SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
The anti-allergic activity and mechanism of cinnarizine was investigated in guinea pigs. Nifedipine, a calcium antagonist, and tranilast, a potent, orally active anti-allergic agent, were used as comparative drugs. Cinnarizine protected against fatal systemic anaphylactic shock in guinea pigs passively sensitized with IgE antibody. Cinnarizine reduced many of the features of severe respiratory disorders. Nifedipine and tranilast showed similar effects. Cinnarizine and nifedipine inhibited the contractile response to antigen of sensitized tracheal smooth muscle when the challenge was carried out at low antigen concentrations. Tranilast showed a tendency to inhibit the antigen-induced contraction of tracheal smooth muscle. Cinnarizine and nifedipine inhibited Ca-induced contraction in potassium-depolarized tracheal smooth muscle, tranilast had no effect. Cinnarizine showed antagonistic action to the contraction by histamine or leukotriene D4 (LTD4) of tracheal muscle. Nifedipine showed similar antagonistic action, although its potency is lower than cinnarizine. Tranilast showed slight antagonistic action to LTD4. Antigen-induced release of histamine and slow reacting substance of anaphylaxis (SRS-A) from sensitized lung tissues was inhibited by nifedipine and tranilast but not by cinnarizine. The release of histamine and SRS-A from lung tissues by calcium ionophore A23187 was inhibited by nifedipine and tranilast but not by cinnarizine. These results suggest that the anti-allergic action of cinnarizine is mainly due to the antagonistic action to allergic mediators and not by interfering with the release of mediators. Cinnarizine's mechanism seems to be related to its antagonistic action to Ca in smooth muscle, but not to the transport of Ca in releasing the anaphylactic chemical mediators in mast cells and other target cells.
The absolute bioavailabilities (Fabs) of cinnarizine after oral administration as two modified beta-cyclodextrin (SBE4-beta-CD or HP-beta-CD) solutions, an aqueous suspension, and two capsules in fasted beagle dogs were determined. Cinnarizine was administered orally (25.0 mg) and intravenously (12.5 mg) to four dogs. Blood samples were drawn for 24.5 h postdosing, and cinnarizine levels in plasma were determined by HPLC with spectrofluorometric detection. Cinnarizine pharmacokinetics after iv administration as a 1.25 mg/mL SBE4-beta-CD solution followed triexponential behavior (t1/2 = 12.6 +/- 0.4 h and CI = 1.4 +/- 0.17 L/h/kg). A very low bioavailability of cinnarizine with a wide interanimal variation was observed after oral administration as a suspension (Fabs = 8 +/- 4%) or capsule containing only cinnarizine (Fabs = 0.8 +/- 0.4%). Administration of cinnarizine as a CD complex either as a solution (Fabs = 55-60%) or in a capsule (Fabs = 38 +/- 12%) significantly enhanced the bioavailability. Since the solutions showed excellent bioavailability, the logical conclusion is that, once presented as a solution, cinnarizine is well absorbed and that cinnarizine rapidly dissociates from its inclusion complexes. Presumably, the elevated bioavailability from the SBE4-beta-CD containing capsule was due to rapid dissolution and release of cinnarizine.
Effects of cinnarizine on immune response in mice were investigated. Mice were orally administered with cinnarizine and were immunized with sheep red blood cells (SRBC) intravenously. Numbers of plaque forming cells (PFC) to SRBC in spleen of these mice were assayed and delayed-type hypersensitivity (DTH) response to SRBC was measured. 1) PFC response in immunization with 5 X 10(6) cells/mouse of SRBC was enhanced by administration of 25 mg/kg of cinnarizine, while the response in immunization with 5 X 10(8) cells/mouse was suppressed by 25 to 200 mg/kg of cinnarizine. 2) From study on timing of administration, suppression of PFC response by 6.25 to 200 mg/kg of cinnarizine was observed at 24 hr. after the immunization. 3) 12.5 to 200 mg/kg of cinnarizine suppressed polyclonal B cell activation induced by lipopolysaccharide (LPS). 4) Colchicine induced suppressor T cell inactivation was prevented by administration of 50 mg/kg of cinnarizine and it was suggested that cinnarizine may induce suppressor T cells from the study of adoptive cell transfer system. 5) 50 mg/kg of cinnarizine showed the suppression of DTH response in expression phase, but not in induction phase. It was concluded that immune responses in mice were modified by cinnarizine.
