[Vestibular rehabilitation for peripheral vestibular hypofunction: an interdisciplinary consensus]. / Vestibulyarnaya reabilitatsiya pri perifericheskoi vestibulyarnoi gipofunktsii: mezhdistsiplinarnyi konsensus.

The literature review presents approaches to the management of patients with vestibular disorders. The principles of organization of vestibular rehabilitation in peripheral vestibular hypofunction, indications for appointment, factors influencing its implementation, technique, methods of evaluating effectiveness are considered in detail. Attention is drawn to the fact that the selection of exercises and the duration of vestibular rehabilitation is carried out individually and depends on many factors, including the nature of vestibular deficiency and the specific characteristics of the patient. The possibilities of using additional pharmacological therapy with histamine preparations, which can accelerate the onset of vestibular compensation, are shown. It is noted that vestibular rehabilitation is a safe and effective method of treating peripheral vestibular hypofunction and should be recommended to patients of all ages with vestibular disorders leading to limited social and physical activity.

Epigenetic Histone Methylation of PPARγ and CPT1A Signaling Contributes to Betahistine Preventing Olanzapine-Induced Dyslipidemia.

As a partial histamine H1 receptor agonist and H3 antagonist, betahistine has been reported to partially prevent olanzapine-induced dyslipidemia and obesity through a combination therapy, although the underlying epigenetic mechanisms are still not known. Recent studies have revealed that histone regulation of key genes for lipogenesis and adipogenesis in the liver is one of the crucial mechanisms for olanzapine-induced metabolic disorders. This study investigated the role of epigenetic histone regulation in betahistine co-treatment preventing dyslipidemia and fatty liver caused by chronic olanzapine treatment in a rat model. In addition to abnormal lipid metabolism, the upregulation of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein (C/EBPα), as well as the downregulation of carnitine palmitoyltransferase 1A (CPT1A) in the liver induced by olanzapine, were significantly attenuated by betahistine co-treatment. In addition, betahistine co-treatment significantly enhanced the global expression of H3K4me and the enrichment of H3K4me binding on the promoter of Cpt1a gene as revealed by ChIP-qPCR, but inhibited the expression of one of its site-specific demethylases, lysine (K)-specific demethylase 1A (KDM1A). Betahistine co-treatment also significantly enhanced the global expression of H3K9me and the enrichment of H3K9me binding on the promoter of the Pparg gene, but inhibited the expression of two of its site-specific demethylases, lysine demethylase 4B (KDM4B) and PHD finger protein 2 (PHF2). These results suggest that betahistine attenuates abnormal adipogenesis and lipogenesis triggered by olanzapine through modulating hepatic histone methylation, and thus inhibiting the PPARγ pathway-mediated lipid storage, while at the same time promoting CP1A-mediated fatty acid oxidation.

A triple blind, placebo controlled, randomised controlled trial of betahistine dihydrochloride in the treatment of primary tinnitus.

OBJECTIVES: To evaluate the effectiveness of betahistine in the treatment of primary tinnitus. DESIGN: To evaluate the effectiveness of betahistine in the treatment of primary tinnitus. SETTING: Universidade estadual Paulista Julio de Mesquita Filho, Botucatu Medical School, São paulo, Brazil. PARTICIPANTS: Adult patients with primary tinnitus who had not undergone treatment for tinnitus in the last 6 months were included. Patients with profound sensorineural deafness, hearing aid users and patients with metabolic, neurological, psychiatric or decompensated cardiovascular diseases were excluded. STUDY GROUPS: in the betahistine group, patients received betahistine 24 mg every 12 h for 90 days; in the control group, patients received placebo tablets every 12 h for 90 days. MEAN OUTCOME MEASURES: Primary outcome measure: Tinnitus Handicap Inventory (THI). SECONDARY OUTCOME MEASURES: Clinical Global Impression Improvement (CGI-I) and a question of 'Yes' or 'No' to participants about their perception of improvement in symptoms. RESULTS: Of 284 participants initially identified, 62 were randomised (betahistine group n = 31; control group n = 31). Median age (IQR) 54 (48-60) years, with a balanced number of men and women. There was no difference in THI outcome between the study groups (median difference, -2 points; 95% CI, -8 to 6 points); the THI after the intervention was a median (IQR) 4 (-4 to 14) lower points in the betahistine group, and a median (IQR) 2 (-6 to 10) in the control group. There was no statistical difference in secondary outcome measures. Adverse events were mild and there was no statistical difference between groups. CONCLUSIONS: Betahistine dihydrochloride was ineffective in the treatment of primary tinnitus in adults.

