Efficacy and Safety of Intranasal Betahistine in the Treatment of Surgery-Induced Acute Vestibular Syndrome: A Double-Blind, Randomized, Placebo-Controlled Phase 2 Study.

OBJECTIVE: To evaluate the safety and efficacy of AM-125 nasal spray (intranasal betahistine) in the treatment of surgery-induced acute vestibular syndrome (AVS). STUDY DESIGN: Prospective, double-blind, randomized, placebo-controlled exploratory phase 2 study with dose escalation (part A) followed by parallel dose testing (part B); open-label oral treatment for reference. SETTING: Twelve European study sites (tertiary referral centers). PATIENTS: One hundred and twenty-four patients 18 to 70 years old undergoing surgery for vestibular schwannoma resection, labyrinthectomy or vestibular neurectomy with confirmed bilateral vestibular function presurgery and acute peripheral vertigo postsurgery. INTERVENTIONS: AM-125 (1, 10, or 20 mg) or placebo or betahistine 16 mg p.o. t.i.d. for 4 weeks, starting 3 days postsurgery; standardized vestibular rehabilitation. MAIN OUTCOME MEASURES: Tandem Romberg test (TRT) for primary efficacy, standing on foam, tandem gait, subjective visual vertical and spontaneous nystagmus for secondary efficacy, Vestibular Rehabilitation Benefit Questionnaire (VRBQ) for exploratory efficacy; nasal symptoms and adverse events for safety. RESULTS: At treatment period end, mean TRT improvement was 10.9 seconds for the 20-mg group versus 7.4 seconds for the placebo group (mixed model repeated measures, 90% confidence interval = 0.2 to 6.7 s; p = 0.08). This was corroborated by nominally higher frequency of complete spontaneous nystagmus resolution (34.5% vs. 20.0% of patients) and improvement in the VRBQ; the other secondary endpoints showed no treatment effect. The study drug was well tolerated and safe. CONCLUSIONS: Intranasal betahistine may help accelerate vestibular compensation and alleviate signs and symptoms of vestibular dysfunction in surgery-induced AVS. Further evaluation in a confirmatory manner appears warranted.

Betahistine prevents development of endolymphatic hydrops in a mouse model of insulin resistance and diabetes.

BACKGROUND: Diabetes is associated with inner ear dysfunction. Furthermore, C57BL/6J mice fed high fat diet (HFD), a model for insulin resistance and diabetes, develop endolymphatic hydrops (EH). AIM: Evaluate if betahistine, spironolactone (aldosterone antagonist) and empagliflozin (sodium -glucose cotransporter2 inhibitor) can prevent EH induced by HFD and explore potential mechanisms. METHODS: C57BL/6J mice fed HFD were treated with respective drug. The size of the endolymphatic fluid compartment was measured using contrast enhanced MRI. Secondarily, mice treated with cilostamide, a phosphodiesterase3 inhibitor, to induce EH and HEI-OC1 auditory cells were used to study potential cellular mechanisms of betahistine. RESULTS: HFD-induced EH was prevented by betahistine but not by spironolactone and empagliflozin. Betahistine induced phosphorylation of protein kinaseA substrates but did not prevent cilostamide-induced EH. CONCLUSIONS: Betahistine prevents the development of EH in mice fed HFD, most likely not involving pathways downstream of phosphodiesterase3, an enzyme with implications for dysfunction in diabetes. The finding that spironolactone did not prevent HFD-induced EH suggests different mechanisms for EH induction/treatment since spironolactone prevents EH induced by vasopressin, as previously observed. SIGNIFICANCE: This further demonstrates that independent mechanisms can cause hydropic inner ear diseases which suggests different therapeutic approaches and emphazises the need for personalized medicine.

Efficacy and Safety of a Fixed-Dose Combination of Cinnarizine 20 mg and Dimenhydrinate 40 mg in the Treatment of Patients with Vestibular Vertigo: An Individual Patient Data Meta-Analysis of Randomised, Double-Blind, Controlled Clinical Trials.

