Extrapyramidal symptoms after exposure to calcium channel blocker-flunarizine or cinnarizine.

PURPOSE: Flunarizine (fz) and cinnarizine (cz) have well-known extrapyramidal side effects (EPSEs). The aim of this study was to evaluate the incidence and occurrence time of cz- and fz-related EPSEs. METHOD: Patients who took fz or cz for more than 1 month were identified from the longitudinal health insurance database 2005 and 2010. Excluded were patients with any of the underlying diseases that may cause parkinsonism. Drug-induced EPSEs were defined as the new diagnosis of parkinsonism, dyskinesia, or secondary dystonia during drug use or within 3 months after discontinuing the medication. Age- and sex-matched controls were included in this study. RESULTS: Recruited for analysis were individuals who took fz (n = 26,133) and cz (n = 7186). The incidence rates of fz- and cz-induced EPSEs were 21.03 and 10.3 per 10,000 person-months, respectively. The hazard ratios (HRs) of EPSEs among fz and cz subjects were 8.03 (95% CI 6.55-9.84) and 3.41 (95% CI 2.50-4.63) when compared with the control individuals. Both fz and cz patients had a higher cumulative incidence of EPSEs than their control individuals (p < 0.001). Among subjects who took fz, the incidence of EPSEs was higher in the second than first year of drug exposure (45.59 vs 21.03 per 10,000 person-months). CONCLUSIONS: Fz and cz significantly increased the risk of parkinsonism, dyskinesia, and dystonia. Potential benefits and risks should be weighed when considering long-term use of these drugs especially fz.

Risk of parkinsonism induced by flunarizine or cinnarizine: a population-based study.

PURPOSE: This retrospective cohort study used a population-based dataset to test the risk for parkinsonism in patients receiving flunarizine and cinnarizine, compared with matched controls. METHODS: Data were obtained from the National Health Insurance Research Dataset of Taiwan. Patients receiving flunarizine or cinnarizine for more than 1 month between 2000 and 2005 were enrolled. Exclusion criteria included receiving flunarizine, cinnarizine, or antipsychotics for more than 1 month during 1997-1999, a history of neurodegenerative diseases, and an age of less than 30 years. One matched control for each patient was selected. Each participant was followed for diagnosis of parkinsonism within a 3-year observation period. Stroke, diabetes mellitus, total prescription days, and doses of flunarizine or cinnarizine were recorded. RESULTS: The study and control groups consisted of 9830 subjects. In the study group, 280 patients (2.9 %) were diagnosed with parkinsonism with a median observation period of 1.2 years, and 49 participants (0.5 %) were diagnosed in the control group with a median observation period of 1.9 years. The adjusted hazard ratio for parkinsonism among patients receiving flunarizine and cinnarizine was 5.117 (95 % CI = 3.758-6.967). Age, stroke, and diabetes mellitus were significant risk factors, but female sex and total doses of the study drugs were not. CONCLUSIONS: This study demonstrates that flunarizine and cinnarizine significantly increase the risk for parkinsonism. The treatment benefits of these two agents should be balanced with this adverse effect. Physicians must look carefully for early signs of parkinsonism in patients treated with flunarizine and cinnarizine.

Beyond anxiety and agitation: A clinical approach to akathisia.

BACKGROUND: When patients suddenly become restless and are unable to sit or stand still, especially in general medical settings, anxiety is often the topmost differential on every clinician's mind. However, the possibility of the very subjectively distressing condition called 'akathisia' should always be considered. OBJECTIVE: The aim of this article is to discuss a clinical approach to the management of akathisia, drawing on the presentation of a patient who was admitted to a general medical ward. DISCUSSION: Akathisia, a subjective and very distressing feeling of restlessness, has been found to be caused by a wide range of medications used in general medical settings, such as azithromycin, antiemetics and antipsychotics. Despite its high incidence and association with an increase in suicidal thoughts, it often goes unrecognised. This paper highlights the need for its early recognition, provides a diagnostic guide and an approach to its management.