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.
Cinnarizine was evaluated for the prevention of seasickness in a laboratory and sea study. The effects of 25 mg cinnarizine on the vestibulo-ocular reflex were investigated in 13 subjects. Significant reduction of the gain in response to sinusoidal oscillations at 0.02, 0.08, and 0.16 Hz (p < 0.05) and increased phase lead at 0.16 Hz (p < 0.01) were observed. The effect of 25 and 50 mg cinnarizine on seasickness severity was examined in 95 subjects during a voyage in rough seas. Seasickness symptoms were improved in 69% of the subjects by 50 mg cinnarizine versus 35% and 31% in the groups receiving 25 mg cinnarizine and placebo (p < 0.05 and p < 0.01, respectively). The percentage of vomiting protection provided by 50 mg cinnarizine was 63% (p < 0.05). We conclude that 50 mg cinnarizine is an effective drug for the prevention of seasickness. The reduction in vestibular sensitivity observed even after administration of 25 mg cinnarizine may explain the potency of cinnarizine in the prevention of seasickness.
Cinnarizine, a piperazine derivative, is a widely prescribed medication for the treatment of vestibular disorders and motion sickness. Cinnarizine has antihistaminic, antiserotoninergic, antidopaminergic, and calcium channel-blocking properties. We present the first report in the English literature of cinnarizine poisoning and toxicokinetics. A 30-month-old toddler ingested 225 mg of cinnarizine, 18 times the recommended dose for older children. Four hours later, she became jittery with a wide-based gait and vomited 3 times. She was examined by her family physician, who reported stupor and twitching in both hands. On admission to the hospital, 6 hours after the ingestion, she was stuporous and had 3 short, generalized tonic-clonic convulsions that were controlled with a single dose of midazolam. Full clinical recovery was seen 10 hours after ingestion. Serum cinnarizine levels were 7407, 2629, and 711 ng/mL on admission and at 4 and 12 hours thereafter, respectively, 26.9 times higher than the therapeutic levels in adults. Elimination rate constant, calculated by linear regression of the ln concentrations of the 3 data points, was 0.19. Half-life, calculated from the equation t(1/2) = 0.693/kel, where kel is the elimination rate constant, was 3.65 hours. The manufacturing company revealed that their database contains 23 reports of cinnarizine overdose (adult and children), received between 1972 and 2004. Clinically, these cases reflect mainly symptoms of alterations in consciousness ranging from somnolence to stupor and coma, vomiting, extrapyramidal symptoms, and hypotonia. In a small number of young children, convulsions developed; recovery was uneventful in 4 cases and not reported in 1. The neurologic complication may be explained by the antihistaminic effect of cinnarizine because central nervous system depression and convulsions are known complications of antihistaminic overdose. It is hypothesized that cinnarizine-induced convulsions also are related to the antidopaminergic effect of the drug. Apart from the convulsions, no other adverse effects related to calcium channel-blocking properties, such as bradycardia or hemodynamic instability, were observed. Pediatric patients with cinnarizine overdose need to be observed in a health care facility for potential neurologic complications and be treated symptomatically. The delay to onset of clinical effect should be considered in the observation period.
