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At least 19 recordsLinked to original sources
PubMed1997

Propranolol vs flunarizine vs flunarizine plus propranolol in migraine without aura prophylaxis. A double-blind trial.

Fourty-five migraine without aura patients underwent a parallel double-blind trial aiming the comparison of the effects of propranolol 60 mg/day to flunarizine 10 mg/day and to propranolol 60 mg/day plus flunarizine 10 mg/day simultaneously. There were 3 groups, each one with 15 patients. After a 20-day-baseline period, each group received one kind of treatment during 120 days. Migraine index on propranolol was 23.4*, on flunarizine 18.7* and on both drugs 14.4*, mean frequency of attacks on propranolol was 1.26**, on flunarizine 1.2** and on both drugs 1.13** (*p < 0.05, **p < 0.01 compared to baseline) and global evaluation was reduced with all forms of treatment. It was not found statistical differences between groups, nevertheless there was a trend in the group using two drugs reaching lower values in migraine index, frequency of attacks and global evaluation. In individuals using flunarizine (alone or associated with propranolol) the therapeutic effect was largely maintained up to 45 days after drug withdrawal.

1-Propanol↗
PubMed2002

Topical flunarizine reduces IOP and protects the retina against ischemia-excitotoxicity.

PURPOSE: To determine whether topical application of flunarizine reduces intraocular pressure (IOP) and acts as a retinal neuroprotectant and to compare the effectiveness of flunarizine with betaxolol and nifedipine at reducing the influx of calcium and sodium. METHODS: Ischemia was delivered to the rabbit retina by raising the IOP. After 3 days, a flash electroretinogram (ERG) was recorded, and the retina processed for the localization of certain antigens. In the rat, N-methyl-D-aspartate (NMDA) was injected intravitreally, and 8 days later, the retinas were analyzed for the localization of Thy-1 or the relative amounts of mRNAs for antigens located to ganglion cells or photoreceptors. Rats and rabbits received topical flunarizine or vehicle before and after ischemia or NMDA. IOP was measured in rabbits after a single topical application of 2% flunarizine. Studies were conducted on isolated rat retinas, cortical cultures, and brain synaptosomes to compare the effectiveness of flunarizine with nifedipine and betaxolol at reducing the influx of calcium or sodium. RESULTS: Changes in rabbit retinal choline acetyltransferase and parvalbumin immunoreactivities and the b-wave of the ERG caused by ischemia-reperfusion were blunted by topical treatment with flunarizine. Similarly, NMDA induced reductions in Thy-1 immunoreactivity and mRNA for rat ganglion cell antigens (Thy-1 and neurofilament light form) were counteracted by topical application of flunarizine. Topical application of 2% flunarizine significantly lowered the IOP in rabbits over a period of 5 hours. Flunarizine was more effective than betaxolol and much stronger than nifedipine at attenuating veratridine-induced influx of sodium into synaptosomes. Nifedipine, flunarizine, and betaxolol all reduced the NMDA-induced influx of calcium into the isolated retina or cortical neurons, but betaxolol was the least effective. CONCLUSIONS: Topically applied flunarizine reduces IOP and attenuates injury to the whole of the retina, including the ganglion cells. The neuroprotective action of flunarizine is to reduce the influx of calcium and sodium into stressed neurons. The potent effect of flunarizine on sodium influx would be particularly protective to axons.

Administration, Topical↗
PubMed1995

Dotarizine versus flunarizine as calcium antagonists in chromaffin cells.