The effects of cinnarizine versus sodium valproate in migraine prophylaxis.

AIM: The aim of this randomized, double-blind, parallel-group study was to compare the efficacy and safety of low-dose cinnarizine and sodium valproate in migraine prophylaxis. METHODS: A total of 104 patients were treated during a 12-week treatment period. Cinnarizine dose of 25 mg and 200-mg sodium valproate were administered every 12 hours. During follow-up period, frequency, intensity and duration of migraine attacks, symptoms associated with headache, analgesics use, as well as drugs' side effects were studied. Participants completed Migraine Disability Assessment (MIDAS) and Headache Impact Test (HIT-6) questionnaires before and after treatment. RESULTS: Frequency, intensity and duration of migraine headaches as well as MIDAS score and administration of symptomatic medications decreased significantly between repeated follow-up visits in both groups. Reduction of 4-week migraine frequencies in patients receiving cinnarizine and valproate was 36.4% and 55%, respectively, and the difference between two groups was statistically significant (p < 0.001). CONCLUSION: Our results showed that administration of 25-mg cinnarizine every 12 hours can significantly decrease headache duration (p ≤ 0.001) and headache frequency (p ≤ 0.001) in patients with migraine. These results suggest that cinnarizine may be an appropriate substitution for first-line migraine prophylaxis such as valproate.

Permanent non-progressive cinnarizine and flunarizine-induced parkinsonism: An under-recognized tardive syndrome in the elderly?

Secondary parkinsonism induced by exposure to dopamine (DA) receptor antagonists as first and second generation antipsychotics, DA storage depleters, calcium channel blockers, benzamides substituted and other classes of drugs is traditionally believed to be completely reversible in most of patients following withdrawal of the offending drug even though after a variable time delay. The lack of recovery or initial full recovery with subsequent development of progressive parkinsonism has been regarded to result from an underlying subclinical degenerative process like PD unmasked by the inducing drug. These well-recognized clinical outcomes of drug-induced parkinsonism (DIP) have disregarded the existence of another outcome, characterized by permanent non-progressive parkinsonism. This syndrome may fullfil the criteria of tardive parkinsonism, a controversial entity currently referred to as a persistent condition without indication of its long-term course and clinical features. On reviewing the published literature on DIP, we have identified two prospective long-term follow-up of elderly patients in which parkinsonism induced by the calcium channel antagonists cinnarizine and flunarizine became permanent and non-progressive following drug discontinuation in a non-negligible proportion of patients, consistent with the clinical concept of a true tardive syndrome, according to currently accepted criteria. The authors hypothesize that the development of tardive parkinsonism might be due to a neurotoxic effect of the pharmacodynamic proprieties of the calcium channel blockers and their metabolites, exerted on post-synaptic striatal neurons and/or a neurotoxic damage on presynaptic DA neurons in patients without an underlying subclinical degenerative parkinsonism, so accounting for the stable and non-progressive course over time.

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.

The effects of cinnarizine on menopausal symptoms in women.

OBJECTIVE: To evaluate the effectiveness and safety of cinnarizine in the treatment of menopausal symptoms. DESIGN: A total of 100 climacteric and symptomatic women participated in a double-blind, placebo-controlled study. They were divided into two groups of the same size: Gcin, intake of 25 mg of cinnarizine every 12 h for 6 months (n=50); and Gpla, placebo intake every 12 hours for 6 months (n=50). Menopausal symptoms were evaluated according to the Kupperman menopausal index on the first visit and at 6 months of treatment. A total of 62 women completed the study: 27 from the Gcin group and 35 from the Gpla group. RESULTS: Based on the Kupperman menopausal index, there were no statistically significant differences between the two groups before and after the treatment. CONCLUSION: Our data suggest cinnarizine is not effective on menopausal symptoms because it had no more efficacy than placebo.

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.

Efficacy and tolerability of a fixed low-dose combination of cinnarizine and dimenhydrinate in the treatment of vertigo: a 4-week, randomized, double-blind, active- and placebo-controlled, parallel-group, outpatient study.

