001 mg/kg b. w. in NaCl 0.9% or NaCl 0.9% alone as placebo. Cochlear blood flow and mean arterial pressure were continuously monitored by intravital fluorescence microscopy and invasive blood pressure measurements 3 minutes before and 15 minutes after administration of Betahistine. Results When Betahistine was administered in a dose of 1.000 mg/kg b. w. cochlear blood flow was increased to a peak value of 1.340 arbitrary units (SD: 0.246; range: 0.933–1.546 arb. units) compared to baseline (p<0.05; Two Way Repeated Measures ANOVA/Bonferroni t-test). The lowest dosage of 0.001 mg/kg b. w. Betahistine or NaCl 0.9% had the same effect as placebo. Nonlinear regression revealed that there was a sigmoid correlation between increase in blood flow and dosages. Conclusions Betahistine has a dose-dependent effect on the increase of blood flow in cochlear capillaries. The effects of the dosage range of Betahistine on cochlear microcirculation corresponded well to clinically used single dosages to treat Meniere’s disease. Our data suggest that the improved effects of higher doses of Betahistine in the treatment of Meniere’s disease might be due to a corresponding increase of cochlear blood flow.

Michel Lacour - One of the best experts on this subject based on the ideXlab platform.

  • Good Clinical Approach: Delphi Consensus for the Use of Betahistine in Menière's Disease.
    International journal of otolaryngology, 2018
    Co-Authors: Augusto Pietro Casani, Elena Navari, Giorgio Guidetti, Michel Lacour
    Abstract:

    Meniere’s disease is a disorder of the inner ear that causes vertigo, tinnitus, fullness, and hearing loss. Several pharmacological treatments are available, but none of them has shown significant results. Betahistine has been largely used but its effect on the main symptoms of Meniere’s disease remains unclear. In order to improve clinical appropriateness and to reduce the heterogeneity of the therapeutic approaches for Meniere’s disease, we proposed a European Consensus Conference on Betahistine’s prescription. A group of European experts in vestibular disorders completed a questionnaire, prepared by opinion leaders, on the use of Betahistine in Meniere’s disease. The Delphi method was used as an iterative investigation method in order to increase and establish the consensus. While Betahistine was considered useful to reduce the number of the vertigo attacks during the intercritical phase of the disease, its use during attacks was considered helpful only when associated with other drugs. Betahistine was not considered useful for preventing hearing loss. The experts support the use of Betahistine during the intercritical phase of the disease to reduce the number and severity of vertigo episodes. They also defined the parameters for a good clinical approach to evaluate the efficacy of Betahistine treatment for Meniere’s disease.

  • Betahistine treatment in a cat model of vestibular pathology pharmacokinetic and pharmacodynamic approaches
    Frontiers in Neurology, 2018
    Co-Authors: Brahim Tighilet, Jacques Leonard, Isabelle Watabe, Laurence Bernarddemanze, Michel Lacour
    Abstract:

    This study is a pharmacokinetic (PK) and pharmacodynamics (PD) approach using Betahistine doses levels in unilateral vestibular neurectomized cats (UVN) comparable to those used in humans for treating patients with Meniere's disease. The aim is to investigate for the first time oral Betahistine administration (0.2 and 2 mg/kg/day) with plasma concentrations of Betahistine and its major metabolite 2-pyridylacetic acid (2-PAA) (N = 9 cats), the time course of posture recovery (N = 13 cats), and the regulation of the enzyme synthesizing histamine (histidine decarboxylase: HDC) in the tuberomammillary nuclei (TMN) of UVN treated animals (N = the same 13 cats plus 4 negative control cats). In addition the effect of co-administration of the lower Betahistine dose (0.2 mg/kg/day) and selegiline (1 mg/kg/day), an inhibitor of the monamine oxidase B (MAOBi) implicated in Betahistine catabolism was investigated. The PK parameters were the peak concentration (Cmax), the time when the maximum concentration is reached (Tmax) for both Betahistine and 2-PAA and the area under the curve (AUC). The PD approach consisted at quantifying the surface support area, which is a good estimation of posture recovery. The plasma concentration-time-profiles of Betahistine and 2-PAA in cats were characterized by early Cmax-values followed by a phase of rapid decrease of plasma concentrations and a final long lasting low level of plasma concentrations. Co administration of selegiline and Betahistine increased values of Cmax and AUC up to 146- and 180-fold, respectively. The lowest dose of Betahistine (0.2 mg/kg) has no effects on postural function recovery but induced an acute symptomatic effect characterized by a fast balance improvement (4-6 days). The higher dose (2 mg/kg) and the co-administration treatment induced both this acute effect plus a significant acceleration of the recovery process. The histaminergic activity of the neurons in the TMN was significantly increased under treatment with the 2 mg/kg Betahistine daily dose, but not with the lower dose alone or in combination with selegiline. The results show for the first time that faster balance recovery in UVN treated cats is accompanied with high plasma concentrations of Betahistine and 2-PAA, and upregulation of HDC immunopositive neurons in the TMN. The higher Betahistine dose gives results similar to those obtained with the lower dose when co-administrated with an inhibitor of Betahistine metabolism, selegiline. From a clinical point of view, the study provides new perspectives for Meniere's disease treatment, regarding the daily Betahistine dose that should be necessary for fast and slow metabolizers.