1. Dotarizine is a novel piperazine derivative structurally related to flunarizine that is currently being evaluated in clinical trials for its antimigraine and antivertigo effects. This clinical profile may be related to its Ca2+ antagonist properties. Therefore, the actions of both compounds as calcium antagonists were compared in bovine chromaffin cells. 2. Dotarizine and flunarizine blocked 45Ca2+ uptake into K+ depolarized chromaffin cells (70 mM K+/0.5 mM Ca2+ for 60 s) in a concentration-dependent manner, with IC50s of 4.8 and 6.7 microM, respectively. 3. Dotarizine and flunarizine also inhibited the whole-cell Ca2+ and Ba2+ currents (ICa, IBa) in voltage-clamped chromaffin cells, induced by depolarizing test pulses to 0 mV, during 50 ms, from a holding potential of -80 mV. Blockade exhibited IC50s of 4 microM for dotarizine and 2.2 microM for flunarizine. Dotarizine increased the rate of inactivation of ICa and IBa; inhibition of whole-cell currents was use-dependent. 4. Transient increases of the cytosolic Ca2+ concentration, [Ca2+]i, produced by K+ stimulation (70 mM K+ for 5 s) of single fura-2-loaded chromaffin cells, were also inhibited by dotarizine and flunarizine with IC50s of 1.2 and 0.6 microM, respectively. Upon washout of dotarizine, the [Ca2+]i increases recovered fully after 5-10 min. In contrast, the responses remained largely inhibited 10 min after washing out flunarizine. 5. Catecholamine release induced by K+ stimulation (10-s pulses of 70 mM) was inhibited by dotarizine with an IC50 of 2.6 microM and by flunarizine with an IC50 of 1.2 microM. The blocking effects of both compounds developed slowly, and was fully established after 20-30 min of superfusion. While blockade by dotarizine quickly reversed upon its washout, that of flunarizine lasted even 25 min after washing out.6. Catecholamine release from electroporated chromaffin cells triggered by 10 micro M Ca2+ was not affected by 10 micro M dotarizine or flunarizine.7. Overall, the results suggest that dotarizine behaves as a Ca2+ antagonist in bovine chromaffin cells. It exhibits a potency similar to flunarizine in blocking Ca2+ entry, Ca2+ channels, Cai2+ signals and secretion. The dotarizine effects are readily reversible suggesting that in contrast to flunarizine, it does not accumulate in cells. Dotarizine is devoid of intracellular effects on the secretory machinery. All its blocking effects on Ca2+ entry, [Ca2+]i rise and secretion are probably due to blockade of various Ca2+channel subtypes in chromaffin cells. This blockade is use-dependent and seems to be due to the increase by dotarizine of the rate of Ca2+ channel inactivation.

Animals↗
PubMed1980

Selective abolition of Ca-dependent responses of smooth and cardiac muscles by flunarizine.

The inhibitory effect of flunarizine on the Ca-dependent responses was compared with that of verapamil in isolated smooth and cardiac muscles. Flunarizine at a small dose shifted to the right the dose-response curve for Ca2+ of the phasic contraction due to electric stimuli in rabbit basilar strips, while in a large dose, flunarizine reduced the maximum tension and slope of the dose-response curve. The high K+-induced vasoconstriction of the rabbit basilar artery was inhibited by flunarizine. However, the action of flunarizine was about 30 times slower than findings with verapamil. The spontaneous activity of the rat portal vein was less susceptible to flunarizine, whereas that of rat uterus was completely inhibited by flunarizine. Flunarizine possessed moderate negative chronotropic and inotropic actions on the right atria and papillary muscles of the rabbit. Our experiments indicate that flunarizine is selective in antagonizing Ca-dependent contraction of the rabbit basilar artery, probably by blockade of the transmembrane Ca. It is also possible that the slow onset of action and nonsurmountable antagonism produced by flunarizine is due to other pharmacological interventions such as delayed effect of metabolites, stabilizing action or tight binding on the cell membrane of vascular smooth muscles.

Animals↗
PubMed1986

Anticonvulsant properties of flunarizine on reflex and generalized models of epilepsy.

