Analysis of the nystagmus characteristics of cupula diseases: A case report.

INTRODUCTION: Clinically, there is a kind of patients with positional vertigo or dizziness, which occurs when they turn left or right, look down or up, lie down or sit up. With a long duration and varying frequency, it is not consistent with the manifestations of benign paroxysmal positional vertigo (BPPV). In addition, the persistent geotropic direction-changing positional nystagmus (PG-DCPN) was observed in a supine head-roll test. PATIENT CONCERNS: With no apparent trigger for visual rotation and a sense of self instability, an 81-year-old female patient had suffered from vertigo for 3 days. The vertigo occurred every day, lasting several minutes each time, and associated with head movements and changes in body position. In a supine head-roll test, it appeared persistent geotropic direction-changing positional nystagmus for a long time, without latency, fatigability and in the presence of 3 zero planes. DIAGNOSIS: Light cupula. INTERVENTIONS: Difenidol hydrochloride 25 mg orally 3 times/day for 2 weeks and betahistine hydrochloride 12 mg orally 3 times/day for 1 month were administered. OUTCOMES: After 1 month of treatment, the patient's vertigo symptoms disappeared. And in the supine head-roll test, the persistent geotropic direction-changing positional nystagmus disappeared. CONCLUSION: We report the characteristics of nystagmus produced in a typical patient with light cupula during the supine head-roll test. After reviewing the relevant literatures, we believe that a simpler method can be used to identify canalolithiasis and cupula disease, to distinguish light and heavy cupula, and to determine the pathological semicircular canal to which the lesion belongs.

Crosstalk of hypothalamic chemerin, histamine, and AMPK in diet-and olanzapine-induced obesity in rats.

AIM: Contradiction overwhelms chemerin link to feeding behavior. Neither the chemerin central role on appetite regulation nor its relation to hypothalamic histamine and AMPK is verified. MAIN METHODS: Food intake, body weight and hypothalamic biochemical changes were assessed after a single intra-cerebroventricular or intraperitoneal injection (ip) (1 µg/kg or 16 µg/kg, respectively) or chronic ip administration (8 µg/kg/day) of chemerin for 14 or 28 days. Hypothalamic neurobiochemical changes in chemerin/histamine/AMPK induced by either 8-week high fat diet (HFD) or food restriction were also investigated. To confirm chemerin-histamine crosstalk, these neurobiochemical changes were assessed under settings of H1-receptor agonism and/or antagonism by betahistine and/or olanzapine, respectively for 3 weeks. KEY FINDINGS: Chemerin-injected rats exhibited anorexigenic behavior in both acute and chronic studies that was associated with a decreased AMPK activity in the arcuate nucleus (ARC). However, with long-term administration, chemerin anorexigenic effect gradually ceased. Contrarily to food restriction, 8-week HFD increased ARC expression of chemerin and its receptor CMKLR1, reducing food intake via an interplay of H1-receptors and AMPK activity. Blockage of H1-receptors by olanzapine disrupted chemerin signaling pathway with an increased AMPK activity, augmenting food intake. These changes were reversed to normal by betahistine coadministration. SIGNIFICANCE: Chemerin is an anorexigenic adipokine, whose dysregulation is implicated in diet, and olanzapine-induced obesity through a histamine/AMPK axis in the ARC. Hypothalamic chemerin/CMKLR1 expression is a dynamic time-dependent response to changes in body weight and/or food intake. Targeting chemerin as a novel therapeutic approach against antipsychotic- or diet-induced obesity is worth to be further delineated.

Influence of betahistine repeated administration on a weight gain and selected metabolic parameters in the model of excessive eating in rats.

It is important to search for a promising therapeutic target or small molecules that can control excessive eating since limiting the intake of foods, especially tasty ones, could be effective in the treatment or prevention of obesity. Some studies indicate betahistine as an unique drug having the ability to ameliorate, for example, antipsychotic-induced weight gain. This study aimed to determine whether repeated administration of betahistine (histamine H1R agonist and H3R antagonist) could be beneficial in reducing the intake of tasty foods or the body's response to overeating via mechanisms such as by influencing the levels of hormones involved in the regulation of food intake or the levels of selected metabolic parameters. Studies were performed in the excessive eating model in rats, which perfectly illustrates the harmful high-caloric intake from freely available tasty products rich in sugar and fat. Our results indicated that repeated administration of betahistine to rats caused lower gain of body mass compared to the control rats fed palatable feed. Interestingly, betahistine treatment increased the consumption of cheese, which is a source of histamine. Although betahistine did not prevent the development of metabolic disorders, such as reduced glucose tolerance, in test animals, it significantly increased the level of high-density lipoprotein cholesterol, which could certainly be considered beneficial. Further studies should be conducted to investigate the effect of repeated administration of betahistine on satiety, gastrointestinal disorders, and the preference for histamine-containing foods.