BACKGROUND: Most cases of vertigo are attributable to both peripheral and central vestibular disorders. Therefore, it would be of interest to determine whether a combination therapy having both peripheral and central actions would translate into more efficient symptom relief. OBJECTIVE: This study was conducted to evaluate the efficacy and tolerability of a fixed low-dose combination of cinnarizine 20 mg + dimenhydrinate 40 mg in the treatment of vertigo of central, peripheral, or combined central/peripheral origin. METHODS: This was a prospective, multicenter, randomized, double-blind, active- and placebo-controlled, parallel-group, outpatient study in men and women (age >30 years) with central, peripheral, or combined central/peripheral vestibular vertigo. Patients who assessed > or =1 vertigo symptom as being of medium intensity (> or =2) on a 5-point visual analog scale (from 0 = no symptoms to 4 = very severe symptoms) and who had abnormal vestibulospinal movement patterns on cramocorpography were eligible. Patients were randomly assigned to receive 1 tablet of the fixed combination of cinnarizine 20 mg + dimenhydrinate 40 mg, cinnarizine 50 mg, dimenhydrinate 100 mg, or placebo 3 times daily for 4 weeks. The primary efficacy end point was the decrease in mean vertigo score (MVS), which was composed of 12 individual vertigo symptoms, each assessed on the 5-point visual analog scale after 4 weeks of treatment. RESULTS: The study enrolled 246 patients, of whom 239 were evaluable for efficacy. Approximately two thirds of the efficacy population were female and one third male. The mean age was 51.3 years, and the mean duration of vertigo was 2.6 years. The least squares mean (SD) change from baseline in MVS was significantly greater in the group receiving the fixed combination (1.37 [0.66]) than in any of the comparator groups (cinnarizine 50 mg: 0.87 [0.53]; dimenhydrinate 100 mg: 0.83 [0.66]; placebo: 0.76 [0.48]; all comparisons, P < 0.001). The differences were clinically relevant, based on the Mann-Whitney estimator. The incidence of vertigo-associated nausea was significantly reduced in the fixed-combination group relative to the comparator groups (P< or = 0.016). Thirty-four patients reported adverse events, 6 each in the fixed combination and placebo groups, 12 in the cinnarizine group, and 10 in the dimenhydrinate group. None of these adverse events were considered serious. After 4 weeks of treatment, the tolerability of treatment was rated as very good or good by 57 (96.6%) patients in the fixed-combination group; the values for cinnarizine, dimenhydrinate, and placebo were 54 (93.1%), 42 (72.4%), and 50 (87.7%), respectively. CONCLUSIONS: In this study, the fixed low-dose combination of cinnarizine 20 mg + dimenhydrinate 40 mg was effective, clinically beneficial, and well tolerated in patients with vestibular vertigo of central and/or peripheral origin. It was significantly more effective in reducing the MVS compared with placebo and the routinely prescribed higher doses of cinnarizine (50 mg) and dimenhydrinate (100 mg).

The effect of cinnarizine and cocculus indicus on simulator sickness.

Pensacola Simulator Sickness Questionnaire (SSQ) is a valuable method to analyse symptoms evoked by exposure to a flight simulator environment that can also be adopted to evaluate the effectiveness of preventive tools, aiming at reducing simulator sickness (SS). In this study we analysed SSQ data in subjects undergoing a standard ground based spatial disorientation training inside a flight simulator, in order to evaluate the SS prevention obtained with two different pharmacological tools. Twelve males volunteers participated to an experimental design based on a double-blind, balanced administration of either 30 mg cinnarizine (CIN), or Cocculus Indicus 6CH (COC), or placebo (PLC) before one trial of about one hour spent inside a spatial disorientation trainer. All subjects underwent the three different conditions (CIN, COC, PLC) during 3 non-consecutive days separated by at least 2 weeks. During each experimental day, all subjects filled in SSQ. In addition, both postural instability (with the use of a static stabilometric platform), and sleepiness symptoms were evaluated. All the tests were performed before and after the simulated flight, at different times, in one-and-half-hour intervals. Results indicated a strong increase of sickness after flight simulation that linearly decreased, showing pre-simulator scores after 1.30 hours. In contrast to both PLC and COC, CIN showed significant side effects immediately following flight simulation, with no benefit at the simultaneous SSQ scores. Globally, no highly significant differences between COC and PLC were observed, although a minor degree of postural instability could be detected after COC administration. As far as the present exposure to a simulator environment is concerned, none of the pharmacological tools administered in this study resulted effective in reducing SS symptoms as detected by the SSQ. Moreover, CIN significantly increased sleepiness and postural instability in most subjects.