The anticonvulsant activity of 1-bis(4-fluorophenyl)methyl-4-(3-phenyl-2-propenyl)-piperazine, flunarizine, was studied after intraperitoneal administration in DBA/2 mice (seizures induced by sound), intravenous administration in Papio papio (myoclonus induced by photic stimulation) and oral administration in Wistar rats (seizures induced by cefazolin). Protection against sound-induced seizures was observed after intraperitoneal administration of flunarizine (5-40 mg/kg). The ED50 for suppression of tonic, clonic and wild running phases of sound-induced seizures was 3.3, 9.8 and 17.5 mg/kg, respectively. This protective action was significantly reduced by pretreatment with aminophylline (50 mg/kg, i.p.). In photosensitive baboons flunarizine (0.5-1.0 mg/kg, i.v.) provided partial protection against myoclonic responses to stroboscopic stimulation. After flunarizine (2 mg/kg, i.v.) this protection lasted for more than 5 hr (and was complete at 2-3 hr). Cefazolin-induced seizures in rats were prevented by administration of flunarizine (20-40 mg/kg, orally). The ED50 for the suppression of tonic and clonic seizures evoked by subsequent intravenous administration of cefazolin was 25 mg/kg. The protective effects of flunarizine (40 mg/kg, orally) were maximal after 3-6 hr and were maintained for 16-24 hr. Behavioural effects of flunarizine included signs of sedation in both mice and rats. Tolerance to the antiepileptic effects of flunarizine was not seen after chronic treatment in rats. The role of purinergic receptors and of calcium entry blockade in the anticonvulsant action of flunarizine requires further study.

Acoustic Stimulation↗
PubMed1995

Flunarizine enhancement of melphalan activity against drug-sensitive/resistant rhabdomyosarcoma.

Flunarizine, a diphenylpiperazine calcium channel blocker, is known to increase tumor blood flow. It also interferes with calmodulin function, repair of DNA damage and drug resistance associated with P-glycoprotein. Flunarizine was tested for its ability to modulate either cyclophosphamide- or melphalan-induced growth delay for a drug-resistant rhabdomyosarcoma xenograft (TE-671 MR) and the drug-sensitive parent line (TE-671), in which P-glycoprotein is not involved in the mechanism of drug resistance. Tumour blood flow was increased by 30% after a flunarizine dose of 4 mg kg-1, but no modification in growth delay was induced by melphalan (12 mg kg-1). In contrast, a 60 mg kg-1 dose of flunarizine had no effect on tumour blood flow, but the same dose created significant enhancement in melphalan-induced tumour regrowth delay in both tumour lines. The dose-modifying factor for flunarizine as an adjuvant to melphalan was approximately 2 for both tumour lines. Although blood flow measurements were not performed with the combination of flunarizine and melphalan, the results from flunarizine alone suggested that augmentation of melphalan cytotoxicity is not mediated by changes in blood flow. In contrast, flunarizine did not affect drug sensitivity to cyclophosphamide in groups of animals bearing the drug-sensitive parent tumour line. These results suggest that the mechanism of drug sensitivity modification by flunarizine is not related to modification of tumour blood flow, but may be mediated by modification of transport mechanisms that are differentially responsible for cellular uptake and retention of melphalan as compared with cyclophosphamide.

Animals↗
PubMed2006

Flunarizine is a highly potent inhibitor of cardiac hERG potassium current.

Flunarizine has been widely used for the management of a variety of disorders such as peripheral vascular diseases, migraine, and epilepsy. The majority of its beneficial effects have been attributed to its ability to inhibit voltage-gated Ca2+ channels in the low micromolar range, albeit non-selectively, as flunarizine has been shown to inhibit a variety of ion channels. We examined the effects of flunarizine on potassium currents through cardiac channels encoded by the human ether-a-go-go related gene (hERG) stably expressed in CHO cells. In this study, we have characterized the effect of flunarizine on biophysical properties of hERG potassium currents with standard whole-cell voltage-clamp techniques. Notably, flunarizine is a highly potent inhibitor of hERG current with an IC50 value of 5.7 nM. The effect of flunarizine on hERG potassium current is concentration and time dependent, and displays voltage dependence over the voltage range between -40 and 0 mV. At concentrations near or above the IC50, flunarizine causes a negative shift in the voltage dependence of hERG current activation and accelerates tail current deactivation. Flunarizine preferentially blocks the activated state of the channel and displays weak frequency dependence of inhibition. Flunarizine also inhibits KCNQ1/KCNE1 channel current with an IC50 of 0.76 microM.