Four new methods were developed and validated for the determination of cinnarizine HCl in its binary mixture with piracetam in pure and pharmaceutical preparations. The first one was a densitometric analysis that provides a simple and rapid method for the separation and quantification of cinnarizine HCI. The method depends on the quantitative densitometric evaluation of thin-layer chromatograms of cinnarizine HCI at 252 nm over concentration range of 1-6 microg/spot, with a mean accuracy of 100.05 +/- 0.91%. The second method was determination of the drug using a colorimetric method that utilizes the reaction of 3-methyl-benzothiazolin-2-one in the presence of FeCl3 as an oxidant. The green color of the resulting product was measured at 630 nm over concentration range 10-40 microg/mL, with a mean accuracy of 100.10 +/- 1.13%. The third method was a direct spectrophotometric determination of cinnarizine HCI at 252 nm over the concentration range 7-20 microg/mL, while piracetam was determined by derivative ratio spectrophotometry at 221.6 nm over concentration range 5-30 microg/mL, with a mean accuracy of 100.14 +/- 0.79 and 100.26 +/- 1.24% for cinnarizine HCI and piracetam, respectively. The last method was a liquid chromatography analysis of both cinnarizine HCI and piracetam, depending on quantitative evaluation of chromatograms of cinnarizine HCI and piracetam at 252 and 212 nm, respectively, over the concentration range 10-200 microg/mL for cinnarizine HCI and 20-500 microg/mL for piracetam, with a mean accuracy of 100.03 +/- 0.89 and 100.40 +/- 0.94% for cinnarizine HCI and piracetam, respectively. The proposed procedures were checked using laboratory-prepared mixtures and successfully applied for the analysis of their pharmaceutical preparations. The validity of the proposed procedures was further assessed by applying the standard addition technique. Recoveries were quantitative, and the results obtained agreed with those obtained by other reported methods.
The present investigation is concerned with an improvement of the bioavailability of cinnarizine by administering its beta-cyclodextrin complex together with another compound which competes with the beta-cyclodextrin molecule in complex formation in aqueous solution (competing agent). The bioavailability of cinnarizine on oral administration of the cinnarizine-beta-cyclodextrin inclusion complex was enhanced by the simultaneous administration of DL-phenylalanine as a competing agent, e.g., the AUC was 1.9 and 2.7 times as large as those of the cinnarizine-beta-cyclodextrin complex alone and cinnarizine alone, respectively. The enhancement of AUC and Cmax completely depended on the dose of DL-phenylalanine. It was found from these results that DL-phenylalanine acted as a competing agent in the GI tract and the minimum effective dose required of DL-phenylalanine might be 1 g for 50 mg of cinnarizine in the cinnarizine-beta-cyclodextrin complex. Evaluating the competing effect of DL-phenylalanine in vitro using an absorption simulator, it was found that the decreased penetration rate of cinnarizine through the artificial lipid barrier with addition of beta-cyclodextrin was restored with the addition of DL-phenylalanine.
The present study was an attempt to develop a new dosage form of cinnarizine, which is slightly soluble in water, using lipid as a vehicle. The solubility of cinnarizine in several organic solvents was determined. It was found that cinnarizine dissolved well in oleic and linoleic acids. The bioavailability of cinnarizine from the oral administration of an oleic acid solution in a hard capsule was investigated and compared with that of a cinnarizine tablet, using beagle dogs. When cinnarizine was administered in a capsule, the bioavailability was greatly enhanced [i.e., the maximum concentration (Cmax) and AUC values were 2.9 and 4.0 times larger than those of a cinnarizine tablet, respectively]. Meanwhile, the tmax value (the time to reach Cmax) was unchanged. The absorption of cinnarizine from an oleic acid solution was considered to depend on the action of bile salts. This was supported by the results of a dissolution test using a bile salts solution as the dissolution test medium.
OBJECTIVE: To report four cases of cinnarizine-induced weight gain. DATA SOURCES: Case reports from a local obesity center and review articles. DATA EXTRACTION: Data were abstracted from spontaneous comments made by patients to one of the authors, who was a doctor at the clinic, and reviewed by the remaining authors. DATA SYNTHESIS: We reviewed the cases of four women, aged 50-57 years without endocrine or metabolic pathologies, that showed weight gain associated with the intake of cinnarizine for one to two years. No other drugs usually were administered during the period in which the women gained weight, although in two cases cinnarizine was associated with dihydroergocristine in the same medicine (Clinadil). The mean weight increase was 6.25 kg (range 4-10). The increases do not appear to be related to whether the patients' initial weight was ideal or excessive. The weight gain was always associated with increased appetite and food intake. One patient discontinued cinnarizine treatment and her weight returned to its previous level. CONCLUSIONS: Cinnarizine is a piperazine derivative used in the treatment of vertigo and in the prophylaxis of migraine. In contrast to related drugs, data about cinnarizine are scarce because randomized trials of cinnarizine have been inconclusive. Our observations indicate that cinnarizine may cause weight gain, as observed with other drugs in the same class.