  • Betahistine Treatment in a Cat Model of Vestibular Pathology: Pharmacokinetic and Pharmacodynamic Approaches.
    Frontiers in neurology, 2018
    Co-Authors: Brahim Tighilet, Jacques Leonard, Isabelle Watabe, Laurence Bernard-demanze, Michel Lacour
    Abstract:

    This study is a pharmacokinetic and pharmacodynamic approach using Betahistine doses levels in unilateral vestibular neurectomized cats (UVN) comparable to those used in humans for treating patients with Meniere’s disease. The aim is to investigate for the first time oral Betahistine administration (0.2 and 2 mg/kg/day) with plasma concentrations of Betahistine and its major metabolite 2PAA (N=9 cats), the time course of posture recovery (N=13 cats), and the regulation of histidine decarboxylase (HDC: enzyme synthesizing histamine) in the tuberomammillary nuclei (TMN) of UVN treated animals (N= the same 13 cats plus 4 negative control cats). In addition the effect of co-administration of the lower Betahistine dose (0.2 mg/kg/day) and selegiline (1 mg/kg/day), an inhibitor of the monamine oxidase B (MAOBi) implicated in Betahistine catabolism was investigated. The pharmacokinetic parameters were the peak concentration (Cmax), the time when the maximum concentration is reached (Tmax) for both Betahistine and 2PAA and the area under the curve (AUC). The pharmacodynamic approach consisted at quantifying the surface support area, which is a good estimation of posture recovery. The plasma concentration-time-profiles of Betahistine and 2PAA in cats were characterized by early Cmax values followed by a phase of rapid decrease of plasma concentrations and a final long lasting low level of plasma concentrations. Co administration of selegiline and Betahistine increased values of Cmax and AUC up to 146- and 180-fold, respectively. The lowest dose of Betahistine (0.2 mg/kg) has no effects on postural function recovery but induced an acute symptomatic effect characterized by a fast balance improvement (4-6 days). The higher dose (2 mg/kg) and the co-administration treatment induced both this acute effect plus a significant acceleration of the recovery process. The histaminergic activity of the neurons in the TMN was significantly increased under treatment with the 2mg/kg Betahistine daily dose, but not with the lower dose alone or in combination with selegiline. The results show for the first time that faster balance recovery in UVN treated cats is accompanied with high plasma concentrations of Betahistine and 2PAA, and upregulation of HDC immunopositive neurons in the TMN. The higher Betahistine dose gives results similar to

  • Betahistine Treatment in a Cat Model of Vestibular Pathology: Pharmacokinetic and Pharmacodynamic Approaches
    Frontiers Media S.A., 2018
    Co-Authors: Brahim Tighilet, Jacques Leonard, Isabelle Watabe, Laurence Bernard-demanze, Michel Lacour
    Abstract:

    This study is a pharmacokinetic (PK) and pharmacodynamics (PD) approach using Betahistine doses levels in unilateral vestibular neurectomized cats (UVN) comparable to those used in humans for treating patients with Menière's disease. The aim is to investigate for the first time oral Betahistine administration (0.2 and 2 mg/kg/day) with plasma concentrations of Betahistine and its major metabolite 2-pyridylacetic acid (2-PAA) (N = 9 cats), the time course of posture recovery (N = 13 cats), and the regulation of the enzyme synthesizing histamine (histidine decarboxylase: HDC) in the tuberomammillary nuclei (TMN) of UVN treated animals (N = the same 13 cats plus 4 negative control cats). In addition the effect of co-administration of the lower Betahistine dose (0.2 mg/kg/day) and selegiline (1 mg/kg/day), an inhibitor of the monamine oxidase B (MAOBi) implicated in Betahistine catabolism was investigated. The PK parameters were the peak concentration (Cmax), the time when the maximum concentration is reached (Tmax) for both Betahistine and 2-PAA and the area under the curve (AUC). The PD approach consisted at quantifying the surface support area, which is a good estimation of posture recovery. The plasma concentration-time-profiles of Betahistine and 2-PAA in cats were characterized by early Cmax-values followed by a phase of rapid decrease of plasma concentrations and a final long lasting low level of plasma concentrations. Co administration of selegiline and Betahistine increased values of Cmax and AUC up to 146- and 180-fold, respectively. The lowest dose of Betahistine (0.2 mg/kg) has no effects on postural function recovery but induced an acute symptomatic effect characterized by a fast balance improvement (4–6 days). The higher dose (2 mg/kg) and the co-administration treatment induced both this acute effect plus a significant acceleration of the recovery process. The histaminergic activity of the neurons in the TMN was significantly increased under treatment with the 2 mg/kg Betahistine daily dose, but not with the lower dose alone or in combination with selegiline. The results show for the first time that faster balance recovery in UVN treated cats is accompanied with high plasma concentrations of Betahistine and 2-PAA, and upregulation of HDC immunopositive neurons in the TMN. The higher Betahistine dose gives results similar to those obtained with the lower dose when co-administrated with an inhibitor of Betahistine metabolism, selegiline. From a clinical point of view, the study provides new perspectives for Menière's disease treatment, regarding the daily Betahistine dose that should be necessary for fast and slow metabolizers