Animals↗
PubMed1992

Further observations to confirm the arrhythmia mechanism-specific effects of flunarizine.

In conscious dogs with chronic atrioventricular (AV) block, we recently demonstrated that flunarizine is effective against ouabain-induced arrhythmias (triggered activity resulting from delayed afterdepolarizations, DADs) but fails to suppress spontaneous ventricular tachycardias (VT) occurring 24 h after left anterior descending coronary artery occlusion (abnormal automaticity). Neither does flunarizine affect normal automaticity, which suggests that flunarizine could be used as a clinical tool to recognize cardiac arrhythmias based on triggered activity. To elucidate further the arrhythmia mechanism-specific action of flunarizine, we investigated (a) its hemodynamic and electrophysiologic effects in 6 anesthetized dogs, (b) its ability to prevent pacing-induced VT 7 days after myocardial infarction (reentry) in 9 anesthetized animals, and (c) its effect on premature escape beats (PEBs) in 9 conscious dogs with chronic AV block. PEBs are probably caused by DADs. Flunarizine decreased systemic blood pressure (p less than 0.01), and left ventricular dP/dt (p less than 0.01), but did not affect AH or HV internal, QRS duration, QT time, or the effective refractory period of either AV node or right ventricle over a wide range of (paced) cycle lengths. Flunarizine decreased the inducibility of PEBs by 42% (p less than 0.01), but not that of the reentrant VT in any of the 6 inducible dogs. Therefore, we conclude that although flunarizine has no electrophysiologic effects in normal heart, it prevents induction of PEBs. The inability of flunarizine to prevent induction of reentrant VT confirms the mechanism-specific action of flunarizine against triggered activity.

Analysis of Variance↗
PubMed1990

Comparison of the calcium entry and calcium overload blocking properties of R71811 and flunarizine.

The effects of several calcium antagonists on cell death induced by A23187 were studied. Furthermore, R71811, 1-[Bis(4-fluorophenyl)methyl-4-[(4-methoxyphenyl)- carbamoylmethyl-trans-2,5-dimethyl-piperazine has been evaluated as a calcium overload blocker and compared to flunarizine. The viability of cultured glial cells was decreased by incubation with the calcium ionophore, A23187. The cytotoxicity of A23187 was reduced by flunarizine and cinnarizine at 10 mumol/l; nicardipine, nifedipine, and verapamil, but not diltiazem, reduced cytotoxicity at 100 mumol/l. N-(6-aminohexyl)-5-chloro-1- naphthalenesulfonamide (W-7) and trifluoperazine did not reduce cytotoxicity and trifluoperazine enhanced cytotoxicity at 100 mumol/l. Leupeptin reduced cytotoxicity at 100 mumol/l. [8-(N,N-dimethylamino)-octyl-3,4,5- trimethoxybenzoate] (TMB-8) showed no effect. The results indicate that flunarizine, a recognized calcium overload blocker, was most effective in inhibiting the A23187-induced cytotoxicity and that calcium entry blockade does not appear to be implicated in the cytoprotective effect. R71811 inhibited A23187 cytotoxicity at similar concentrations to flunarizine. R71811, as well as flunarizine, also inhibited erythrocyte crenation induced by A23187. Although R71811 showed a relaxant effect in isolated rat aorta contracted by high potassium, its activity was less than that of flunarizine (IC50 values, 4.1 and 0.045 mumol/l, respectively). On the other hand, R71811 and flunarizine showed similar inhibitory effects on A23187-induced contractions (IC50 values, 14 and 11 mumol/l, respectively). The results indicate that R71811 has a similar protective effect against A23187-induced cytotoxicity but only weak calcium entry blocking action in comparison to flunarizine.

Animals↗
PubMed1990

Flunarizine treatment in poor-grade aneurysm patients.