Effect of betahistine treatment on dizziness and anxiety symptoms of BPPV patients.

Background: Patients with benign paroxysmal positional vertigo (BPPV) may experience significant deterioration in their quality of life due to dizziness and anxiety symptoms. Aim: To evaluate the effect of betahistine add-on therapy on dizziness and anxiety symptoms of BPPV patients. Materials and Methods: Eighty-four patients who were diagnosed as having posterior canal BPPV were included in the study. Patients were divided into two groups according to the treatment regimen: Group 1 included 42 subjects who were treated with the Epley maneuver alone and Group 2 included 42 subjects who received betahistine 48 mg/day for ten days with the Epley maneuver. Dizziness handicap inventory (DHI) and Beck anxiety inventory (BAI) were evaluated at the time of diagnosis and at the control examination on the tenth day. Results: The mean before and after treatment DHI scores were 38.8 ± 14.6 and 5.47 ± 6.4 for Group 1 (P < 0.001), and 45.8 ± 21.1 and 10.3 ± 12.9 for Group 2 (P < 0.001). The mean before and after treatment BAI scores were 11.8 ± 6 and 1.33 ± 1.8 for Group 1 (P < 0.001), and 13.6 ± 8.3 and 2.9 ± 3.8 for Group 2 (P < 0.001). There was no significant difference between the before and after treatment DHI and BAI score differences of the two groups (P = 0.27, P = 0.43). Conclusion: Canalith repositioning maneuvers (CRMs) should be the main treatment modality in the management of BPPV patients and adding on betahistine treatment to CRMs have no impact in the relieving of dizziness and anxiety symptoms.

Betahistine alleviates benign paroxysmal positional vertigo (BPPV) through inducing production of multiple CTRP family members and activating the ERK1/2-AKT/PPARy pathway.

BACKGROUND: Betahistine is a clinical medication for the treatment of benign paroxysmal positional vertigo (BPPV). Otolin, a secreted glycoprotein with a C-terminal globular domain homologous to the immune complement C1q, has been identified as a biomarker for BPPV. However, the role of complement C1q/TNF-related proteins (CTRPs) with a C-terminal globular domain in BPPV is unclear, so we explored the change of CTRPs in betahistine treated BPPV. METHODS: We treated BPPV patients with Betahistine (12 mg/time, 3 times/day) for 4 weeks and observed the clinical efficacy and the expression of CTRP family members in BPPV patients. Then, we constructed a vertigo mice model of vestibular dysfunction with gentamicin (150 mg/Kg) and a BPPV model of Slc26a4loop/loop mutant mice. Adenoviral vectors for CTRP expression vector and small interfering RNA were injected via the intratympanic injection into mice and detected the expression of CTRP family members, phosphorylation levels of ERK and AKT and the expression of PPARγ. In addition, we treated mice of vestibular dysfunction with Betahistine (10 mg/Kg) and/or ERK inhibitor of SCH772984 (12 mg/Kg) and/or and PPARγ antagonist GW9662 (1 mg/Kg) for 15 days, and evaluated the accuracy of air righting reflex, the time of contact righting reflex and the scores of head tilt and swimming behavior. RESULTS: After treatment with Betahistine, the residual dizziness duration and the score of the evaluation were reduced, and the expression of CTRP1, 3, 6, 9 and 12 were significantly increased in BPPV patients. We also found that Betahistine improved the accuracy of air righting reflex, reduced the time of contact righting reflex and the scores of head tilt and swimming behavior in gentamicin-treated mice and Slc26a4loop/loop mutant mice. The expression levels of CTRP1, 3, 6, 9 and 12, phosphorylation levels of ERK and AKT, and PPARγ expression were significantly increased, and the scores of head tilt and swimming behavior were decreased in vestibular dysfunction mice with overexpression of CTRPs. Silencing CTRPs has the opposite effect. SCH772984 reversed the effect of Betahistine in mice with vestibular dysfunction. CONCLUSION: Betahistine alleviates BPPV through inducing production of multiple CTRP family members and activating the ERK1/2-AKT/PPARy pathway.