BACKGROUND AND OBJECTIVE: The source data of four individual randomised, double-blind, reference- and/or placebo-controlled clinical trials with virtually identical study design were pooled for the present meta-analysis. The main objective was to further evaluate the efficacy and safety of the fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg in comparison to various other antivertigo treatments in patients suffering from central and/or peripheral vestibular vertigo. METHODS: Adult male and female outpatients were subjected to a 4-week treatment with the fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg, cinnarizine (20 mg, 50 mg), dimenhydrinate (40 mg, 100 mg), betahistine dimesylate (12 mg), betahistine dihydrochloride (16 mg) and placebo, respectively. The primary efficacy endpoint was the reduction of a validated mean vertigo score (MVS), a composite score of 12 individual vertigo symptoms, the intensities of which were each evaluated by the patients on a 5-point visual analogue scale. For analysis of primary and further secondary efficacy endpoints, baseline-adjusted analysis of covariance (ANCOVA) was used to calculate adjusted least squares means (LSM) with associated two-sided 95% confidence intervals (CIs) for the difference in MVS reductions between treatment groups. Moreover, various sensitivity analyses, responder and subgroup analyses as well as descriptive analyses with respect to safety/tolerability of the treatments were conducted. RESULTS: Of 795 randomised patients, 779 belonged to the intent-to treat (ITT) and 723 to the per-protocol (PP) population. The main efficacy analysis was based on the ITT population (mean age 52.1 years, 61% female). The mean decrease of the MVS from baseline to Week 4 in the cinnarizine/dimenhydrinate group (-1.10) proved to be significantly larger than in any of the comparator groups. LSM differences for comparators versus the fixed combination ranged between 0.16 (95% confidence interval (CI) 0.03; 0.30, p = 0.017) for cinnarizine 20 mg and 0.60 (95% CI 0.42; 0.78; p < 0.001) for betahistine dimesylate 12 mg in favour of the fixed combination. Furthermore, after 4 weeks of treatment, 74 patients (24.7%) in the cinnarizine/dimenhydrinate group were completely symptom free (MVS = 0), a significantly greater proportion than in any of the comparator groups. Sensitivity analyses showed that baseline characteristics such as age, sex, duration of vertigo and antivertigo pretreatment had only a very minor and clinically non-relevant impact on the efficacy results regarding the primary efficacy outcome. Subgroup analyses with respect to age groups (< 65 years/≥ 65 years) and sex showed no significant differences in efficacy within any of the treatment groups. All treatments were well tolerated. A total of 55 patients (6.9%) reported 75 non-serious adverse events (AEs), and 19 patients (2.4%) discontinued the study prematurely because of AEs. Nearly 95% of the patients (cinnarizine/dimenhydrinate group: 97.9%) rated the tolerability of the study medications as either "good" or "very good". CONCLUSION: The findings of the present meta-analysis indicate that the fixed combination of cinnarizine and dimenhydrinate is a safe and potentially superior treatment option for patients suffering from central and/or peripheral vestibular vertigo, as compared to current standard treatments such as cinnarizine, dimenhydrinate or betahistine given alone in monotherapy.

Using betahistine in the treatment of patients with Menière's disease: a meta-analysis with the current randomized-controlled evidence.

Background: Betahistine is used worldwide to treat patients with Menière's disease. However, despite it being used for decades, diverging opinions on the effect of betahistine on Menière's symptomatology still exist.Aims: The objective of this systematic review was to provide an overview and rate the certainty of the current evidence base regarding the use of betahistine to treat patients with Menière's disease.Materials and methods: A systematic literature search was conducted in October 2019. The search strategy was subdivided into searches for existing guidelines, systematic reviews and individual randomized controlled trials (RCT) investigating the usage of betahistine as compared to placebo, in patients with Ménière's disease. The primary outcome was the frequency of vertigo attack(s) and occurrence of serious adverse events.Results: We identified three relevant guidelines and three systematic reviews: however, neither included any relevant trials matching our inclusion criteria. An individual search for RCTs identified one trial. The results from this particular trial showed no difference in effects on symptoms following treatment with betahistine.Conclusions and Significance: There is a need for further well-conducted placebo RCTs. Currently, there is still a lack of substantial evidence supporting betahistine as a significant and adequate treatment for patients diagnosed with Menière's disease. Trial registration number: The protocol is registered in PROSPERO. Registration number: CRD42018110127 Accepted 11.10.2018.