A cerebral Ca2+ overload blocker--flunarizine hydrochloride--was used with excellent results for prophylaxis of delayed ischaemic neurological deficit (DIND) in severe subarachnoid haemorrhage. The drug was administered orally at a dose of 10 mg, four times daily for four days, followed by three times daily for three days and twice daily for 14 more days. Of 72 patients treated with flunarizine, only one developed permanent DIND. 37 consecutive patients who were in Fisher's group III and were treated with flunarizine from immediately after early surgery were compared retrospectively with the 37 consecutive Control Group patients, who also belong to Fisher's group III. Among the Control Group patients, eight died from DIND and ten developed infarction from DIND, while flunarizine strongly prevented (p less than 0.001) DIND. Furthermore, the only one DIND was attributable to failure of administration of flunarizine. There were no side-effects from flunarizine. The association of severe angiographic vasospasm was less frequent in the Flunarizine Group (18% vs 57%, p less than 0.02). From this evidence, it might be concluded that flunarizine significantly inhibits the occurrence of severe neurological deficit due to delayed vasospasm. This highly beneficial effect on severe delayed vasospasm might be attributable to its intense inhibitory action on intracellular Ca2+ overloads especially in severe pathological situations.

Adult↗
PubMed1996

Postmarketing study of the use of flunarizine in vestibular vertigo and in migraine.

OBJECTIVE: This international postmarketing observational study of flunarizine was designed to evaluate, in routine clinical practice, the risk/benefit ratio of flunarizine in its approved indications, namely prophylaxis of migraine and treatment of vertigo. Comparator drugs were propranolol in migraine and betahistine in vertigo. The study was carried out by 498 general practitioners in Belgium, The Netherlands and Germany, whose participation had been requested by mail. In total 3186 patients were entered: 1601 in the two migraine cohorts and 1585 in the two vertigo cohorts. RESULTS: In the migraine study, treatment results with propranolol tended to be somewhat better than those with flunarizine, but a selection bias cannot be excluded. There was no clear difference regarding efficacy between flunarizine and betahistine in the vertigo study. The safety evaluation focused on extrapyramidal symptoms (EPS) and depression. Overall, EPS were noted in only four patients, two in the vertigo-betahistine and two in the migraine-flunarizine cohort. A total of 70 patients developed depressive symptoms (34 in the flunarizine and 24 in the propranolol migraine cohorts, but only 7 in the flunarizine and 5 in the betahistine vertigo cohorts). Patients with migraine were clearly more prone to depression than patients with vertigo, regardless of their treatment. Additional risk factors for depression were a history of depression, and, in the migraine flunarizine cohort, a high number of previous migraine treatments.

Basal Ganglia Diseases↗
PubMed2006

A calcium channel blocker flunarizine attenuates the neurotoxic effects of iron.

Iron is a metal highly concentrated in liver and brain tissue, and known to induce neuronal hyperactivity and oxidative stress. It has been established that iron levels rise in the brain in some neurodegenerative diseases such as Parkinson's and Alzheimer's diseases (AD). A body of evidence indicates a link between neuronal death and intracellular excessive calcium accumulation. The aim of the present study was to investigate the effects of a calcium antagonist, flunarizine, on neurotoxicity induced by intracerebroventricular (i.c.v.) iron injection. For this reason rats were divided into three groups as control, iron and iron+flunarizine groups. Animals in iron and iron+flunarizine groups received i.c.v. FeCl(3) injection (200 mM, 2.5 microl), while control rats received the same amount of saline into the cerebral ventricles. Rats in iron+flunarizine group also received i.c.v. flunarizine (1 microM, 2 microl) following FeCl(3) injection. All animals were kept alive for ten days following the operation and animals in iron+flunarizine group received intraperitoneal (i.p.) flunarizine injections once a day (10 mg/kg/day) during this period. After ten days, rats were sacrificed. The total numbers of neurons in hippocampus of all rats were estimated with the latest, unbiased stereological techniques. Findings of the present study suggest that flunarizine may attenuate the neurotoxic effects of iron injection by inhibiting the cellular influx of excessive calcium ions.

Animals↗
PubMed1992

Effect of flunarizine on micro-regional distributions of intravascular HbO2 saturations in RIF-1 and KHT sarcomas.