[Betahistine in vestibular disorders: current concepts and perspectives]. / Sovremennye predstavleniya o roli betagistina v lechenii zabolevanii vestibulyarnoi sistemy.

The goal of this paper is to review the pharmacological profile of betahistine and evidence for using it in the treatment of common vestibular disorders. Betahistine is a weak agonist for histamine H1 receptors and strong antagonist for histamine H3 receptors. It demonstrates the maximum benefit in different types of peripheral vertigo, especially in Meniere's disease. The best results in decreasing intensity of vertigo, frequency of attacks and stimulation of vestibular compensation were obtained in daily dose 48 mg during 3 months. In benign paroxysmal positional vertigo betahistine is used to treat residual dizziness after successful treatment of otolithiasis and to reduce the severity of vertigo during repositioning maneuvers. In vestibular neuritis betahistine stimulates central compensation during vestibular rehabilitation. A new once-daily drug formulation of modified-release betahistine is non-inferior to traditional and has a comparable safety profile, and could improve patient adherence. The implication of betahistine in the treatment of central vestibular disorders is under-researched. The efficacy of betahistine in increasing of vestibular compensation in post-stroke central vestibular disorders, persistent postural-perceptual dizziness and its role in vestibular migraine need further investigation.

Betahistine, prevents kindling, ameliorates the behavioral comorbidities and neurodegeneration induced by pentylenetetrazole.

A seizure may occur because of the imbalance between glutamate and gamma-aminobutyric acid (GABA). Recurrent seizures induce some cognitive problems, such as, depression, learning and memory deficits, and neurodegeneration. Histamine is an appropriate therapeutic target for epilepsy via its effect on regulating neurotransmitter release. Also, evidence indicates the effect of histamine on neuroprotection and alleviating cognitive disorders. An ideal antiepileptic drug is a substance, which has both anticonvulsant effects and decreases the comorbidities that are induced by repeated seizures. Betahistine dihydrochloride (betahistine) is a structural analog of histamine. It acts as histamine H1 receptor agonist and H3 receptor antagonist, which enhances histaminergic neuronal activities. In the present study, we examined the effect of betahistine administration on seizure scores, memory deficits, depression, and neuronal loss induced by pentylenetetrazole (PTZ). Eight- to ten-week-old BALB/c male mice (20-25 g) received betahistine, 1, and 10 mg/kg daily from 7 days before the onset of PTZ-induced kindling until the end of the establishment of the kindling. We found that betahistine prevented generalized tonic-clonic seizures induction and diminished forelimb clonic seizures intensity. Also, it decreased cell death in the hippocampus and cortex, ameliorated the memory deficit and depression induced by PTZ in the kindled animals. Altogether, these results indicate that pretreatment and repetitive administration with betahistine exerts antiepileptogenic and anticonvulsant activity. These findings might be due to the neuroprotective impact of betahistine in the hippocampus and cortex.

Management of peripheral vertigo with antihistamines: New options on the horizon.

