Betahistine Treatment in a Cat Model of Vestibular Pathology: Pharmacokinetic and Pharmacodynamic Approaches

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.

Current Insights into Treating Vertigo in Older Adults

“…With respect to betahistine, both preclinical and clinical studies have suggested a wide range of potential effects. Firstly, it modulates histaminergic neurotransmission by partially agonizing the activity of the H 1 receptor, but it has, however, more potent antagonistic properties on the histamine H 3 receptor, inducing an overall increase in histamine turnover and release [25,26]. Secondly, it affects neuronal excitability and spike generation in lateral and medial vestibular nuclei.…”

“…Ideally, drugs capable of enhancing vestibular compensation may be prescribed in order to induce an acceleration of functional recovery, especially in those patients with reduced mobility, which may prevent a successful vestibular physical rehabilitation. For this purpose, some reports indicate that betahistine [26] or Ginkgo biloba extract, an antioxidant agent with mild antiplatelet activity [35], seem to induce an acceleration of functional recovery. However, the use of betahistine in the routine treatment protocol of patients with AUV may be considered as an option, on the basis of a Cochrane review affirming that low-quality evidence suggests that in patients suffering from vertigo from different causes, there may be a positive effect of this drug in terms of reduction in vertigo symptoms [36].…”

Vestibular Disorders

“…Individual treatment trials suggest that combining orally administered betahistine with the MAO-B inhibitor selegiline may enhance its efficacy: this can be understood in light of the fact that 99% of orally ingested betahistine is metabolized in the gastrointestinal tract by MAO-B/A. This approach has received support from experimental studies in animals in a model of acute unilateral vestibulopathy (21). On the whole, more randomized and controlled trials are needed to study the therapeutic effects of betahistine.…”

L-Thyroxine improves vestibular compensation in a rat model of acute peripheral vestibulopathy

“…Unilateral vestibular lesion also results in an increase in the support surface delimited by the animal’s four paws. This parameter is a good estimate of postural stability and restoration of balance (4, 8, 24, 25). When we compared the support surface area of each group between the preoperative values and the values obtained after UVN (D1-D30), we observed that the UVN-NaCl group significantly increased their support surface area the first 3 days following vestibular lesion (D1 to D3: p < 0.001) and reached pre-operative control values from D7 until D30 ( Figure 1C ).…”