Conservative Treatment Possibilities of Ménière Disease, Involving Vertigo Diaries.

Ménière disease is a disorder of the inner ear, characterized by rotational vertigo, hearing loss, tinnitus, and vegetative symptoms. The aim of the present research is to examine the effectiveness of betahistine and piracetam in the reduction of vertigo attacks in Ménière disease. To verify our hypothesis, 105 (31 male and 74 females, mean age [standard deviation], 57.4 [11.05]) adult patients with definite Ménière disease were enrolled in this investigation. Beside the analysis of the hospital records, the subjective complaints of the patients and the completed vertigo diaries were taken into consideration too. The statistical analysis was completed using the IBM SPSS version 24 software. Retrospective analysis, including a 12 years period was conducted. Based on our results, betahistine was successful in the reduction of attacks. Statistically significant decrease was achieved in frequency of dizziness (P = .000331) and vertigo (P < .00001) and in the duration of them (P = .000098), although in the mean power of them was not (P = .0887). The mean dose in the symptomatic treatment was determined as 87.5 ± 27.2 mg per day; however, there was no connection detected between the dose of the agent and the effectiveness of the symptomatic control. By using dual therapy (betahistine and piracetam), vertigo episodes appeared significantly less often (P = .027, Odds ratio: 4.9, 95% confidence interval: 1.2-20.2). Finally, it can be concluded that betahistine is effective in Ménière disease, but the daily dose of it should be set up for every patient individually. The advantage of the dual therapy was also confirmed.

Effects of haloperidol inhalation on MK-801- and memantine-induced locomotion in mice.

The administration of therapeutic agents is difficult in many patients, such as patients with post-operative delirium or dementia or patients with schizophrenia, who are upset in an emergency room. Therefore, the development of a new method for administering therapeutic agents to the central nervous system is desired. In this study, we investigated if inhalation was an effective route of administration for haloperidol, a commonly used, strong antipsychotic. Dizocilpine, also known as MK-801, is a noncompetitive antagonist of the N-methyl-D-aspartate receptor. MK-801 or memantine-induced motor hyperactivity was evaluated in mice following either intraperitoneal injection or inhalation of haloperidol or the histamine neuroactivator betahistine. Pretreatment with haloperidol inhalation inhibited the MK-801-induced or memantine-induced increase in locomotor activity. This effect was similar to that of the intraperitoneal administration of haloperidol. However, pretreatment with inhaled betahistine or the intraperitoneal administration of betahistine did not suppress the MK-801-induced or memantine-induced increase in locomotor activity. Thus, haloperidol when inhaled acts on the central nervous system of mice and suppresses the MK-801-induced increase in mouse locomotor activity. Our findings suggest that inhalation may be a novel method for administering haloperidol. ABBREVIATIONS: ANOVA: analysis of variance.

The pharmacological management of vertigo in Meniere disease.

INTRODUCTION: The term Meniere disease (MD) gathers a set of rare diseases involving the inner ear characterized by episodic vertigo associated with fluctuating auditory symptoms. Five clinical subgroups of patients have been defined, including familial MD, autoimmune MD, and MD with migraine. The diagnosis is based on clinical criteria as no biomarker is available, but genetic factors have a significant contribution in familial and non-familial MD. AREAS COVERED: In this review, the authors summarize the pharmacological treatment for vertigo in MD, providing evidence from preclinical and clinical studies. However, evidence supporting the efficacy for betahistine, diuretics, and intratympanic administration of corticosteroids or gentamicin is limited. EXPERT OPINION: Randomized clinical trials should consider stratification by MD clinical subgroups. The treatment plan should be personalized according to the clinical subgroup, hearing stage, duration of the disease, vertigo attack profile, and comorbidities. The treatment should include therapeutic counseling, sodium-free diet, high-water intake, and a diary of vertigo attacks with symptoms during the episodes to improve phenotyping. Migraine or autoimmune comorbidities will also require pharmacotherapy. Genetic testing by exome/genome sequencing should be discussed with the patient for familial MD and individuals with an early onset for genetic counseling and future gene therapies.