Vertigo is associated with a wide range of vestibular pathologies. It increasingly affects the elderly, with a high cost to society. Solutions include vestibular suppressants and vestibular rehabilitation, which form the mainstay of therapy. Antihistamines represent the largest class of agents used to combat vestibular vertigo symptoms. Agents targeting the H1 and H3 receptors have been in clinical use for several decades as single agents. Nonetheless, effective management of vertigo proves elusive as many treatments largely address only associated symptoms, and with questionable efficacy. Additionally, the primary and limiting side effect of sedation is counterproductive to normal functioning and the natural recovery process occurring via central compensation. To address these issues, the timing of administration of betahistine, the mainstay H3 antihistamine, can be fine-tuned, while bioavailability is also being improved. Other approaches include antihistamine combination studies, devices, physical therapy and behavioural interventions. Recently demonstrated expression of H4 receptors in the peripheral vestibular system represents a new potential drug target for treating vestibular disorders. A number of novel selective H4 antagonists are active in vestibular models in vivo. The preclinical potential of SENS-111 (Seliforant), an oral first-in-class selective H4 antagonist is the only such molecule to date to be translated into the clinical setting. With an excellent safety profile and notable absence of sedation, encouraging outcomes in an induced vertigo model in healthy volunteers have led to ongoing clinical studies in acute unilateral vestibulopathy, with the hope that H4 antagonists will offer new effective therapeutic options to patients suffering from vertigo.

Cinnarizine/betahistine combination vs. the respective monotherapies in acute peripheral vertigo: a randomized triple-blind placebo-controlled trial.

PURPOSE: To compare the efficacy of cinnarizine/betahistine combination with the respective monotherapies in patients with acute peripheral vertigo (APV). METHOD: A randomized, triple-blind placebo-controlled phase III trial was performed on 162 patients with APV to compare the efficacy of cinnarizine/betahistine combination with the respective monotherapies. Patients were randomly allocated into three groups (n = 54 each) of Bet. (betahistine and placebo), Cin. (cinnarizine and placebo), and Bet. + Cin. (betahistine and cinnarizine). The first group received cinnarizine tablets (25 mg) plus placebo three times a day, the second group received betahistine tablets (8 mg) plus placebo three times a day, and the third group received betahistine (8 mg) plus cinnarizine (25 mg) combination three times a day. The treatments were continued for 1 week. Patients were followed up to 3 days and 1 week after initiation of the treatments for changes in vertigo severity measured by visual grading scale (VAS), mean vertigo score (MVS), and mean concomitant symptom score (MCSS). RESULTS: Results showed a significant difference between the groups in VAS (p = 0.001), MVS (p = 0.0001), and MCSS (p = 0.0001) at 1-week follow-up, where the respective values were significantly lower in the Cin. + Bet. group as compared with the respective monotherapies. Efficacy and tolerability of the treatment were found to be higher in the Cin. + Bet. group at 3-day and 1-week follow-up periods (p = 0.0001, for all comparisons). None of the patients reported any side effects during the study. CONCLUSION: This study indicated the superiority of the cinnarizine/betahistine combination over the respective monotherapies in the treatment of APV. TRIAL REGISTRATION: IRCT20130710013947N9.

An LC-MS/MS assay for the quantitative determination of 2-pyridyl acetic acid, a major metabolite and key surrogate for betahistine, using low-volume human K2 EDTA plasma.

Betahistine is widely used for the treatment of vertigo. Owing to first-pass metabolism, 2-pyridyl acetic acid (2PAA, major metabolite of betahistine) was considered as surrogate for quantitation. A specific and sensitive LC-MS/MS method was developed and validated for quantitation of 2PAA using turbo-ion spray in a positive ion mode. A solid-phase extraction was employed for the extraction of 2PAA and 2PAA d6 (IS) from human plasma. Chromatographic separation of analytes was achieved using an ACE CN, 5 µm (50 × 4.6 mm) column with a gradient mobile phase comprising acetonitrile-methanol (90:10% v/v) and 0.7% v/v formic acid in 0.5 mm ammonium trifluoroacetate in purified water (100% v/v). The retention times of 1.15 and 1.17 min for 2PAA and internal standard, respectively, were achieved. Quantitation of 2PAA and internal standard was achieved by monitoring multiple reaction monitoring transition pairs (m/z 138.1 to m/z 92.0 and m/z 142.1 to m/z 96.1, respectively). The developed method was validated for various parameters. The calibration curves of 2PAA showed linearity from 5.0 to 1500 ng/mL, with a lower limit of quantitation of 5.0 ng/mL. The bias and precision for inter- and intra-batch assays were <10%. The developed method was used to support clinical sample analysis.