The risk of fractures, acute myocardial infarction, atrial fibrillation and ventricular arrhythmia in geriatric patients exposed to promethazine.

Objectives: This study aimed to compare the risk of fractures, acute myocardial infarction, atrial fibrillation, and ventricular arrhythmia among Danish citizens aged ≥ 65 which were new users of promethazine or domperidone, triazolam, loratadine, and betahistine. Secondly, the study aimed to perform a risk stratification to identify the most relevant predictors for the study outcomes.Methods: The study period was 01/01/2015 to 31/12/2016. The data sources were the Danish registers. Each patient was followed for 90 days. A logistic regression model was used to compute the unadjusted and adjusted odds ratios (OR), and a conditional inference tree was used to identify the most relevant predictors for the study outcomes.Results: Promethazine had a higher risk of hospitalization for atrial fibrillation than loratadine and betahistine (OR 1.58; 95% CI 1.07-2.63 and OR 3.22; 95% CI 1.69-7.14, respectively). For fractures, acute myocardial infarction, and ventricular arrhythmia hospitalizations, no statistically significant differences were found among drugs under investigation. The medical history of cardiac arrhythmia (OR 4.14; 95% CI 2.94-5.78, p < 0.0001) was the most relevant predictor for atrial fibrillation hospitalizations.Conclusion: This study found an increased risk of atrial fibrillation hospitalization among promethazine users, and the risk was higher among patients with prior cardiac arrhythmia.

[A study of the efficacy and safety of a new modified-release betahistine formulation in the treatment of vestibular vertigo and Meniere's disease]. / Issledovanie effektivnosti i bezopasnosti novoi formy Betagistina s modifitsirovannym vysvobozhdeniem v lechenii vestibulyarnogo golovokruzheniya i bolezni Men'era.

OBJECTIVE: To evaluate the efficacy and safety of modified-release (MR) betahistine (48 mg once daily) versus betaserc (24 mg twice daily) in patients with Meniere's disease or vestibular vertigo. MATERIAL AND METHODS: A multicentre, double-blind, randomized clinical study in patients with an established diagnosis of Meniere's disease (35%) or vestibular vertigo (65%) was carried out. A total of 264 patients were randomized (132 in each group).The inclusion criteria were a Dizziness Handicap Inventory (DHI) total score of more than 30 points and at least 2 vertigo attacks within the previous 4 weeks. The primary efficacy variable was the change in the DHI total score from baseline to after 12 weeks of treatment. The predefined non-inferiority margin was set at 9 points for the DHI total score. RESULTS: After 12 weeks of treatment, the DHI total score was significantly (p<0.001) decreased compared with baseline, by 32.0±20.7 in the betahistine MR group and by 31.8±19.8 in the betaserc group. The adjusted difference in the change in the DHI total score with a one-sided 97.5% CI was 0.9 (--; 5.3) points, the upper confidence limit (+5.3) fell below the predefined margin of non-inferiority of 9 points, and the non-inferiority of betahistine MR to betaserc was established. The treatment groups were comparable in terms of reduced scores for the functional, emotional and physical subdomains of DHI; reduced frequency, intensity and duration of vertigo attacks; decreased proportion of patients with prolonged attacks and severe symptoms during attacks; and scores on the Clinical Global Impression - Improvement scale. The safety profile of betahistine MR was comparable to that of betaserc, the most frequently reported adverse event was headache in both treatment groups. CONCLUSION: Betahistine MR (48 mg once daily) is non-inferior to betaserc (24 mg twice daily) in patients with Meniere's disease or vestibular vertigo and has a comparable safety profile.