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.

Measuring dynamic Eustachian tube function using tympanometry in a pressure chamber: the effect of nasal betahistine application.

OBJECTIVE: To assess the effect of topical betahistine on Eustachian tube function in subjectively abnormal subjects in a hyperbaric chamber. METHOD: Active and passive Eustachian tube function was examined using tympanometry in a pressure chamber. RESULTS: Active Eustachian tube function was tested against the negative middle ear pressure induced by increasing the chamber pressure to +3 kPa. One voluntary swallow decreased middle-ear pressure by a mean of 1.36 kPa. Passive Eustachian tube function was tested by measuring spontaneous Eustachian tube openings as the chamber pressure dropped from +10 kPa to ambient. Four distinct patterns of Eustachian tube behaviour were seen, three of which indicated Eustachian tube dysfunction. Betahistine had no positive effect on Eustachian tube opening, although previous animal studies had suggested a beneficial effect. CONCLUSION: Topical betahistine had no effect on Eustachian tube function. Combining a hyperbaric chamber with tympanometry proved ideal for evaluating Eustachian tube function.

Randomized trial of betahistine mesilate tablets as augmentation for oxcarbazepine and carbamazepine in treating vestibular paroxysmia.

BACKGROUND: Vestibular paroxysmia (VP) is a rare episodic peripheral vestibular disorder. This study was conducted to compare the efficacy and acceptability of carbamazepine (CBZ) plus betahistine mesilate tablets (BMT) (CBZ+BMT) and oxcarbazepine (OXC) plus BMT (OXC+BMT) in treating VP, and investigated whether the synergistic effect could be increased along with the increased dose of BMT. METHODS: VP patients were recruited and randomly assigned to receive CBZ+BMT or OXC+BMT. The doses of CBZ and OXC were set to 200 and 300 mg/time, twice daily, respectively. The doses of BMT were set to 12 and 18 mg/time, twice daily. Half of the patients in each group received BMT 12 mg/time and the other half received BMT 18 mg/time. The treatment was continued for 12 weeks. The vertigo frequency, vertigo score, vertigo duration, response rate, and drug-related side effects were analyzed. RESULTS: In total, 92 patients in the CBZ+BMT group and 93 patients in the OXC+BMT group completed this trial. After 12 weeks of treatment, the two groups had similar average vertigo frequency, average vertigo score, average vertigo duration, and response rate. But the incidence of side effects was significantly higher in the CBZ+BMT group than in the OXC+BMT group (p=0.04). Subgroup analysis found that patients receiving BMT (18 mg) had greater reductions in average vertigo frequency, average vertigo duration, and average vertigo score, and higher response rates than patients receiving BMT (12 mg). CONCLUSION: These results demonstrated that OXC+BMT may be suitable as an alternative method in VP patients with CBZ hypersensitivity, and the synergistic effect could be increased along with the increased dose of BMT.

Menière's disease: combined pharmacotherapy with betahistine and the MAO-B inhibitor selegiline-an observational study.

OBJECTIVES: Since oral betahistine has a very high first-pass effect (ca. 99%), metabolized by monoamine oxidases (MAO), the benefits of a high-dosage betahistine monotherapy were compared with those of a lower dosage of betahistine in combination with the MAO-B inhibitor (MAO-B) selegiline on the frequency of acute attacks of vertigo in patients with Menière's disease (MD). METHODS: Thirteen adults aged 40-75 years (mean 58.9 years; six females) had initially been treated with a high dosage of betahistine dihydrochloride for at least 1 year. Under this therapy, all of them had ≤ 1 attack for ≥ 3 months prior to the combination pharmacotherapy. Subsequently, they received 5 mg/day selegiline and the dosage of betahistine was reduced to about one tenth and then individually adjusted to the dosage needed to achieve the same treatment response (≤ 1 per 3 months, observational period of at least 6 months). RESULTS: The initial dosage for the long-term "titration" of the attacks of vertigo was 9-80 24-mg tablets/day (mean 37.3), i.e. 216-1920 mg/day (mean 895.4 mg/day). After the combination with selegiline, the dosage needed to achieve the same benefit for ≥ 3 months was 3-36 24-mg tablets (mean 8.5), i.e., 72-864 mg/day [mean 204.9 mg/day, p < 0.001 (paired t test)]. One patient transiently stopped the treatment with selegiline, another one reduced the dosage to 2.5 mg/day and the attacks re-occurred after 2-4 weeks. Six out of 13 patients reported transient fullness of the head during the combined treatment; in 2 of them this went away when they switched to 2.5 mg bid. In the longer term (> 9 months), one patient had to increase the selegiline dosage to 5 mg bd, one patient stopped the treatment with selegiline. CONCLUSIONS: The achievement of the same clinical effect with a significantly lower (about 1/5) dosage of betahistine can be explained by the inhibition of the MAO-B by selegiline leading to higher serum concentrations of betahistine. This approach is in line with recent developments to bypass the first-pass effect of betahistine by transbuccal or intranasal application. Despite the substantial methodological limitations of such an observational study, this combined pharmacotherapy could be an alternative to a high-dosage monotherapy with betahistine of MD.