Analysis of risk factors influencing the outcome of the Epley maneuver.

Benign paroxysmal positional vertigo (BPPV) is the most frequent type of vertigo. The treatment of canalithiasis of the posterior semicircular canal consists in performing a particle-repositioning maneuver, such as the Epley maneuver (EM). However, the EM is not effective in all cases. The objective of this study is to identify risk factors, which predict the EM failure, among the clinical variables recorded in anamnesis and patient examination. This is an observational prospective multicentric study. All patients presenting with BPPV were recruited and applied the EM and appointed for a follow-up visit 7 days later. The following variables were recorded: sex, age, arterial hypertension, diabetes, hyperlipidemia, smoking habit, alcohol consumption, migraine, osteoporosis, diseases of the inner ear, previous ipsilateral BPPV, previous traumatic brain injury, previous sudden head deceleration, time of evolution, sulpiride or betahistine treatment, experienced symptoms, outcome of the Halmagyi maneuver, laterality, cephalic hyperextension of the neck, intensity of nystagmus, intensity of vertigo, duration of nystagmus, occurrence of orthotropic nystagmus, symptoms immediately after the EM, postural restrictions, and symptoms 7 days after the EM. Significant differences in the rate of loss of nystagmus were found for six variables: hyperlipidemia, previous ipsilateral BPPV, intensity of nystagmus, duration of nystagmus, post-maneuver sweating, and subjective status. The most useful significant variables in the clinical practice to predict the success of the EM are previous BPPV and intensity of nystagmus. In the other significant variables, no physiopathological hypothesis can be formulated or differences between groups are too small.

Management of Benign Paroxysmal Positional Vertigo: A Comparative Study between Epleys Manouvre and Betahistine.

ABSTRACT: Benign paroxysmal positional vertigo (BPPV) is the most common peripheral vestibular disorder, accounting for 20% of all vertigo cases. Idiopathic BPPV is most common between the ages of 50 and 70, although the condition is found in all age groups. This study was conducted in our institute on 90 patients who presented to the outpatient department with history of vertigo and were diagnosed with BPPV via a positive Dix Hallpike test. Patients were randomnly placed in three groups of 30 each. Patients in Group A were treated with Epleys manoeuvre alone, in Group B were treated with Epleys Manouvre followed by oral Betahistine and patients in Group C were treated with Betahistine alone. All the patients were followed up after 1 week and 4 weeks following treatment. In our study we found that patients responded better when they were treated with Epleys Manouvre with Betahistine with less relapse and recurrence. Treatment with Epleys manouvre resulted in early improvement of symptoms. It was found in our study that Betahistine as a sole modality of treatment of vertigo in BPPV can be preferred in patients who are unfit to undergo canal repositioning manouvres.

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications.

Second generation antipsychotic drugs (SGAs) cause substantial body weight gain/obesity and other metabolic side-effects such as dyslipidaemia. Their antagonistic affinity to the histaminergic H1 receptor (H1R) has been identified as one of the main contributors to weight gain/obesity side-effects. The effects and mechanisms of betahistine (a histaminergic H1R agonist and H3 receptor antagonist) have been investigated for ameliorating SGA-induced weight gain/obesity in both animal models and clinical trials. It has been demonstrated that co-treatment with betahistine is effective in reducing weight gain, associated with olanzapine in drug-naïve patients with schizophrenia, as well as in the animal models of both drug-naïve rats and rats with chronic, repeated exposure to olanzapine. Betahistine co-treatment can reduce food intake and increase the effect of thermogenesis in brown adipose tissue by modulating hypothalamic H1R-NPY-AMPKα (NPY: neuropeptide Y; AMPKα: AMP-activated protein kinase α) pathways, and ameliorate olanzapine-induced dyslipidaemia through modulation of AMPKα-SREBP-1-PPARα-dependent pathways (SREBP-1: Sterol regulatory element binding protein 1; PPARα: Peroxisome proliferator-activated receptor-α) in the liver. Although reduced locomotor activity was observed from antipsychotic treatment in rats, betahistine did not affect locomotor activity. Importantly, betahistine co-treatment did not influence the effects of antipsychotics on serotonergic receptors in the key brain regions for antipsychotic therapeutic efficacy. However, betahistine co-treatment reverses the upregulated dopamine D2 binding caused by chronic olanzapine administration, which may be beneficial in reducing D2 supersensitivity often observed in chronic antipsychotic treatment. Therefore, these results provide solid evidence supporting further clinical trials in treating antipsychotics-induced weight gain using betahistine in patients with schizophrenia and other mental disorders.