Efficacy and Safety of a Fixed Combination of Cinnarizine 20 mg and Dimenhydrinate 40 mg vs Betahistine Dihydrochloride 16 mg in Patients with Peripheral Vestibular Vertigo: A Prospective, Multinational, Multicenter, Double-Blind, Randomized, Non-inferiority Clinical Trial.

BACKGROUND AND OBJECTIVE: Vertigo derived from peripheral vestibular disorders is quite frequently encountered in daily clinical practice and can be a severely disabling symptom associated with substantial impairment of health-related quality of life for the affected patients. Betahistine, a structural analogue of histamine and presumably the most widely prescribed anti-vertigo drug worldwide, has previously been shown to be an effective and safe treatment for these patients. The objective of the present study was to evaluate whether the fixed combination of cinnarizine and dimenhydrinate (Arlevert®) is non-inferior and thus a potentially useful alternative to betahistine dihydrochloride in the treatment of patients suffering from peripheral vestibular vertigo. METHODS: In this prospective, multicenter, double-blind, randomized, non-inferiority clinical trial, outpatients from 8 ENT clinics in Austria, Bulgaria, the Czech Republic and Russia were randomly assigned to receive three times daily one tablet of either the fixed combination cinnarizine 20 mg/dimenhydrinate 40 mg or betahistine dihydrochloride 16 mg for 4 weeks. Primary endpoint was the reduction of the mean vertigo score (MVS), a validated 12-item composite score defined as the mean of 6 vertigo symptoms (dystasia and walking unsteadiness, staggering, rotary sensation, tendency to fall, lift sensation, blackout) and 6 trigger factors for vertigo (change of position, bowing, getting up, driving by car/train, head movements, eye movement), after 4 weeks of therapy, as judged by the patient on a 5-point visual analogue scale (VAS). The non-inferiority margin was set to 0.3. Secondary outcomes included the patient's and investigator's judgment of global efficacy, the patient's rating of impairment of daily activities, and safety/tolerability of the treatments. RESULTS: Three hundred and six patients (mean age 53.5 years, approximately 60% female) were enrolled and randomized to the fixed combination cinnarizine/dimenhydrinate (n = 152) or betahistine (n = 154) groups; 297 patients completed the study and 294 (146 and 148, respectively) were valid for the per-protocol analysis, which was used for the non-inferiority analysis. Treatment with cinnarizine/dimenhydrinate led to a stronger reduction of the MVS [least squares mean (LSM)] after 4-week therapy (primary endpoint) in comparison to betahistine (0.395 vs 0.488; difference: - 0.093, 95% CI - 0.180; - 0.007, p = 0.035); since the upper limit of the two-sided 95% confidence interval was not only below the non-inferiority margin of 0.3, but also entirely below 0, superiority of the fixed combination could be demonstrated. The combination preparation was also more effective after 1 week of therapy and received more favorable patient's ratings on overall efficacy and impairment of daily activities. Both treatments were very well tolerated. Only 12 patients (3.92%) reported 13 non-serious adverse events; 2 cinnarizine/dimenhydrinate-treated patients discontinued the study prematurely due to adverse events as compared to 5 betahistine-treated patients. CONCLUSION: The fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg was found to be not only non-inferior, but superior to betahistine 16 mg in the improvement of peripheral vestibular vertigo. Furthermore, taking into account a good and slightly favorable safety profile, the present study provides evidence that the fixed-combination preparation is a potent and even superior alternative to betahistine in the treatment of vertigo related to peripheral vestibular disorders. STUDY REGISTRATION: EudraCT No. 2011-004025-27.

Pregnancy outcomes after maternal betahistine exposure: A case series.