Tardive blepharospasm associated with cinnarizine use.

OBJECTIVE: To report a patient with chronic blepharospasm possibly induced by the calcium-channel blocker cinnarizine. CASE REPORT: A 53-year-old woman developed chronic blepharospasm during a prolonged therapy with calcium-channel blocker cinnarizine for the treatment of vertigo. CONCLUSIONS: "Tardive blepharospasm" should be considered as a possible adverse effect of cinnarizine.

[Treatment costs of otogenic vertigo]. / Die Kosten der Behandlung des otogenen Schwindels. Therapie mit einem Kombinationspräparat (Cinnarizin 20 mg und Dimenhydrinat 40 mg) im Vergleich zur Therapie mit Betahistin (12 mg).

PURPOSE: In this decision-tree analysis, the costs of otogenic vertigo treatment were investigated from the third-party payer's perspective. Either the combination preparation, with cinnarizine 20 mg and dimenhydrinate 40 mg as active substances, or betahistine (12 mg betahistinedimesilate) was administered. METHODS: A core model, based on clinical studies, was developed and a cost-effectiveness analysis was conducted. Both differences in effectiveness of the alternative treatments and adverse reactions and side effects were included. The number of cases, in which no more symptoms of dizziness were detected after 4 weeks of therapy, served as the effectiveness parameter. RESULTS: The effectiveness-adjusted costs amounted to 130.11 Euros for patients treated with the combination preparation and 629.28 Euros for treatment with betahistine. CONCLUSION: From the third-party payer's perspective, therapy of otogenic vertigo with the combination preparation is more cost-effective than a treatment with betahistine. From the patient's perspective, the higher effectiveness and the superior profile of side effects militate in favor of a therapy with the combination preparation.

[Calcium antagonists in the urethral syndrome of women with urinary incontinence and urgency]. / Uso de antagonistas del calcio en el tratamiento del síndrome uretral en las mujeres con urgencia e incontinencia urinaria.

OBJECTIVE: The action of the antagonists of the calcium was evaluated in the Urethral Syndrome of the woman (incontinence, urgency, disury). PATIENT AND METHODS: In 60 female's patients that went for urethral syndrome. I used the Cinarizina in 20 patients, and the Flunarizina in 20 patients. And in 20 patients were used placebo. RESULTS: In the patients that used Flunarizina and Cinarizina were observed a reduction of the urine incontinence, of the urgency, and the disury, the micturition was lingering and easy, the number of the micturitions decreased by the morning, compared with the patients that used placebo. CONCLUSIONS: The antagonists of the calcium can be useful in those patients with urethral syndrome especially the biggest women.

Effects of cinnarizine, a calcium antagonist that produces human parkinsonism, in parkin knock out mice.

Cinnarizine, a calcium antagonist that produces parkinsonism in humans, induces behavioural changes such as alopecia, buco-lingual dyskinesia and reduction of motor activity in female parkin knock out (PK-KO) mice but not in wild-type (WT) controls. PK-KO mice have high striatal dopamine levels and increased dopamine metabolism in spite of low reduced tyrosine hydroxylase protein. Cinnarizine, which blocks dopamine receptors and increases dopamine release, further increased dopamine metabolism. PK-KO mice increased GSH levels as a compensatory mechanism against enhanced free radical production related to acceleration of dopamine turnover. Neuronal markers, such as beta-tubulin slightly increased in PK-KO and furthermore with cinnarizine. Astroglial markers were decreased in PK-KO mice, and this effect was potentiated by cinnarizine, suggesting abnormal glia in these animals. Microglia was hyperactivated in PK-KO midbrain, suggesting inflammation in these animals. Proapoptotic proteins were increased by cinnarizine and, to a lesser extent, in PK-KO mice. Our data indicate that mutation of parkin is a risk factor for drug-induced parkinsonism.