Label-free versus conventional cellular assays: Functional investigations on the human histamine H1 receptor.

A set of histamine H1 receptor (H1R) agonists and antagonists was characterized in functional assays, using dynamic mass redistribution (DMR), electric cell-substrate impedance sensing (ECIS) and various signaling pathway specific readouts (Fura-2 and aequorin calcium assays, arrestin recruitment (luciferase fragment complementation) assay, luciferase gene reporter assay). Data were gained from genetically engineered HEK293T cells and compared with reference data from GTPase assays and radioligand binding. Histamine and the other H1R agonists gave different assay-related pEC50 values, however, the order of potency was maintained. In the luciferase fragment complementation assay, the H1R preferred ß-arrestin2 over ß-arrestin1. The calcium and the impedimetric assay depended on Gq coupling of the H1R, as demonstrated by complete inhibition of the histamine-induced signals in the presence of the Gq inhibitor FR900359 (UBO-QIC). Whereas partial inhibition by FR900359 was observed in DMR and the gene reporter assay, pertussis toxin substantially decreased the response in DMR, but increased the luciferase signal, reflecting the contribution of both, Gq and Gi, to signaling in these assays. For antagonists, the results from DMR were essentially compatible with those from conventional readouts, whereas the impedance-based data revealed a trend towards higher pKb values. ECIS and calcium assays apparently only reflect Gq signaling, whereas DMR and gene reporter assays appear to integrate both, Gq and Gi mediated signaling. The results confirm the value of the label-free methods, DMR and ECIS, for the characterization of H1R ligands. Both noninvasive techniques are complementary to each other, but cannot fully replace reductionist signaling pathway focused assays.

Expression of histamine receptors in the human endolymphatic sac: the molecular rationale for betahistine use in Menieres disease.

The human endolymphatic sac (ES) is situated in a duplicature of the dura in the posterior cranial fossa and constitutes a part of the inner ear. The sac possesses immunological capacities and is responsible for a major part of the trans-epithelial ion transport occurring within the inner ear, via molecular mechanisms similar to that of the kidney collecting duct epithelia. Dysfunction of the trans-epithelial ion transport has been hypothesized as the reason for the endolymphatic hydrops occurring in Menieres diseases. Thus, candidate drug selection for medical treatment of Menieres disease has been based on a potential capability of improving trans-epithelial ion transport. However, recent human studies seems to rule out diuretic therapy and The Committee for Medicinal Products for Human Use redrew the recommendation for trimetazidine (Vastarel) treatment in the management of Meniere disease in 2012. This leaves betahistine (Betaserc) as the only drug for potential prevention of the incapacitating attacks of dizziness, tinnitus and hearing loss. However, the histamine receptors targeted by betahistine have never been demonstrated in the human ES. Accordingly, this study aims to investigate the expression of histamine receptors of the human ES epithelium and sub-epithelial stroma. Following sampling of human endolymphatic sac tissue during translabyrinthine surgery, the expression of histamine receptor genes was determined by cDNA microarray analysis. Results were subsequently verified by immuno-histochemistry. The combined results of microarrays and immuno-histochemistry showed expression of the histamine receptor HRH1 in the epithelial lining of the ES, whereas HRH3 was expressed exclusively in the sub-epithelial capillary network. Receptors HRH2 and -4 were not expressed. The present data provide the first direct evidence of a molecular rationale for betahistine treatment in Menieres disease. A potential betahistine effect in Menieres disease may primarily be through the H3-receptor antagonism, leading to inhibition of vestibular neuro-transmission and central vaso-dilation. The H1-receptor localization in the ES epithelium suggests an immuno-regulatory effect.