In a double-blind, placebo-controlled study, we evaluated the effect of two different doses of cinnarizine in the prevention of seasickness in very rough seas. We divided 95 healthy male subjects into 3 groups which received: cinnarizine 50 mg, cinnarizine 25 mg, and placebo. Seasickness susceptibility and severity were evaluated by a standard questionnaire concerning the subject's condition on previous voyages (seasickness susceptibility), and the subject's condition immediately after a 4-6-h voyage in very rough seas with 3.5 m waves (seasickness severity). Possible side effects of the drug were also evaluated by filling in a further questionnaire. Of the 31 subjects who received cinnarizine 50 mg, 65% felt better during the present voyage than on previous voyages, compared to 41% of the 32 subjects who received cinnarizine 25 mg and 31% of the 32 who received placebo. A significant difference (p < 0.05) was found between the cinnarizine 50 mg and placebo groups, while cinnarizine 25 mg was no more effective than placebo. No notable side effects were found for any drug group. In conclusion, cinnarizine 50 mg was found to be effective in the prevention of seasickness in rough seas.
In vestibular hair cells, K+ currents induced by rises in hydrostatic pressure have recently been demonstrated. These currents are inhibited by charybdotoxin, a blocker of Ca2+-dependent K+ channels. On the other hand, cinnarizine is a blocker of voltage-gated Ca2+ currents in hair cells and is used as a drug in conditions with vestibular vertigo. Our aim was to test in patch-clamp experiments (conventional whole-cell mode) whether cinnarizine, by reducing Ca2+ influx, inhibited Ca2+ and pressure-sensitive K+ currents in vestibular type-II hair cells of guinea pigs. A quantitatively similar inhibition of K+ currents was evoked by extracellular Ca2+ removal, cinnarizine (0.5 microM), and the L-type Ca2+ channel blocker nifedipine (3 microM). Cinnarizine abrogated increases of K+ currents induced by increases in the hydrostatic pressure (from 0.2 to 0.5 cm H2O). At a higher concentration (1 microM), cinnarizine elicited K+ current inhibitions larger than those elicited by Ca2+ removal. Moreover, it reduced K+ currents in the absence of Ca2+, in contrast to nifedipine. However, charybdotoxin abolished these effects of cinnarizine. We thus conclude that cinnarizine inhibits, by two mechanisms, pressure-induced currents that are sensitive to charybdotoxin and Ca2+. It reduces Ca2+ influx and exerts a Ca2+-independent inhibition, with a lower IC50 than that required for Ca2+ channel blockade. These two actions may importantly contribute to its therapeutic effects.
Cinnarizine, a drug known as a calcium channel blocker, is currently used for the treatment of migraine and vertigo. Induction of extrapyramidal signs by cinnarizine has been reported in the elderly, which is related to its moderate antagonistic properties at dopamine D2 receptors, resembling the mechanism of action of most antipsychotic drugs. Despite this effect, cinnarizine has never been tested as a putative antipsychotic drug. Here we evaluate the potential effect of cinnarizine in two pharmacological models of psychosis, namely amphetamine- and MK-801-induced hyperlocomotion, as well as its ability to induce catalepsy. Cinnarizine significantly counteracted MK-801 (0.25 mg/kg) and amphetamine (5mg/kg) locomotor effects at doses as low as 20mg/kg, having no incremental effect at 60 or 180 mg/kg. Regarding side-effects, cinnarizine induced no catalepsy in mice at the effective dose of 20 mg/kg, inducing only mild catalepsy at the doses of 60 and 180 mg/kg. Based on these results and on the antagonist effect of cinnarizine on dopamine D2 receptors, we suggest that it has a potential antipsychotic effect with an atypical profile that should be evaluated clinically.
The antiemetic efficacy of cinnarizine was assessed in 17 cancer patients receiving platin-based chemotherapy (cisplatin dose-range 30-160 mg, or carboplatin 270-600 mg) in a randomised, cross-over study. The patients were prophylactically given oral metoclopramide 3 x 1 mg/kg and lorazepam 2 x 1 mg with or without cinnarizine 3 x 75 mg. The antiemetic combination with cinnarizine prevented emesis completely on 51% of 35 days with chemotherapy and less than 3 emetic episodes occurred on 86% of the days, compared with 43% and 57% (p less than 0.01) without cinnarizine respectively. Severe nausea was significantly less frequent with cinnarizine and 59% of the chemotherapy days were without nausea, compared to 46% of the days without cinnarizine (p less than 0.05). Side-effects were uncommon and minor with both antiemetic regimens. The study suggests that addition of cinnarizine to metoclopramide and lorazepam improves antiemetic prophylaxis in low to medium dose platin-based chemotherapy.