[Iatrogenic neurological disorders in old people: a review].

Aged people are frequently the victims of iatrogenic diseases, especially adverse effects of drugs since they are affected by many age-related diseases and are given many drugs. Geriatric medicine in Japan has a bitter history of having produced many victims by adverse effects of cerebral vasodilators and cerebral stimulants; they included parkinsonism and depression induced by flunarizine and cinnarizine, and Reye-like encephalopathy induced by calcium hopantenate. Parkinsonism induced by sulpiride, tiapride, metoclopramide or atypical anti-psychotics, dyskinesia induced by anti-parkinsonian drugs or anti-psychotics, and psychotic symptoms induced by anti-parkinsonian drugs, anti-cholinergic drugs, anti-depressants or histamine H2 antagonists are still very common. Wernicke encephalopathy caused by intravenous glucose infusion without thiamine, central pontine myelinolysis by too rapid correction of hyponatremia are important though infrequent. Iatrogenic Creutzfeldt-Jakob disease by dura grafts is a warning against the easy use of medical materials produced with human organs or blood. Iatrogenic diseases are preventable, and geriatricians have to pay attention to the information on adverse effects of drugs and medical materials and carefully observe the early signs of iatrogenic diseases.

D2 receptor blockade by flunarizine and cinnarizine explains extrapyramidal side effects. A SPECT study.

Twenty-six patients under treatment with the calcium channel blockers flunarizine (Fz) or cinnarizine (Cz) were examined-with single-photon emission computed tomography using [123I]iodobenzamide as a ligand. The striatal dopamine D2 receptor-binding potential was determined and found to be reduced by 14 to 63% (39.5 +/- 15.0%; p < 0.0001) in patients compared with age-matched control values. This reduction was larger in 12 patients with extrapyramidal symptoms and was only slowly reversible after discontinuation of treatment. Patients treated for > 6 months had significantly larger reductions than patients treated for a shorter period. Parkinsonian symptoms were only seen in patients older than 50 years. Our findings prove a neuroleptic-like action of Fz and Cz, which seems to be the major reason for their extrapyramidal side effects. Older age and long-term treatment are predisposing factors for these effects.

Flunarizine- and cinnarizine-induced extrapyramidal reactions.

Cinnarizine and flunarizine are selective calcium blockers that have been used to treat and prevent vertigo. We studied 15 patients who had extrapyramidal syndromes after taking these drugs. Eleven patients had parkinsonism, one with persistent akathisia as well; one had an orofacial tremor; one, acute akathisia alone; and one an acute dystonic reaction. All but one improved when the drug therapy was discontinued. Seven patients were also depressed during treatment. Cinnarizine and flunarizine must therefore be added to the list of potentially risky drugs known to induce extrapyramidal reactions and depression.

Promethazine, scopolamine and cinnarizine: comparative time course of psychological performance effects.

Single oral doses of promethazine (12.5 mg, 25 mg), scopolamine (0.6 mg), and cinnarizine (30 mg), were compared in a double-blind, placebo controlled trial. Twelve normal volunteers undertook a battery of psychological performance tests and a feeling state questionnaire, before drug administration, and at 2-h intervals after. Promethazine and cinnarizine significantly impaired psychomotor performance, information processing and feelings of alertness. With promethazine these reductions were maximal 3-4 h post-drug, with performance returning near to baseline 8-9 h post-drug. With cinnarizine these impairments were maximal 5-6 h post-drug, and performance remained depressed 8-9 h post-drug. Scopolamine significantly reduced feelings of alertness, and memory task performance; the overall performance effects were most evident 1-4 h post-drug.

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.