Betahistine co-treatment ameliorates dyslipidemia induced by chronic olanzapine treatment in rats through modulation of hepatic AMPKα-SREBP-1 and PPARα-dependent pathways.

Second-generation antipsychotics including olanzapine are associated with weight gain, dyslipidemia and other metabolic disorders. Both animal and clinical studies have shown that co-treatment with betahistine (a histamine H1 receptor agonist/H3 receptor antagonist) is effective in controlling olanzapine-induced weight gain. In the present study, we investigate whether co-treatment with betahistine is able to prevent dyslipidemia induced by chronic olanzapine treatment and the underlying mechanisms. Female rats were orally administered with olanzapine (1 mg/kg, t.i.d.) for 3.5 consecutive weeks and then a 2.5-week drug withdrawal. Then, rats were divided into 4 groups for 5 weeks treatment: (1) vehicle, (2) olanzapine-only (1 mg/kg, t.i.d.), (3) betahistine-only (9.6 mg/kg, t.i.d.), and (4) olanzapine and betahistine (O+B) co-treatment. After completing treatment, hepatic mRNA expression was measured by qRT-PCR, while the protein levels were detected by western blot. In our study, olanzapine-only treatment significantly increased triglyceride accumulation and non-esterified fatty acids (NEFA), and upregulated mRNA expression of sterol regulatory element binding protein 1 (SREBP-1) and its target genes, while these alterations were ameliorated by O+B co-treatment. Hepatic AMP-activated protein kinase α (AMPKα) was activated in the O+B co-treatment group, with a significant reduction in nuclear SREBP-1 protein expression but an increased expression of peroxisome proliferator-activated receptor-α (PPARα) and its-responsive molecule(CPT1A), compared with olanzapine-only treatment. In addition, olanzapine significantly increased hepatic histamine H1 receptors, while O+B co-treatment significantly reversed them to normal levels. This study provided the first evidence that betahistine could act on hepatic H1 receptors via modulation of AMPKα-SREBP-1 and PPARα-dependent pathways to ameliorate olanzapine-induced dyslipidemia in rats.

Betahistine exacerbates amikacin ototoxicity.

OBJECTIVE: Betahistine augments cochlear blood flow and is currently used as an efficient therapeutic agent. Amikacin is used in a wide range of areas, but its ototoxic effect continues to be problematic. This study investigates the effect of betahistine on amikacin-induced ototoxicity. METHODS: Thirty-two healthy rats were randomized to 4 groups of 8 rats in each group (amikacin, amikacin+betahistine, betahistine, and no treatment). Amikacin was administered intramuscularly to groups 1 and 2 for 14 days. Betahistine was delivered by oral gavage to groups 2 and 3 for 21 days. Distortion-product otoacoustic emissions (DPOAE) and auditory brainstem response (ABR) tests were conducted on all rats. RESULTS: There were significant decreases in the DPOAE levels and significant increases in the ABR thresholds of the amikacin and amikacin+betahistine groups on the 7th, 14th, and 21st days, as compared to their basal values. The DPOAE levels of the amikacin+betahistine group significantly decreased on days 7, 14, and 21, and the ABR thresholds significantly increased on the same days, as compared to the amikacin group. CONCLUSION: Our study implies that amikacin's ototoxic effects are augmented by the concurrent use of betahistine. Experimental and clinical research, supported by histopathological studies, is needed to affirm our findings.

Safety, tolerability and pharmacokinetics of 2-pyridylacetic acid, a major metabolite of betahistine, in a phase 1 dose escalation study in subjects with ADHD.

