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.

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.

A novel N-chlorotaurine-corticosteroid combination as a preservative-free local disinfectant: influence on the ciliary beat frequency in vitro.

CONCLUSIONS: The combination of N-chlorotaurine (NCT) and a corticosteroid seems to be a very promising substance for the local therapy of ENT infections. As it can be used without any preservatives, the effect on the ciliary beat frequency (CBF) is much less than that of products containing benzalkonium chloride (BAC). The in vitro results obtained in this study encourage us to perform clinical trials on this novel combination for intranasal application. OBJECTIVE: To investigate the influence of a novel mixture of NCT and a corticosteroid [fluticasone propionate (FP)] on the CBF of human ciliated cells in vitro. MATERIAL AND METHODS: The study was designed as an in vitro study. CBF was measured by means of a photometric technique involving the combination of a light microscope, a photometer, a photographic multiplier and a computerized analyzing unit. RESULTS: The combination of 1% NCT + 0.5 mg/ml FP decreased the CBF to 42.17% of its original value after 20 min. Treatment with BAC lowered the CBF depending on the concentration to 96.61% of its original value with 0.04 mg/ml, to 91.90% with 0.1 mg/ml, to 63.46% with 0.2 mg/ml and to 0% with 0.5 mg/ml. After rinsing in saline, the CBF of samples treated with 1% NCT + 0.5 mg/ml FP recovered to 68.93% of its original value.

Olfactory functions and volumetric measures of orbitofrontal and limbic regions in schizophrenia.

OBJECTIVE: Olfactory deficits in schizophrenia patients have been suggested to reflect medial temporal and/or prefrontal brain abnormalities. In this study, we examined the relationship between different olfactory functions and volumes of the hippocampus-amygdala complex (HAC) and the orbitofrontal brain region using magnetic resonance imaging (MRI). METHODS: Thirty-three young men with schizophrenia (DSM-IV) and 40 healthy controls performed unirhinal olfactory assessment including the main olfactory functions (threshold, discrimination, and identification), and odor judgements (intensity, edibility, familiarity, and pleasantness). Volumes of regions in the medial temporal lobe (hippocampus and amygdala) and the prefrontal region (orbitofrontal gray and white matter) were measured on MRI scans. RESULTS: Compared with controls, patients showed bilaterally impaired thresholds, quality discrimination and identification, as well as edibility judgements. Olfactory deficits were not attributable to smoking, premorbid intelligence, or impaired thresholds. Relative to controls, patients had bilateral reduced hippocampus and amygdala volumes. In patients, smaller hippocampus volumes were associated with poorer olfactory discrimination ability. CONCLUSIONS: Olfactory deficits in schizophrenia appear to be associated with morphometric abnormalities in the medial temporal rather than the orbitofrontal region (OFR). These results indicate that olfactory quality discrimination deficits are related to structural hippocampus abnormalities. Future studies of genetic and behavioral high-risk samples seem warranted.

Various bilateral olfactory deficits in male patients with schizophrenia.

Olfactory identification deficits in schizophrenia patients are well documented. Less is known about the functioning of other olfactory domains and the possibility of lateralized dysfunctions. Thirty male schizophrenia patients and 30 male healthy controls underwent unirhinal assessment of various olfactory domains: detection threshold (dimethyl disulfide, phenyl ethanol), quality discrimination, and odor ratings (familiarity, pleasantness, edibility, intensity) of pure chemicals (Munich Olfaction Test), as well as familiarity and edibility judgments and identification of everyday odors. Aside from impaired identification, patients showed impaired familiarity and edibility judgments of everyday odors. With regard to odor ratings of pure chemicals, group differences were observed only in pleasantness ratings, with higher ratings in patients. Furthermore, patients had reduced sensitivity with dimethyl disulfide and reduced quality discrimination compared with controls. Further analyses showed that identification deficits were not attributable to reduced sensitivity but may be associated with impairments in quality discrimination. Olfactory dysfunctions were found across both nostrils. Results suggest specific dysfunctions in olfactory processing in schizophrenia patients, including early stages of the odor identification process.

Treatment of vertigo due to acute unilateral vestibular loss with a fixed combination of cinnarizine and dimenhydrinate: a double-blind, randomized, parallel-group clinical study.

BACKGROUND: Acute unilateral vestibular loss is a balance disorder that is accompanied by vertigo symptoms and concomitant vegetative symptoms, including nausea and vomiting. Patients are frequently confined to bed rest but may continue to experience vertigo symptoms. A well-established antivertiginous therapy consisting of cinnarizine and dimenhydrinate at low doses may offer rapid relief of acute vertigo symptoms due to acute vestibular loss, without inhibiting physiological compensation processes. OBJECTIVE: The purpose of this study was to compare the clinical efficacy and tolerability of a fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg versus monotherapy with its respective components in the treatment of acute vertigo symptoms due to acute unilateral vestibular loss. METHODS: In this prospective, single-center, randomized, double-blind, parallel-group clinical study, 50 patients with acute vestibular vertigo were randomly assigned to receive 4 weeks of treatment (1 tablet 3 times daily) with a fixed combination of 20 mg cinnarizine and 40 mg dimenhydrinate, 20 mg cinnarizine alone, or 40 mg dimenhydrinate alone. All patients received a 15% mannitol infusion as standard therapy during the first 6 days of treatment. Efficacy was determined by the patients' assessments of vertigo symptoms after 1 and 4 weeks of treatment using a verbal rating scale (vertigo score) and by vestibulo-ocular and vestibulospinal tests. The primary efficacy criterion was defined as the relief of vertigo symptoms after 1 week of treatment. RESULTS: After 1 week of treatment, the fixed combination was significantly more effective than 20 mg cinnarizine (P < 0.001) and 40 mg dimenhydrinate (P < 0.01). After 4 weeks, the fixed combination was still significantly more effective than cinnarizine in reducing vertigo symptoms (P < 0.01) and significantly more effective than dimenhydrinate in improving the patients' balance while standing (P < 0.05). The tolerability of the fixed combination was rated good or very good by 100% of the patients (cinnarizine alone, 82.4%; dimenhydrinate alone, 94.4%). No serious adverse events occurred. Four patients in the fixed combination and the cinnarizine groups, and 6 patients in the dimenhydrinate group reported nonserious adverse events. CONCLUSIONS: The results of this study suggest a distinct benefit in using a fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg versus the respective monotherapies in this population of patients with acute vestibular vertigo.