Betahistine dihydrochloride transdermal delivery via optimized thermosensitive gels: percutaneous absorption evaluation using rat growth as a biomarker.

The aim of this study was to develop and optimize a betahistine dihydrochloride (BH) thermoreversible bioadhesive gel intended for transdermal delivery. The gels were obtained via cold method. A full factorial design was employed to investigate the joint effect of Poloxamer 407 concentration (18 and 20%), adhesive polymer type (Polyvinyl pyrolidone, Hydroxypropyl methylcellulose, and Carbopol 934), and adhesive polymer concentration (0.5 and 1.5%) on gelling temperature, viscosity at 37 °C, and adhesion strength. Data collected were analyzed using multiple linear regression. A desirability index approach with relative importance weight was used to choose the most desirable formulation. F4 (20% Poloxamer+1.5% Carbopol) was selected for further characterization. F4 released 96.97% drug in 12 h across hairless rat skin. F4 gelation temperature and time were 36 ± 0.35 °C, and 6 ± 0.7 min, respectively. F4 adhesive force was 8835.68 dyne/cm2. F4 was tested for its appetite suppressing effect in a rat model and it was evaluated histopathologically. Rats' chow intake and weight gain was significantly decreased with no signs of inflammation or lipolysis when the optimized BH gel formulation, F4, was compared with untreated animals and animals treated with BH free gel. The results suggest that BH is percutaneously absorbed from the gel base and that the BH gel is tolerable. The desirability index approach with relative importance weight of responses was effective in determination of the optimum formulation. BH is systemically effective and well-tolerated when applied topically in hydrogel-based systems. The Carbopol-Poloxamer gel is a promising modality for transdermal delivery of BH.

A novel transdermal nanoethosomal gel of betahistine dihydrochloride for weight gain control: in-vitro and in-vivo characterization.

BACKGROUND: Betahistine dihydrochloride (BDH) is a histamine analog used to control weight gain, with short elimination half-life and gastric irritation as side effects. OBJECTIVE: The aim of the current investigation is to formulate and optimize a topical BDH ethosomal gel for weight gain control. MATERIALS AND METHODS: Box-Behnken design was applied to study the effect of independent variables: phosphatidylcholine (PC), propylene glycol (PG), and ethanol on vesicle size; entrapment efficiency; % drug release; and flux. The morphology and zeta potential of the optimized formulation were evaluated. The % drug release, flux, and pharmacodynamics of the optimized formulation gel were studied. RESULTS: The size and entrapment efficiency percent had a direct positive relationship with the concentration of PC and negative relationship with ethanol and PG. The % drug release and flux decreased with increasing PC and PG, while ethanol enhanced both responses. Regression modeling indicated a good correlation between dependent and independent variables, where F16 was chosen as the optimized formulation. F16 showed well-defined spherical vesicles and zeta potential of -24 mV, and % release from the gel exceeded 99.5% over 16 h with the flux of 0.28 mg/cm2/h. Food intake and weight gain of rats were significantly decreased after transdermal application of the BDH ethosomal gel when compared with control, placebo, and BDH gel. The histopathological findings proved the absence of inflammation and decrease in adipose tissue. CONCLUSION: Results obtained showed a significant, sustained transdermal absorption of BDH ethosomal gel and, consequently, a decrease in food intake and weight gain.

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.

Effectiveness of betahistine (48 mg/day) in patients with vestibular vertigo during routine practice: The VIRTUOSO study.