Betahistine, a potent histamine H3 receptor antagonist, is being developed for the treatment of attention deficit hyperactivity disorder (ADHD) that manifests with symptoms such as hyperactivity, impulsivity and inattention. This study describes the pharmacokinetics of betahistine in ADHD subjects at doses higher than 50 mg. These assessments were made during a randomized, placebo-controlled, single blind, dose escalation study to determine the safety, tolerability and pharmacokinetics of once daily doses of 50 mg, 100 mg and 200 mg of betahistine in subjects with ADHD. Plasma levels of 2-pyridylacetic acid (2-PAA), a major metabolite of betahistine were quantified using a validated LC-MS/MS method and used for pharmacokinetic analysis and dose proportionality of betahistine. A linear relationship was observed in Cmax and AUC0-4 of 2-PAA with the betahistine dose (R2 0.9989 and 0.9978, respectively) and dose proportionality coefficients (ß) for the power model were 0.8684 (Cmax) and 1.007 (AUC0-4). A population pharmacokinetic model with first-order absorption of betahistine and metabolism to 2-PAA, followed by a first-order elimination of 2-PAA provides estimates of clearance that underscored the linear increase in systemic exposure with dose. There were no serious adverse events reported in the study, betahistine was safe and well tolerated at all the dose levels tested.

Betahistine metabolites, aminoethylpyridine, and hydroxyethylpyridine increase cochlear blood flow in guinea pigs in vivo.

OBJECTIVE: Betahistine is a histamine-like drug that is used in the treatment of Ménière's disease. It is commonly believed that betahistine increases cochlear blood flow and thus decreases the endolymphatic hydrops that is the cause of Ménière'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 increase in cochlear blood flow in comparison to placebo. The effect seen under aminoethylpyridin was greatest. The group treated with pyridylacetic acid showed no significant effect on cochlear blood flow. CONCLUSION: Aminoethylpyridine and hydroxyethylpyridine are, like betahistine, able to increase cochlear blood flow significantly. The effect of aminoethylpyridine was greatest. Pyridylacetic acid had no effect on cochlear microcirculation.

Historical Therapies for Suspected Autonomic Dysregulation in Meniere's Disease.

OBJECTIVE: This narrative review examines how speculative belief that the autonomic nervous system causes Meniere's Disease (MD) led otolaryngologists to adopt invasive surgical procedures and medical treatments still offered today. DATA SOURCES: Google Scholar, PubMed. REVIEW METHODS: A comprehensive literature review (1860-2022) was performed using the terms "Meniere AND (sympathetic OR sympathectomy OR vasomotor OR cervical ganglion)," returning 5360 items. All abstracts were briefly reviewed, relevant publications selected for further study, and key articles discussed by all authors. As it became clear that betahistine was related to the historical narrative, an additional search was performed using "Betahistine AND Meniere AND (vasomotor OR sympathetic OR sympathectomy OR cervical ganglion OR autonomic)," which yielded 336 results. RESULTS: In the 19th and 20th centuries, growing knowledge of human anatomy led the scientific community to speculate that autonomic dysregulation caused many medical conditions. Excessive sympathetic mediated vasomotor changes were thought to cause hypertension, ischemia, and tissue damage. Clinicians applied the hypothesis to MD, assigning the sympathetic nervous system responsible for vertigo secondary to paroxysmal vasospasm and for hearing loss to poor cochlear nutrition. Despite limited animal experiments and isolated clinical observations, otolaryngologists performed sympathectomies, and, in the 1970s, replaced the procedure with betahistine as an alternative medical treatment. CONCLUSION: Premature excitement about a plausible hypothesis led to unnecessary and unwarranted operations. Despite absent evidence of sympathetic overactivation in MD, surgeons eagerly adopted sympathectomies, and later betahistine. Rigorous evaluation of the validity of these treatment practices is needed. LEVEL OF EVIDENCE: 5 Laryngoscope, 134:535-542, 2024.