OBJECTIVE: To investigate the pregnancy outcomes of women who were exposed to betahistine during their pregnancies. METHODS: We identified and evaluated the outcomes of 27 pregnant women who were referred to Terafar (Teratology Information Service, Izmir, Turkey) for a teratological risk assessment. RESULTS: Of 24 pregnancies with known outcomes, 21 resulted in live births (including two pairs of twins) whereas two ended with miscarriage and three with elective terminations. Among the 20 live births for whom the malformation details were available, there were 17 normal outcomes, one major and two minor congenital malformations. CONCLUSIONS: Despite a number of limitations, this case series may be of value regarding counseling pregnant women with inadvertent betahistine exposure. Further epidemiological studies with larger sample sizes and control groups are necessary to draw more definite conclusions.

Is betahistine effective for Ménière’s disease? / ¿Es efectiva la betahistina en la enfermedad de Ménière?

PROBLEM: Meniere’s disease is an inner ear disorder characterized by episodes of spontaneous vertigo, fluctuating hearing loss and tinnitus. Betahistine has been used to reduce intensity and frecuency of vertigo attacks, but there is controversy regarding its effectiveness. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified four systematic reviews including 12 trials overall. We concluded betahistine might reduce the number of attacks, vertigo intensity and lead to a symptomatic improvement according to global judgement in patients with Meniere’s disease, but the certainty of evidence is low. On the other hand, it probably does not have significant adverse effects.

INTRODUCCIÓN: La enfermedad de Ménière es una anomalía del oído interno caracterizada por episodios de vértigo espontáneo, hipoacusia fluctuante y tinnitus. La betahistina ha sido utilizada para reducir la intensidad y frecuencia de las crisis de vértigo, pero existe controversia respecto a su eficacia. MÉTODOS: Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud a nivel mundial, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, realizamos un metanálisis, preparamos tablas de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos 4 revisiones sistemáticas que en conjunto incluyen 12 estudios primarios, todos ellos corresponden a ensayos aleatorizados. Concluimos que el uso de betahistina podría disminuir el número de crisis, la intensidad del vértigo y llevar a una mejoría global sintomática en los pacientes con enfermedad de Ménière, pero la certeza de la evidencia es baja. Por otra parte, probablemente no tiene efectos adversos importantes.

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.

Betahistine for symptoms of vertigo.

BACKGROUND: Vertigo is a symptom in which individuals experience a false sensation of movement. This type of dizziness is thought to originate in the inner ear labyrinth or its neural connections. It is a commonly experienced symptom and can cause significant problems with carrying out normal activities. Betahistine is a drug that may work by improving blood flow to the inner ear. This review examines whether betahistine is more effective than a placebo at treating symptoms of vertigo from different causes. OBJECTIVES: To assess the effects of betahistine in patients with symptoms of vertigo from different causes. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Trials Register; Central Register of Controlled Trials (CENTRAL 2015, Issue 8); PubMed; EMBASE; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. We also contacted manufacturers and researchers in the field. The date of the search was 21 September 2015. SELECTION CRITERIA: We included randomised controlled trials of betahistine versus placebo in patients of any age with vertigo from any neurotological diagnosis in any settings. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. Our primary outcome was the proportion of patients with reduction in vertigo symptoms (considering together the intensity, frequency and duration those symptoms). MAIN RESULTS: We included 17 studies, with a total of 1025 participants; 12 studies were published (567 patients) and five were unpublished (458 patients). Sixteen studies including 953 people compared betahistine with placebo. All studies with analysable data lasted three months or less. The majority were at high risk of bias, but in some the risk of bias was unclear. One study, at high risk of bias, included 72 people with benign paroxysmal positional vertigo (BPPV) and compared betahistine with placebo; all patients also had particle repositioning manoeuvres. The studies varied considerably in terms of types of participants, their diagnoses, the dose of betahistine and the length of time it was taken for, the study methods and the way any improvement in vertigo symptoms was measured. Using the GRADE system, we judged the quality of evidence overall to be low for two outcomes (proportion of patients with improvement and proportion with adverse events).Pooled data showed that the proportion of patients reporting an overall reduction in their vertigo symptoms was higher in the group treated with betahistine than the placebo group: risk ratio (RR) 1.30, 95% confidence interval (CI) 1.05 to 1.60; 606 participants; 11 studies). This result should be interpreted with caution as the test for statistical heterogeneity as measured by the I(2) value was high.Adverse effects (mostly gastrointestinal symptoms and headache) were common but medically serious events in the study were rare and isolated: there was no difference in the frequency of adverse effects between the betahistine and placebo groups, where the rates were 16% and 15% respectively (weighted values, RR 1.03, 95% CI 0.76 to 1.40; 819 participants; 12 studies).Sixteen per cent of patients from both the betahistine and the placebo groups withdrew (dropped out) from the studies (RR 0.96, 95% CI 0.65 to 1.42; 481 participants; eight studies).Three studies looked at objective vestibular function tests as an outcome; the numbers of participants were small, techniques of measurement very diverse and reporting details sparse, so analysis of this outcome was inconclusive.We looked for information on generic quality of life and falls, but none of the studies reported on these outcomes. AUTHORS' CONCLUSIONS: Low quality evidence suggests that in patients suffering from vertigo from different causes there may be a positive effect of betahistine in terms of reduction in vertigo symptoms. Betahistine is generally well tolerated with a low risk of adverse events. Future research into the management of vertigo symptoms needs to use more rigorous methodology and include outcomes that matter to patients and their families.