  • Data_Sheet_1_Betahistine Treatment in a Cat Model of Vestibular Pathology: Pharmacokinetic and Pharmacodynamic Approaches.docx
    2018
    Co-Authors: Brahim Tighilet, Jacques Leonard, Isabelle Watabe, Laurence Bernard-demanze, Michel Lacour
    Abstract:

    This study is a pharmacokinetic (PK) and pharmacodynamics (PD) approach using Betahistine doses levels in unilateral vestibular neurectomized cats (UVN) comparable to those used in humans for treating patients with Menière's disease. The aim is to investigate for the first time oral Betahistine administration (0.2 and 2 mg/kg/day) with plasma concentrations of Betahistine and its major metabolite 2-pyridylacetic acid (2-PAA) (N = 9 cats), the time course of posture recovery (N = 13 cats), and the regulation of the enzyme synthesizing histamine (histidine decarboxylase: HDC) in the tuberomammillary nuclei (TMN) of UVN treated animals (N = the same 13 cats plus 4 negative control cats). In addition the effect of co-administration of the lower Betahistine dose (0.2 mg/kg/day) and selegiline (1 mg/kg/day), an inhibitor of the monamine oxidase B (MAOBi) implicated in Betahistine catabolism was investigated. The PK parameters were the peak concentration (Cmax), the time when the maximum concentration is reached (Tmax) for both Betahistine and 2-PAA and the area under the curve (AUC). The PD approach consisted at quantifying the surface support area, which is a good estimation of posture recovery. The plasma concentration-time-profiles of Betahistine and 2-PAA in cats were characterized by early Cmax-values followed by a phase of rapid decrease of plasma concentrations and a final long lasting low level of plasma concentrations. Co administration of selegiline and Betahistine increased values of Cmax and AUC up to 146- and 180-fold, respectively. The lowest dose of Betahistine (0.2 mg/kg) has no effects on postural function recovery but induced an acute symptomatic effect characterized by a fast balance improvement (4–6 days). The higher dose (2 mg/kg) and the co-administration treatment induced both this acute effect plus a significant acceleration of the recovery process. The histaminergic activity of the neurons in the TMN was significantly increased under treatment with the 2 mg/kg Betahistine daily dose, but not with the lower dose alone or in combination with selegiline. The results show for the first time that faster balance recovery in UVN treated cats is accompanied with high plasma concentrations of Betahistine and 2-PAA, and upregulation of HDC immunopositive neurons in the TMN. The higher Betahistine dose gives results similar to those obtained with the lower dose when co-administrated with an inhibitor of Betahistine metabolism, selegiline. From a clinical point of view, the study provides new perspectives for Menière's disease treatment, regarding the daily Betahistine dose that should be necessary for fast and slow metabolizers.

Fritz Ihler - One of the best experts on this subject based on the ideXlab platform.

  • Betahistine Exerts a Dose-Dependent Effect on Cochlear Stria Vascularis Blood Flow in Guinea Pigs In Vivo
    2016
    Co-Authors: Fritz Ihler, Mattis Bertlich, Kariem Sharaf, Sebastian Strieth, Martin Canis
    Abstract:

    Objective: Betahistine is a histamine H1-receptor agonist and H3-receptor antagonist that is administered to treat Menière’s disease. Despite widespread use, its pharmacological mode of action has not been entirely elucidated. This study investigated the effect of Betahistine on guinea pigs at dosages corresponding to clinically used doses for cochlear microcirculation. Methods: Thirty healthy Dunkin-Hartley guinea pigs were randomly assigned to five groups to receive Betahistine dihydrochloride in a dose of 1,000 mg/kg b. w. (milligram per kilogram body weight), 0.100 mg/kg b. w., 0.010 mg/kg b. w., 0.001 mg/kg b. w. in NaCl 0.9 % or NaCl 0.9 % alone as placebo. Cochlear blood flow and mean arterial pressure were continuously monitored by intravital fluorescence microscopy and invasive blood pressure measurements 3 minutes before and 15 minutes after administration of Betahistine. Results: When Betahistine was administered in a dose of 1.000 mg/kg b. w. cochlear blood flow was increased to a peak value of 1.340 arbitrary units (SD: 0.246; range: 0.933–1.546 arb. units) compared to baseline (p,0.05; Two Way Repeated Measures ANOVA/Bonferroni t-test). The lowest dosage of 0.001 mg/kg b. w. Betahistine or NaCl 0.9 % had the same effect as placebo. Nonlinear regression revealed that there was a sigmoid correlation between increase in blood flow and dosages. Conclusions: Betahistine has a dose-dependent effect on the increase of blood flow in cochlear capillaries. The effects of th

  • Betahistine metabolites, Aminoethylpyridine, and Hydroxyethylpyridine increase cochlear blood flow in guinea pigs in vivo
    International journal of audiology, 2014
    Co-Authors: Mattis Bertlich, Fritz Ihler, Kariem Sharaf, Michael Strupp, Bernhard G. Weiss, Martin Canis
    Abstract:

    AbstractObjective: Betahistine is a histamine-like drug that is used in the treatment of Meniere's disease. It is commonly believed that Betahistine increases cochlear blood flow and thus decreases the endolymphatic hydrops that is the cause of Meniere's. Despite common clinical use, there is little understanding of the kinetics or effects of its metabolites. This study investigated the effect of the Betahistine metabolites aminoethylpyridine, hydroxyethylpyridine, and pyridylacetic acid on cochlear microcirculation. Design: Guinea pigs were randomly assigned to one of the groups: placebo, Betahistine, or equimolar amounts of aminoethylpyridine, hydroxyethylpyridine, or pyridylacetic acid. Cochlear blood flow and mean arterial pressure were recorded for three minutes before and 15 minutes after treatment. Study sample: Thirty Dunkin-Hartley guinea pigs assigned to one of five groups with six guinea pigs per group. Results: Betahistine, aminoethylpyridine, and hydroxyethylpyridine caused a significant incr...

  • Betahistine exerts a dose dependent effect on cochlear stria vascularis blood flow in guinea pigs in vivo
    PLOS ONE, 2012
    Co-Authors: Fritz Ihler, Mattis Bertlich, Kariem Sharaf, Sebastian Strieth, Michael Strupp, Martin Canis
    Abstract:

    Objective Betahistine is a histamine H1-receptor agonist and H3-receptor antagonist that is administered to treat Meniere’s disease. Despite widespread use, its pharmacological mode of action has not been entirely elucidated. This study investigated the effect of Betahistine on guinea pigs at dosages corresponding to clinically used doses for cochlear microcirculation. Methods Thirty healthy Dunkin-Hartley guinea pigs were randomly assigned to five groups to receive Betahistine dihydrochloride in a dose of 1,000 mg/kg b. w. (milligram per kilogram body weight), 0.100 mg/kg b. w., 0.010 mg/kg b. w., 0.001 mg/kg b. w. in NaCl 0.9% or NaCl 0.9% alone as placebo. Cochlear blood flow and mean arterial pressure were continuously monitored by intravital fluorescence microscopy and invasive blood pressure measurements 3 minutes before and 15 minutes after administration of Betahistine. Results When Betahistine was administered in a dose of 1.000 mg/kg b. w. cochlear blood flow was increased to a peak value of 1.340 arbitrary units (SD: 0.246; range: 0.933–1.546 arb. units) compared to baseline (p<0.05; Two Way Repeated Measures ANOVA/Bonferroni t-test). The lowest dosage of 0.001 mg/kg b. w. Betahistine or NaCl 0.9% had the same effect as placebo. Nonlinear regression revealed that there was a sigmoid correlation between increase in blood flow and dosages. Conclusions Betahistine has a dose-dependent effect on the increase of blood flow in cochlear capillaries. The effects of the dosage range of Betahistine on cochlear microcirculation corresponded well to clinically used single dosages to treat Meniere’s disease. Our data suggest that the improved effects of higher doses of Betahistine in the treatment of Meniere’s disease might be due to a corresponding increase of cochlear blood flow.

Brahim Tighilet - One of the best experts on this subject based on the ideXlab platform.