Flunarizine, a calcium channel-blocker, preferentially active on peripheral blood vessels and red blood cells, has previously been shown to increase not only tumor blood flow, but also both chemosensitivity and radiosensitivity. The mechanisms behind these effects are not clear at present, and different tumor lines have been demonstrated to respond quite differently to the same flunarizine treatment. To clarify the underlying mechanisms at the micro-regional level, the present investigation examined the effects of flunarizine on spatially-resolved distributions of intravascular oxyhemoglobin (HbO2) saturations. Tumors were implanted s.c. in the flanks of C3H mice and grown to a volume of 500-1000 mm3. Flunarizine was injected i.p. at 5 mg/kg; animals were anesthetized, and following a 20 min delay, tumors were quick-frozen. HbO2 saturations were determined cryospectrophotometrically at systematically selected sites across each tumor cross-section. Three primary questions were addressed: (a) Does flunarizine have a direct effect on tumor oxygen delivery as measured by intravascular HbO2 saturations? (b) Are changes in oxygen delivery uniformly distributed throughout the tumor volume? (c) Are HbO2 distributions for tumor lines of dissimilar radiobiological hypoxic fraction affected similarly by flunarizine? For KHT tumors, flunarizine substantially increased the % vessels greater than or equal to 10% saturated throughout the tumor volume, with a somewhat larger increase for the interior vessels than for the peripheral vessels. In contrast, for the RIF-1 tumors, HbO2 saturations following flunarizine remained near control levels. These results indicate that fundamental differences in vascular geometry, hemodynamics, or blood rheology may exist between the KHT and RIF-1 tumor lines, and furthermore, that the response of one tumor line to a given blood-flow modifier may be completely unrelated to that of another.

Animals↗
PubMed2005

In vitro plasma protein binding determination of flunarizine using equilibrium dialysis and liquid chromatography-tandem mass spectrometry.

A highly sensitive method was developed and validated for determining the free fraction of flunarizine in human plasma. Equilibrium dialysis was used for the separation of free (unbound) drug and liquid chromatography/tandem mass spectrometry (LC-MS/MS) was used for quantitation. Post-dialysis plasma or buffer samples of 0.2 mL were extracted using a liquid-liquid extraction procedure and analyzed using a high performance liquid chromatography electrospray tandem mass spectrometer system. The compounds were eluted isocratically on a Supelco Supelcosil ABZ+Plus column, ionized using a positive ion atmospheric pressure electrospray ionization source, and analyzed using multiple reaction monitoring. The ion transitions monitored were m/z 405-->203 for flunarizine and m/z 409-->207 for flunarizine-d4 (internal standard, IS). The chromatographic run time was 3.5 min per injection, with retention times of 2.1 min for both flunarizine and IS. The calibration curve for flunarizine was linear over the concentration range of 0.25-2000 ng/mL (r(2)>0.9989) in the combined matrix of human plasma and isotonic sodium phosphate buffer (1:1, v/v) with the lower limit of quantitation of 0.25 ng/mL. The inter-assay coefficient of variability (CV) for the quality control samples was less than 13.5%, and the inter-assay percent nominal was greater than 98.2%. In vitro protein binding of flunarizine was determined at concentrations of 5, 10 and 100 microg/mL using the validated method. Flunarizine was extensively bound to plasma protein with a 0.083+/-0.005% overall percent free drug in plasma and a CV value less than 7.8%. This validated method will be used for the ex vivo assessment of flunarizine protein binding in human plasma from a drug-drug interaction clinical study.

Anticonvulsants↗
PubMed1999

Effects of dotarizine and flunarizine on chromaffin cell viability and cytosolic Ca2+.