Efficacy and acceptability of oxcarbazepine vs. carbamazepine with betahistine mesilate tablets in treating vestibular paroxysmia: a retrospective review.

OBJECTIVES: Vestibular paroxysmia (VP) is a rare episodic peripheral vestibular disorder that can cause acute short attacks of vertigo. This study aimed to compare the efficacy and acceptability of carbamazepine (CBZ), CBZ plus betahistine mesilate tablets (BMT) and oxcarbazepine (OXC) plus BMT in treating VP within 12 weeks. METHODS: A retrospective analysis of data from 196 VP patients treated in our hospital was conducted. There were 73 patients receiving CBZ, 65 patients receiving CBZ+BMT and 58 patients receiving OXC+BMT. The frequency of vertigo, vertigo duration, vertigo score, response rate (RR) and side effects were compared between groups to assess efficacy and acceptability at the end of 12(th) week. RESULTS: After 12 weeks' treatment, the CBZ+BMT group had a greater reduction in the frequency of vertigo, vertigo duration and vertigo score than the other two groups. The RR was highest in the CBZ+BMT group, second in the OXC+BMT group and lowest in the CBZ group. The incidence of side-effects was highest in the CBZ group, second in the CBZ+BMT group and lowest in the OXC+BMT group. Two patients in the CBZ group were withdrawn. CONCLUSION: These results indicated that using BMT as an augmentation for CBZ or OXC might be a good choice in treating VP.

Betahistine reduces postoperative nausea and vomiting after laparoscopic gynecological surgery.

BACKGROUND: Patients undergoing laparoscopic gynecological surgery are at high risk of postoperative nausea and vomiting (PONV). We compared the antiemetic efficacy of ondansetron plus betahistine with that of ondansetron alone in this patient population. METHODS: In this randomized, double-blinded study, 168 patients were randomly allocated to receive placebo (O group) or betahistine 18 mg (OB group) orally 3 hours before surgery and 24 hours thereafter. In both groups, ondansetron 4 mg was administered at the end of surgery and 8 mg were added to an intravenous patient-controlled analgesia (IV-PCA) fentanyl solution. The primary outcome was complete response (no PONV and no rescue antiemetics) during the first 48 hours after surgery. The severity of nausea, pain score, and adverse events were assessed. RESULTS: The incidence of complete response was significantly higher in OB group than in O group (69% vs. 46%, P=0.004). The severity of nausea was lower in OB group than in O group during 30 minutes to 6 hours and 6 to 24 hours after surgery (P=0.001 and P<0.001). Pain score was similar between the groups. The incidence of dizziness was lower in OB group than in O group (13% vs. 40%, P < 0.001). Six patients (7%) in OB group and 15 patients (18%) in O group required early IV-PCA discontinuation, primarily because of PONV and/or dizziness (P=0.038). CONCLUSIONS: Compared to ondansetron alone, ondansetron plus betahistine was more effective to prevent PONV and dizziness in high-risk patients undergoing laparoscopic gynecological surgery.