Patterns of GABA-like immunoreactivity in efferent fibers of the human cochlea.

Olivocochlear efferent neurons originate in the superior olivary complex of the brainstem and terminate within sensory cell regions of the organ of Corti. Components of this complex include the lateral olivocochlear bundle whose unmyelinated axons synapse with radial afferent dendrites below inner hair cells and the medial olivocochlear bundle, from which myelinated axons form a direct synaptic contact with outer hair cells. gamma-Aminobutyric acid (GABA), a major neurotransmitter of the central nervous system believed to be responsible for most fast-inhibitory transmissions, has been demonstrated with interspecies variation between mammal and primate auditory efferents. In the present study, we evaluate the immunocytochemical presence of GABA in 10 human cochleae using light and electron microscopy. GABA-like immunostaining could be observed in inner spiral fibers, tunnel spiral fibers, tunnel-crossing fibers, and at efferent endings synapsing with outer hair cells. To approximate medial efferent fiber quantifications, we counted labeled terminals at the base of each outer hair cell and then compared this sum with the number of tunnel crossing fibers. We found a 'branching ratio' of 1:2 implicating a doubling in quantifiable efferent fibers at the level of the outer hair cell. In human, the distribution of GABA-like immunoreactivity showed a consistent presence throughout all turns of the cochlea. A new method for application of immunoelectron microscopy on human cochleae using a pre-embedding technique is also presented and discussed.

OCP2 immunoreactivity in the human fetal cochlea at weeks 11, 17, 20, and 28, and the human adult cochlea.

The two most abundant proteins of the organ of Corti, OCP1 and OCP2, are acidic, cytosolic, low molecular weight proteins diffusely distributed within the cytoplasm of supporting cells. A recent study by Henzl et al. (2001) found first, that these two proteins co-localize with connexin 26 along the epithelial gap junction system and second, that OCP2 could participate with OCP1 in an organ of Corti-specific SCF complex (Skp1, cul1in, and Fbp), a ubiquitin ligase complex. Previous study has also implicated OCP2 in the recycling and regulation of intracellular K(+) efflux as well as pH homeostatic mechanisms. In the present study, we document the emergence and distribution features of OCP2 through various stages (weeks 11-28) of gestation in human fetal cochleae. Four fetal cochleae, the cochleae of a normal hearing human adult and a mature rat for positive control were fixed in 4% formalin within 2 h post mortem. Immunohistochemical studies were performed using a rabbit polyclonal antibody raised against a synthetic peptide corresponding to amino acids 3-16. Specimens were mounted in paraffin sections. Results show that OCP2 immunoreactivity is evident at a prenatal age of 11 weeks, peaks in expression at the onset of cochlear function at 20 weeks and achieves adult-like patterns of distribution just prior to histological maturation at 28 weeks. Though this protein could be associated with the development, maturation, and electrochemical maintenance of the cochlear gap junction system, the nature of this protein's function in the developing and mature human cochlea remains unclear.

Neurotransmission in the human labyrinth.

Different neuroactive substances have been found in the efferent pathways of both the olivocochlear and vestibular systems. In the present study, the distribution and role of three neurotransmitters, choline acetyltransferase (ChAT), gamma aminobutyric acid (GABA), and enkephalin were investigated in the human labyrinth of 4 normal-hearing individuals. Immunohistochemical studies in human inner ear research, however, face a problem of procuring well-preserved specimens with maintained neurotransmitter antigenicity and morphology. Methods and findings are reported and discussed.

Ultrastructural evaluation of calcitonin gene-related peptide immunoreactivity in the human cochlea and vestibular endorgans.

Calcitonin gene-related peptide (CGRP) is a neuropeptide widely distributed in the peripheral and central nervous system. Demonstrated in the efferent systems of the mammalian cochlea and vestibule, immunoreactive patterns of CGRP may vary by species. There is, however, no information in the literature investigating CGRP localization in the human cochlea. In the present study, the ultrastructural localization of CGRP immunoreactivity was evaluated in the human inner ear with immunoelectron microscopy. It was found that, in human cochlea, CGRP immunoreactivity was located in unmyelinated nerve fibres of the spiral lamina, inner spiral fibres beneath inner hair cells, tunnel spiral fibres, tunnel crossing fibres and outer radial fibres. In endorgans of human vestibule, CGRP immunoreactivity was located in vesiculated nerve fibres and bouton-type nerve terminals which were seen to contact afferent nerve chalices surrounding type I sensory cells and afferent nerve fibres, or to form an en passant contact with afferent dendrites. CGRP immunoreactivity appeared to be confined to efferent systems in all cases. This study presents evidence that CGRP could serve a role in neurotransmission or neuroregulation in both cochlear and vestibular efferent systems of human.