  • Betahistine treatment in a cat model of vestibular pathology pharmacokinetic and pharmacodynamic approaches
    Frontiers in Neurology, 2018
    Co-Authors: Brahim Tighilet, Jacques Leonard, Isabelle Watabe, Laurence Bernarddemanze, Michel Lacour
    Abstract:

    This study is a pharmacokinetic (PK) and pharmacodynamics (PD) approach using Betahistine doses levels in unilateral vestibular neurectomized cats (UVN) comparable to those used in humans for treating patients with Meniere's disease. The aim is to investigate for the first time oral Betahistine administration (0.2 and 2 mg/kg/day) with plasma concentrations of Betahistine and its major metabolite 2-pyridylacetic acid (2-PAA) (N = 9 cats), the time course of posture recovery (N = 13 cats), and the regulation of the enzyme synthesizing histamine (histidine decarboxylase: HDC) in the tuberomammillary nuclei (TMN) of UVN treated animals (N = the same 13 cats plus 4 negative control cats). In addition the effect of co-administration of the lower Betahistine dose (0.2 mg/kg/day) and selegiline (1 mg/kg/day), an inhibitor of the monamine oxidase B (MAOBi) implicated in Betahistine catabolism was investigated. The PK parameters were the peak concentration (Cmax), the time when the maximum concentration is reached (Tmax) for both Betahistine and 2-PAA and the area under the curve (AUC). The PD approach consisted at quantifying the surface support area, which is a good estimation of posture recovery. The plasma concentration-time-profiles of Betahistine and 2-PAA in cats were characterized by early Cmax-values followed by a phase of rapid decrease of plasma concentrations and a final long lasting low level of plasma concentrations. Co administration of selegiline and Betahistine increased values of Cmax and AUC up to 146- and 180-fold, respectively. The lowest dose of Betahistine (0.2 mg/kg) has no effects on postural function recovery but induced an acute symptomatic effect characterized by a fast balance improvement (4-6 days). The higher dose (2 mg/kg) and the co-administration treatment induced both this acute effect plus a significant acceleration of the recovery process. The histaminergic activity of the neurons in the TMN was significantly increased under treatment with the 2 mg/kg Betahistine daily dose, but not with the lower dose alone or in combination with selegiline. The results show for the first time that faster balance recovery in UVN treated cats is accompanied with high plasma concentrations of Betahistine and 2-PAA, and upregulation of HDC immunopositive neurons in the TMN. The higher Betahistine dose gives results similar to those obtained with the lower dose when co-administrated with an inhibitor of Betahistine metabolism, selegiline. From a clinical point of view, the study provides new perspectives for Meniere's disease treatment, regarding the daily Betahistine dose that should be necessary for fast and slow metabolizers.

  • Betahistine Treatment in a Cat Model of Vestibular Pathology: Pharmacokinetic and Pharmacodynamic Approaches.
    Frontiers in neurology, 2018
    Co-Authors: Brahim Tighilet, Jacques Leonard, Isabelle Watabe, Laurence Bernard-demanze, Michel Lacour
    Abstract:

    This study is a pharmacokinetic and pharmacodynamic approach using Betahistine doses levels in unilateral vestibular neurectomized cats (UVN) comparable to those used in humans for treating patients with Meniere’s disease. The aim is to investigate for the first time oral Betahistine administration (0.2 and 2 mg/kg/day) with plasma concentrations of Betahistine and its major metabolite 2PAA (N=9 cats), the time course of posture recovery (N=13 cats), and the regulation of histidine decarboxylase (HDC: enzyme synthesizing histamine) in the tuberomammillary nuclei (TMN) of UVN treated animals (N= the same 13 cats plus 4 negative control cats). In addition the effect of co-administration of the lower Betahistine dose (0.2 mg/kg/day) and selegiline (1 mg/kg/day), an inhibitor of the monamine oxidase B (MAOBi) implicated in Betahistine catabolism was investigated. The pharmacokinetic parameters were the peak concentration (Cmax), the time when the maximum concentration is reached (Tmax) for both Betahistine and 2PAA and the area under the curve (AUC). The pharmacodynamic approach consisted at quantifying the surface support area, which is a good estimation of posture recovery. The plasma concentration-time-profiles of Betahistine and 2PAA in cats were characterized by early Cmax values followed by a phase of rapid decrease of plasma concentrations and a final long lasting low level of plasma concentrations. Co administration of selegiline and Betahistine increased values of Cmax and AUC up to 146- and 180-fold, respectively. The lowest dose of Betahistine (0.2 mg/kg) has no effects on postural function recovery but induced an acute symptomatic effect characterized by a fast balance improvement (4-6 days). The higher dose (2 mg/kg) and the co-administration treatment induced both this acute effect plus a significant acceleration of the recovery process. The histaminergic activity of the neurons in the TMN was significantly increased under treatment with the 2mg/kg Betahistine daily dose, but not with the lower dose alone or in combination with selegiline. The results show for the first time that faster balance recovery in UVN treated cats is accompanied with high plasma concentrations of Betahistine and 2PAA, and upregulation of HDC immunopositive neurons in the TMN. The higher Betahistine dose gives results similar to