BACKGROUND: Vestibular vertigo is associated with substantially reduced quality of life. Betahistine is effective in improving vertigo-associated symptoms, with longer treatment periods leading to greater improvements; however, it is not known whether these effects persist after treatment cessation. METHODS: VIRTUOSO was a prospective, multinational, non-comparative, post-marketing observational programme investigating the effectiveness of betahistine (48 mg/day) and the course of vertigo after the discontinuation of treatment. Patients with vestibular vertigo who were prescribed 48 mg/day betahistine were enrolled in Russia and Ukraine. Treatment duration was up to 2 months, and patients were followed up for 2 months after discontinuation of betahistine. Efficacy endpoints included clinical response (assessed by change in vertigo severity), monthly attack frequency, and physician and patient grading of overall clinical response and improvement of vertigo-associated symptoms. RESULTS: Overall, 309 patients were enrolled and 305 completed the study. Clinical response was rated as good, very good or excellent in 74.1% of patients at end of treatment, with vertigo severity significantly decreased from baseline (p < 0.001). Monthly vertigo attack frequency decreased significantly during the 2 months of treatment (p < 0.001 from baseline) and further decreased during the 2-month follow-up (p < 0.001 from end of treatment). Overall, clinical response was graded as good or excellent by 94.4% of physicians and 95.4% of patients. Clinical improvement was considered either good or excellent by 82.6-90.5% of physicians and patients for nausea, vomiting and faintness. Only one adverse event was reported, with no serious adverse events. CONCLUSION: Our findings suggest that betahistine (48 mg/day) therapy is effective in treating vertigo in routine clinical settings. The observed effects persisted for 2 months after treatment cessation, suggesting that betahistine may facilitate lasting vestibular compensation.

[Seven principles in the treatment of vestibular vertigo and results of the study of VIRTUOSO]. / Sem' printsipov lecheniia vestibuliarnogo golovokruzheniia i rezul'taty issledovaniia.

This article reports the results of the international post-marketing observational program VIRTUOSO aimed at the evaluation of the efficacy of betahistine dihydrochloride at the dose of 48 mg/day for 1-2 months in patients with paroxysmal vertigo of various origins. The clinical response was rated as good, very good or excellent in 74.1% of the patients (p<0.001). Monthly vertigo attack frequency with betahistine decreased in average from 8.0 to 3.0 (p<0.001). Vertigo attack frequency further decreased during the 2-month follow-up after the end of betahistine treatment. No serious adverse effects of betahistine have been reported.

Transbuccal delivery of betahistine dihydrochloride from mucoadhesive tablets with a unidirectional drug flow: in vitro, ex vivo and in vivo evaluation.

OBJECTIVE: Betahistine dihydrochloride (BH.2HCl), an anti-vertigo histamine analog used in the treatment of Ménière's disease, undergoes extensive first-pass metabolism and suffers from short biological half-life. The aim of the present work was to develop and estimate controlled release mucoadhesive buccal tablets of BH.2HCl with a unidirectional drug flow to overcome this encumbrance. METHODS: A direct compression method was adopted for preparation of the tablets using mucoadhesive polymers like guar gum, hydroxypropyl methyl cellulose K4M, sodium carboxymethyl cellulose and their combinations. The tablets were coated from all surfaces except one surface with a solution of 5% (w/v) cellulose acetate and 1% (w/v) dibutyl phthalate. Different permeation enhancers like 2% sodium deoxycholate, 2% sodium cholate hydrate (SCH) and 5% menthol were tested. Swelling index, ex vivo residence time, mucoadhesion strength, in vivo testing of mucoadhesion time, in vitro dissolution and ex vivo permeation were carried out. Furthermore, compatibility and accelerated stability studies were performed for the drug excipients. Finally, drug bioavailability of the BH.2HCl-optimized buccal mucoadhesive formulation was compared with that of the orally administered Betaserc® 24 mg tablet in six healthy male volunteers. RESULTS: Formulation F10, which contained a combination of 35% guar gum and 5% sodium carboxymethyl cellulose, exhibited long adhesion time, high adhesion strength and diminished irritation to volunteers and showed zero-order release kinetics. SCH produced a significant enhancement in permeation of BH.2HCl across buccal mucosa. BH.2HCl-optimized buccal mucoadhesive formulation showed percentage relative bioavailability of 177%. CONCLUSION: The developed mucoadhesive tablets represent a promising alternative for the buccal delivery of BH.2HCl.