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.

Meta-analysis of clinical studies with betahistine in Ménière's disease and vestibular vertigo.

We present a meta-analysis of 12 double-blind, randomized, placebo-controlled clinical studies with betahistine in patients suffering from vestibular vertigo or Ménière's disease, based on both published and unpublished data. The clinical endpoint we used was the investigator's overall opinion on the response to treatment of the vertigo symptoms, after at least 1 month of treatment. We introduce a new effect parameter, the odds of a favorable treatment outcome, with the odds ratio as measure to compare the responses of betahistine and placebo patients. For each study a separate odds ratio was estimated (the study-specific odds ratio). All but one of the study-specific odds ratios were >1.0, meaning that with the new effect parameter there was evidence of an effect of betahistine on vertigo symptoms in 11 of the 12 studies. Four of the 12 studies showed a statistically significant effect in favor of betahistine compared to placebo. The meta-analytical (i.e., average) odds ratio was 2.58 (95% confidence interval 1.67-3.99), a statistically significant result. This means that on average, the likelihood of a favorable outcome is almost two times higher for patients treated with betahistine than for placebo-treated patients. Sub-analyses conducted for patients with Ménière's disease on one hand and with vestibular vertigo on the other hand also yielded statistically significant results. For Ménière's disease, the meta-analytical odds ratio was 3.37 (95% CI 2.14-5.29); for vestibular vertigo, the odds ratio was 2.23 (95% CI 1.20-4.14). Our meta-analysis supports the therapeutic benefit of betahistine on vertiginous symptoms in both Ménière's disease and vestibular vertigo.

Reducing antipsychotic-induced weight gain in schizophrenia: a double-blind placebo-controlled study of reboxetine-betahistine combination.

RATIONALE: Combination treatment with reboxetine, a selective norepinephrine reuptake inhibitor, and betahistine, a histamine H1 receptor agonist/H3 antagonist, was developed to produce complementary action in CNS pathways regulating appetite and body weight. In the present placebo-controlled study, we evaluated whether a reboxetine-betahistine combination attenuates olanzapine-induced weight gain in schizophrenia patients. METHOD: Forty-three inpatients with DSM-IV schizophrenic disorder participated in a randomized double-blind study. Reboxetine (4 mg/day) with betahistine (48 mg/day) (N = 29) or placebo (N = 14) was co-administered with olanzapine (10 mg/day) for 6 weeks. Mental status was assessed at baseline and endpoint with relevant rating scales. Intention-to-treat method was used for statistical analysis. RESULTS: Seven patients in the study group and four in the placebo group discontinued the trial. At the end of the trial, patients in the olanzapine/reboxetine + betahistine group gained significantly less weight than those in the olanzapine/placebo group [2.02 ± 2.37 and 4.77 ± 3.16 kg, respectively; t = 2. 89, degrees of freedom (df) = 41, p = 0.006]. The weight-attenuating effect of this combination was twofold larger than the weight-attenuating effect previously demonstrated with reboxetine alone. Significantly fewer patients in the study group than in the comparison group increased their initial weight by >7 %, the cutoff for clinically significant weight gain [3/29 (10.3 %) and 6/14 (42.9 %), respectively; χ (2) = 6.03, df = 1, p = 0.014]. The reboxetine-betahistine combination was safe and well tolerated. CONCLUSIONS: Reboxetine-betahistine combination produces a clinically meaningful attenuation of olanzapine-induced weight gain. These results justify direct comparison between the reboxetine-betahistine combination and reboxetine alone.