  • Betahistine Treatment in a Cat Model of Vestibular Pathology: Pharmacokinetic and Pharmacodynamic Approaches
    Frontiers Media S.A., 2018
    Co-Authors: Brahim Tighilet, Jacques Leonard, Isabelle Watabe, Laurence Bernard-demanze, Michel Lacour
    Abstract:

    This study is a pharmacokinetic (PK) and pharmacodynamics (PD) approach using Betahistine doses levels in unilateral vestibular neurectomized cats (UVN) comparable to those used in humans for treating patients with Menière's disease. The aim is to investigate for the first time oral Betahistine administration (0.2 and 2 mg/kg/day) with plasma concentrations of Betahistine and its major metabolite 2-pyridylacetic acid (2-PAA) (N = 9 cats), the time course of posture recovery (N = 13 cats), and the regulation of the enzyme synthesizing histamine (histidine decarboxylase: HDC) in the tuberomammillary nuclei (TMN) of UVN treated animals (N = the same 13 cats plus 4 negative control cats). In addition the effect of co-administration of the lower Betahistine dose (0.2 mg/kg/day) and selegiline (1 mg/kg/day), an inhibitor of the monamine oxidase B (MAOBi) implicated in Betahistine catabolism was investigated. The PK parameters were the peak concentration (Cmax), the time when the maximum concentration is reached (Tmax) for both Betahistine and 2-PAA and the area under the curve (AUC). The PD approach consisted at quantifying the surface support area, which is a good estimation of posture recovery. The plasma concentration-time-profiles of Betahistine and 2-PAA in cats were characterized by early Cmax-values followed by a phase of rapid decrease of plasma concentrations and a final long lasting low level of plasma concentrations. Co administration of selegiline and Betahistine increased values of Cmax and AUC up to 146- and 180-fold, respectively. The lowest dose of Betahistine (0.2 mg/kg) has no effects on postural function recovery but induced an acute symptomatic effect characterized by a fast balance improvement (4–6 days). The higher dose (2 mg/kg) and the co-administration treatment induced both this acute effect plus a significant acceleration of the recovery process. The histaminergic activity of the neurons in the TMN was significantly increased under treatment with the 2 mg/kg Betahistine daily dose, but not with the lower dose alone or in combination with selegiline. The results show for the first time that faster balance recovery in UVN treated cats is accompanied with high plasma concentrations of Betahistine and 2-PAA, and upregulation of HDC immunopositive neurons in the TMN. The higher Betahistine dose gives results similar to those obtained with the lower dose when co-administrated with an inhibitor of Betahistine metabolism, selegiline. From a clinical point of view, the study provides new perspectives for Menière's disease treatment, regarding the daily Betahistine dose that should be necessary for fast and slow metabolizers

  • Data_Sheet_1_Betahistine Treatment in a Cat Model of Vestibular Pathology: Pharmacokinetic and Pharmacodynamic Approaches.docx
    2018
    Co-Authors: Brahim Tighilet, Jacques Leonard, Isabelle Watabe, Laurence Bernard-demanze, Michel Lacour
    Abstract:

    This study is a pharmacokinetic (PK) and pharmacodynamics (PD) approach using Betahistine doses levels in unilateral vestibular neurectomized cats (UVN) comparable to those used in humans for treating patients with Menière's disease. The aim is to investigate for the first time oral Betahistine administration (0.2 and 2 mg/kg/day) with plasma concentrations of Betahistine and its major metabolite 2-pyridylacetic acid (2-PAA) (N = 9 cats), the time course of posture recovery (N = 13 cats), and the regulation of the enzyme synthesizing histamine (histidine decarboxylase: HDC) in the tuberomammillary nuclei (TMN) of UVN treated animals (N = the same 13 cats plus 4 negative control cats). In addition the effect of co-administration of the lower Betahistine dose (0.2 mg/kg/day) and selegiline (1 mg/kg/day), an inhibitor of the monamine oxidase B (MAOBi) implicated in Betahistine catabolism was investigated. The PK parameters were the peak concentration (Cmax), the time when the maximum concentration is reached (Tmax) for both Betahistine and 2-PAA and the area under the curve (AUC). The PD approach consisted at quantifying the surface support area, which is a good estimation of posture recovery. The plasma concentration-time-profiles of Betahistine and 2-PAA in cats were characterized by early Cmax-values followed by a phase of rapid decrease of plasma concentrations and a final long lasting low level of plasma concentrations. Co administration of selegiline and Betahistine increased values of Cmax and AUC up to 146- and 180-fold, respectively. The lowest dose of Betahistine (0.2 mg/kg) has no effects on postural function recovery but induced an acute symptomatic effect characterized by a fast balance improvement (4–6 days). The higher dose (2 mg/kg) and the co-administration treatment induced both this acute effect plus a significant acceleration of the recovery process. The histaminergic activity of the neurons in the TMN was significantly increased under treatment with the 2 mg/kg Betahistine daily dose, but not with the lower dose alone or in combination with selegiline. The results show for the first time that faster balance recovery in UVN treated cats is accompanied with high plasma concentrations of Betahistine and 2-PAA, and upregulation of HDC immunopositive neurons in the TMN. The higher Betahistine dose gives results similar to those obtained with the lower dose when co-administrated with an inhibitor of Betahistine metabolism, selegiline. From a clinical point of view, the study provides new perspectives for Menière's disease treatment, regarding the daily Betahistine dose that should be necessary for fast and slow metabolizers.