A Randomized, Double-Blind, Placebo-Controlled Pilot Study of Betahistine to Counteract Olanzapine-Associated Weight Gain.

Patients with schizophrenia experience higher rates of obesity and related morbidity and mortality than the general population does. Given preclinical studies revealing the role of histamine H1 receptor in human eating behavior, and the potential of olanzapine to block with this system, we hypothesized that histamine H1 receptor agonists may be beneficial in reducing antipsychotic-associated weight gain. In the present study, 36 patients with a diagnosis of schizophrenia or schizoaffective disorder and treated with olanzapine were randomized to betahistine (48 mg/d) or matching placebo for 16 weeks. Study outcomes were change in body weight from baseline and effect on antipsychotic efficacy of olanzapine. The patients in the betahistine group had less weight gain (-1.95 kg) compared with placebo group (5.6 + 5.5 kg vs 6.9 + 5.6 kg, respectively). Positive and Negative Syndrome Scale Questionnaire showed improvement within each group and that subjects treated with betahistine enjoyed an improvement (reduction) by a mean of 35.7 points, higher when compared with placebo subjects who had a reduction of 26.6 points (P = 0.233). An almost equal amount of subjects in both groups experienced adverse effects during the course of this study (87.5% of betahistine vs 85.0% of placebo-treated subjects). Overall, there were no clinically marked differences in safety signals between both groups. A larger study addressing the weaknesses of this pilot study is warranted.

Efficacy and safety of betahistine treatment in patients with Meniere's disease: primary results of a long term, multicentre, double blind, randomised, placebo controlled, dose defining trial (BEMED trial).

STUDY QUESTION: What is the long term efficacy of betahistine dihydrochloride on the incidence of vertigo attacks in patients with Meniere's disease, compared with placebo? METHODS: The BEMED trial is a multicentre, double blind, randomised, placebo controlled, three arm, parallel group, phase III, dose defining superiority trial conducted in 14 German tertiary referral centres (for neurology or ear, nose, and throat). Adults aged 21-80 years (mean age 56 years) with definite unilateral or bilateral Meniere's disease were recruited from March 2008 to November 2012. Participants received placebo (n=74), low dose betahistine (2 × 24 mg daily, (n=73)), or high dose betahistine (3 × 48 mg daily, (n=74)) over nine months. The primary outcome was the number of attacks per 30 days, based on patients' diaries during a three month assessment period at months seven to nine. An internet based randomisation schedule performed a concealed 1:1:1 allocation, stratified by study site. Secondary outcomes included the duration and severity of attacks, change in quality of life scores, and several observer-reported parameters to assess changes in audiological and vestibular function. STUDY ANSWER AND LIMITATIONS: Incidence of attacks related to Meniere's disease did not differ between the three treatment groups (P=0.759). Compared with placebo, attack rate ratios were 1.036 (95% confidence interval 0.942 to 1.140) and 1.012 (0.919 to 1.114) for low dose and high dose betahistine, respectively. The overall monthly attack rate fell significantly by the factor 0.758 (0.705 to 0.816; P<0.001). The population based, mean monthly incidence averaged over the assessment period was 2.722 (1.304 to 6.309), 3.204 (1.345 to 7.929), and 3.258 (1.685 to 7.266) for the placebo, low dose betahistine, and high dose betahistine groups, respectively. Results were consistent for all secondary outcomes. Treatment was well tolerated with no unexpected safety findings. Without a control group of patients who did not receive any intervention to follow the natural course of the disease, the placebo effect could not be accurately assessed and differentiated from spontaneous remission and fluctuation of symptoms. WHAT THIS STUDY ADDS: Current evidence is limited as to whether betahistine prevents vertigo attacks caused by Meniere's disease, compared with placebo. The trial provides information on symptom relief on placebo intervention which is relevant for the design of future studies on potential disease modifying treatments in patients with Meniere's disease. FUNDING, COMPETING INTERESTS, DATA SHARING: Support from the German Federal Ministry of Education and Research (BMBF support code 01KG0708). Potential competing interests have been reported in full at the end of the paper on thebmj.com. Data are available from the corresponding author (Michael.Strupp@med.uni-muenchen.de) or biostatistician (mansmann@ibe.med.uni-muenchen.de). Study registration EudraCT no 2005-000752-32; ISRCTN no ISRCTN44359668.