Severe seasickness could pose a serious problem in diving, and anti-seasickness medication should therefore be prescribed for the seasickness-susceptible diver. Cinnarizine may be used as a medication if it does not increase the risk of central nervous system (CNS) oxygen toxicity when diving with closed-circuit oxygen or O2-enriched gas mixtures. Twenty-six male, white Sprague-Dawley rats were exposed to high O2 pressures (507 and 608 kPa) before and after cinnarizine ingestion (3.3 mg.kg-1), until the appearance of the first electrical discharge (FED) in the electroencephalogram (EEG) which precedes the clinical convulsions. Each rat was tested on five exposure protocols (control and cinnarizine at 507 kPa O2, control, cinnarizine, and 15 h starvation as a control for cinnarizine at 608 kPa O2) at intervals of at least 2 days or until the EEG connector became detached (a mean of 3.1 exposures per rat). Latency to the FED increased after cinnarizine ingestion in 16 of the 17 pairs of measurements at 507 kPa O2 (by more than 61%, P < 0.002) and in 17 of the 19 pairs of measurements at 608 kPa O2 (by 36%, P < 0.002). There was no significant effect of 15 h starvation. Cinnarizine can be further considered for use in seasickness-susceptible divers as it does not increase the risk of CNS O2 toxicity.
The anticonvulsive properties of orally administered cinnarizine [(E)-1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)-piperazine], its difluoro derivative flunarizine [(E)-1-(bis-(4-fluorophenyl)methyl)-4-(3-phenyl-2-propenyl)-piperazine], diphenylhydantoin and phenobarbital, were studied against maximal metrazol seizures (MMS) in rats and maximal electroshock seizures (MES) in mice. In rats (MMS), the lowest ED50 for protection against tonic extension of hindpaws was 4.10 mg/kg (1 h 35 min after treatment) with sodium phenobarbital, 6.04 mg/kg (5 h 45 min) with flunarizine dihydrochloride, 9.84 mg/kg (2 h 34 min) with cinnarizine and 19.30 mg/kg (3 h 38 min) with diphenylhydantoin. In mice (MES), protection against tonic extension of hindpaws was (2 h after treatment) 7.0 mg/kg with diphenylhydantoin, 13.2 mg/kg with sodium phenobarbital, 20.9 mg/kg with flunarizine kihydrochloride and 49.0 mg/kg with cinnarizine. Except at subtoxic doses no side effects were observed in rats and mice given cinnarizine, flunarizine kihydrochloride or kiphenylhydantoin. Phenobarbital induced ataxia in rats and mice at 22 mg/kg and 42.7 mg/kg, respectively, and loss of righting reflex at 112.8 mg/kg and 160 mg/kg, respectively. Flunarizine is the longest-acting drug and has the slowest onset. At a dose of twice the minimal ED50 flunarizine affords protection against tonic extension of hindpaws in rats (MMS) for 23 h 30 min dephenylhydantoin for 11 h 38 min, phenobarbital for 8 h 22 min and cinnarizine for 8 h 16 min. Peak effect was reached with flunarizine at 5 h 45 min, with diphenylhydantoin at 3 h 38 min, with cinnarizine at 2 h 34 min and with phenobarbital at 1 h 35 min. The anti-MMS profiles of cinnarizine and flunarizine resemble that of dephenylhydantoin as all three compounds are selective blockers of tonic extension of hindpaws. Phenobarbital antagonized the whole MMS-pattern, i.e., tremors, clonic convulsions and tonic extension of fore- and hindpaws. However, the effects of phenobarbital against tremors, clonic convulsions and tonic extension of forepaws may reflect more a general CNS-depressant effect than a specific anticonvulsive activity since neurotoxic effects (ataxia and loss of righting reflex) appear at the same doses.