  • Betahistine in the treatment of Ménière’s disease
    2016
    Co-Authors: Michel Lacour, Miroslav Novotny, Paul H Van De Heyning, Brahim Tighilet
    Abstract:

    Abstract: Ménière’s disease and related disease of the vestibular system are common and debilitating. Current therapy is multi-modal and includes drug therapy and lifestyle adaptations. Unfortunately many of the drugs used in treatment (particularly those used to control nausea) are sedative and hamper the process of vestibular compensation. Although Betahistine (Serc®, BetaSerc®; Solvay Pharmaceuticals) is the mainstay of drug treatment in these illnesses, its effi cacy has not, until recently, been evaluated to modern standards. Betahistine is an analog of histamine with weak agonist properties at histamine H1 receptors and more potent anatgonistic effects at histamine H3 receptors. Growing evidence suggests that the mechanism of action of Betahistine lies in the central nervous system and in particularly in the neuronal systems involved in the recovery from process after vestibular loss. The histaminergic neurones of the tuberomamillary and vestibular nuclei are implicated. In recent years the clinical effi cacy of Betahistine has been demonstrated in double-blind, randomized, placebo, and active controlled studies in adequate numbers of patients. Although the results of comparative studies between Betahistine and other drugs (fl unarizine, cinnarizine, and cinnarizine + dimenhydrate) are equivocal, the effi cacy of Betahistine is now clear

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  • role of capillary pericytes and precapillary arterioles in the vascular mechanism of Betahistine in a guinea pig inner ear model
    Life Sciences, 2017
    Co-Authors: Mattis Bertlich, Michael Strupp, Bernhard G. Weiss, Friedrich Ihler, Saskia Freytag, Mark Jakob, Martin Canis
    Abstract:

    Betahistine is a histamine analogue that is used for the treatment of Meniere's disease. Animal studies showed that it increases local blood flow in the stria vascularis. In terms of its mode of action, recent studies have prompted discussion of whether Betahistine actively affects cochlear microcirculation by dilations of pericytes or of precapillary arterioles or by mere downstream effects. Hence, we investigated the effects of Betahistine on cochlear capillary pericytes and precapillary arterioles.The stria vascularis was visualized in 12 guinea pigs by in vivo fluorescence microscopy. In these, 152 pericytes were stained and local diameter at sites of pericyte somas and downstream controls as well as intravascular blood flow were measured before and after Betahistine application. Moreover, in two guinea pigs the precapillary arterioles were visualized by 2-photon-microscopy before and after Betahistine application.There was no significant change in capillary diameter at sites of pericyte somas after Betahistine application compared to controls, baseline or downstream controls, even though cochlear blood flow increased significantly. The two-photon measurements indicated an active dilation of precapillary arterioles.Since we found no evidence that Betahistine affects cochlear microcirculation by cochlear pericytes, its main mode of action is evidently active dilation of pre-capillary arterioles. These findings are in line with similar effects reported in the central nervous system and indicate an active effect on cochlear microcirculation.