Dotarizine (a novel piperazine derivative with antimigraine properties) and flunarizine (a Ca2+ channel antagonist) were compared concerning: first, their ability to cause chromaffin cell damage in vitro; second, the possible correlation of their octanol/water partition coefficients and those of another 28 compounds (i.e., Ca2+ channel antagonists, blockers of histamine H1 receptors, antimycotics, beta-adrenoceptor antagonists, neuroleptics), with their ability to cause cell damage; third, their capacity to protect the cells against the damaging effects of veratridine; and fourth, their capabilities to enhance the basal cytosolic Ca2+ concentration in fura-2-loaded single chromaffin cells, or to modify the pattern of [Ca2+]i oscillations elicited by veratridine. After 24-h exposure to 1-30 microM dotarizine, the viability of bovine adrenal chromaffin cells (measured under phase contrast or as lactate dehydrogenase, released into the medium) was similar to that of control, untreated cells; at 100 microM, 80% lactate dehydrogenase release was produced. At 1-3 microM flunarizine caused no cell damage; however 10 microM caused 20% lactate dehydrogenase release and 30 and 100 microM over 90% lactate dehydrogenase release. The time course of cell damage was considerably faster for flunarizine, in comparison to dotarizine. Out of 30 molecules tested (at 10 microM), having different octanol/water partition coefficients (log P), dotarizine was among the molecules causing no cell damage; flunarizine caused 20% cell loss, lidoflazine and verapamil over 50% cell loss, and penfluridol, draflazine, astemizole or nifedipine over 80% cell loss. No correlation was found between log P and cytotoxicity. Both dotarizine (10-30 microM) and flunarizine (3-10 microM) provided protection against veratridine-induced cell death; however, at 30 microM dotarizine afforded a pronounced protection while flunarizine enhanced the cytotoxic effects of veratridine. Dotarizine (30 microM) (but not flunarizine) caused a prompt transient elevation of the basal [Ca2+]i. Both compounds abolished the K+-induced increases of [Ca2+]i as well as the oscillations of [Ca2+]i induced by veratridine. The blocking effects of dotarizine were readily reversed after washout, while those of flunarizine were long-lasting. These differences might be relevant to the clinical use of dotarizine as an antimigraine drug.

Animals↗
PubMed1997

A postmarketing study of flunarizine in migraine and vertigo.

This prospective, open multi-centre study on flunarizine focused on the risk/benefit ratio of the use of flunarizine in the prophylaxis of migraine and in the treatment of vertigo, due to disorder of the vestibular system. The assessment of risks focused on the incidence of new events of depression and/or extrapyramidal syndrome during flunarizine treatment. For migraine, flunarizine was compared to propranolol in 686 patients; for vertigo, flunarizine was compared to betahistine in 198 patients. The incidence of depression during follow-up in this study was significantly higher in the flunarizine group than in the propranolol group in the condition of migraine. There were no observations of an extrapyramidal syndrome. There was a suggestion that flunarizine has more benefits than propranolol in the condition of migraine, and that betahistine has more benefit than flunarizine in the condition of vertigo. Differences in dosages could possible explain these differences.

Adult↗
PubMed1999

Does the antimigraine action of flunarizine involve the dopaminergic system? A clinical-neuroendocrinological study.

We have investigated the prolactin response to bromocriptine (BRC), a D2 dopamine receptor agonist in migrainous women before and after treatment with flunarizine. We evaluated whether this test was predictive of therapeutic efficacy of flunarizine treatment and whether the therapeutic response to flunarizine treatment was related to its effect on dopaminergic system at tuberoinfundibular level. Ten migrainous women underwent a BRC test in the late follicular phase before and after 1 and 3 months of treatment with flunarizine 10 mg at bedtime. Blood samples of prolactin (PRL), growth hormone, follicle-stimulating hormone, luteinizing hormone, estradiol and progesterone were taken at basal condition. PRL was also evaluated 1 and 2 h after BRC (2.5 mg) administration. Each patient kept a daily headache diary for 1 month prior to the test and throughout the study. The level of PRL inhibition after BRC administration, observed before flunarizine treatment, was not predictive of the therapeutic response observed after 1 and 3 months of treatment. The effect of flunarizine on PRL level was not related to the therapeutic efficacy of the drug. These data suggest that flunarizine does not attenuate the activity of dopaminergic neurons in migrainous patients, and that the antimigraine effect of flunarizine does not seem related to its action on dopaminergic system at least at tuberoinfundibular level.

Adult↗