  • Betahistine Exerts a Dose-Dependent Effect on Cochlear Stria Vascularis Blood Flow in Guinea Pigs In Vivo
    2016
    Co-Authors: Fritz Ihler, Mattis Bertlich, Kariem Sharaf, Sebastian Strieth, Martin Canis
    Abstract:

    Objective: Betahistine is a histamine H1-receptor agonist and H3-receptor antagonist that is administered to treat Menière’s disease. Despite widespread use, its pharmacological mode of action has not been entirely elucidated. This study investigated the effect of Betahistine on guinea pigs at dosages corresponding to clinically used doses for cochlear microcirculation. Methods: Thirty healthy Dunkin-Hartley guinea pigs were randomly assigned to five groups to receive Betahistine dihydrochloride in a dose of 1,000 mg/kg b. w. (milligram per kilogram body weight), 0.100 mg/kg b. w., 0.010 mg/kg b. w., 0.001 mg/kg b. w. in NaCl 0.9 % or NaCl 0.9 % alone as placebo. Cochlear blood flow and mean arterial pressure were continuously monitored by intravital fluorescence microscopy and invasive blood pressure measurements 3 minutes before and 15 minutes after administration of Betahistine. Results: When Betahistine was administered in a dose of 1.000 mg/kg b. w. cochlear blood flow was increased to a peak value of 1.340 arbitrary units (SD: 0.246; range: 0.933–1.546 arb. units) compared to baseline (p,0.05; Two Way Repeated Measures ANOVA/Bonferroni t-test). The lowest dosage of 0.001 mg/kg b. w. Betahistine or NaCl 0.9 % had the same effect as placebo. Nonlinear regression revealed that there was a sigmoid correlation between increase in blood flow and dosages. Conclusions: Betahistine has a dose-dependent effect on the increase of blood flow in cochlear capillaries. The effects of th

  • Betahistine metabolites, Aminoethylpyridine, and Hydroxyethylpyridine increase cochlear blood flow in guinea pigs in vivo
    International journal of audiology, 2014
    Co-Authors: Mattis Bertlich, Fritz Ihler, Kariem Sharaf, Michael Strupp, Bernhard G. Weiss, Martin Canis
    Abstract:

    AbstractObjective: Betahistine is a histamine-like drug that is used in the treatment of Meniere's disease. It is commonly believed that Betahistine increases cochlear blood flow and thus decreases the endolymphatic hydrops that is the cause of Meniere's. Despite common clinical use, there is little understanding of the kinetics or effects of its metabolites. This study investigated the effect of the Betahistine metabolites aminoethylpyridine, hydroxyethylpyridine, and pyridylacetic acid on cochlear microcirculation. Design: Guinea pigs were randomly assigned to one of the groups: placebo, Betahistine, or equimolar amounts of aminoethylpyridine, hydroxyethylpyridine, or pyridylacetic acid. Cochlear blood flow and mean arterial pressure were recorded for three minutes before and 15 minutes after treatment. Study sample: Thirty Dunkin-Hartley guinea pigs assigned to one of five groups with six guinea pigs per group. Results: Betahistine, aminoethylpyridine, and hydroxyethylpyridine caused a significant incr...

  • Betahistine exerts a dose dependent effect on cochlear stria vascularis blood flow in guinea pigs in vivo
    PLOS ONE, 2012
    Co-Authors: Fritz Ihler, Mattis Bertlich, Kariem Sharaf, Sebastian Strieth, Michael Strupp, Martin Canis
    Abstract:

    Objective Betahistine is a histamine H1-receptor agonist and H3-receptor antagonist that is administered to treat Meniere’s disease. Despite widespread use, its pharmacological mode of action has not been entirely elucidated. This study investigated the effect of Betahistine on guinea pigs at dosages corresponding to clinically used doses for cochlear microcirculation. Methods Thirty healthy Dunkin-Hartley guinea pigs were randomly assigned to five groups to receive Betahistine dihydrochloride in a dose of 1,000 mg/kg b. w. (milligram per kilogram body weight), 0.100 mg/kg b. w., 0.010 mg/kg b. w., 0.001 mg/kg b. w. in NaCl 0.9% or NaCl 0.9% alone as placebo. Cochlear blood flow and mean arterial pressure were continuously monitored by intravital fluorescence microscopy and invasive blood pressure measurements 3 minutes before and 15 minutes after administration of Betahistine. Results When Betahistine was administered in a dose of 1.000 mg/kg b. w. cochlear blood flow was increased to a peak value of 1.340 arbitrary units (SD: 0.246; range: 0.933–1.546 arb. units) compared to baseline (p<0.05; Two Way Repeated Measures ANOVA/Bonferroni t-test). The lowest dosage of 0.001 mg/kg b. w. Betahistine or NaCl 0.9% had the same effect as placebo. Nonlinear regression revealed that there was a sigmoid correlation between increase in blood flow and dosages. Conclusions Betahistine has a dose-dependent effect on the increase of blood flow in cochlear capillaries. The effects of the dosage range of Betahistine on cochlear microcirculation corresponded well to clinically used single dosages to treat Meniere’s disease. Our data suggest that the improved effects of higher doses of Betahistine in the treatment of Meniere’s disease might be due to a corresponding increase of cochlear blood flow.