A novel flunarizine hydrochloride-loaded organogel for intraocular drug delivery in situ: Design, physicochemical characteristics and inspection.

We developed a safe and efficacious drug delivery system for treatment of brain diseases. A novel in-situ gel system was prepared using soybean oil, stearic acid and N-methyl-2-pyrrolidinone (NMP) (10:1:3, v/w/v). This system had low viscosity as a sol in vitro and turned into a solid or semi-solid gel in situ after administration. The poorly water-soluble drug flunarizine hydrochloride (FNZ) was incorporated into this "organogel" system. Organogel-FNZ was characterized by light microscopy, differential scanning calorimetry (DSC) and rheology. Drug release in vitro was investigated. The initial "burst" effect did not occur in organogel-FNZ, which is different from other gels formed in situ. Pharmacokinetic studies were undertaken in rats using gel administration (14 mg kg-1), intravenous administration (5 mg kg-1) and administration using drops (14 mg kg-1). Organogel-FNZ could reduce the clearance rate and prolong the duration of action, in the plasma and brain tissues of rats. The peak serum concentration, area under the curve and absolute bioavailability of the organogel-FNZ group were higher than those of the intraocular- drops group. Organogel-FNZ is a promising drug-delivery system for treatment of brain diseases by intraocular administration.

Calcium antagonists for acute ischemic stroke.

BACKGROUND: The sudden loss of blood supply in ischemic stroke is associated with an increase of calcium ions within neurons. Inhibiting this increase could protect neurons and might reduce neurological impairment, disability, and handicap after stroke. OBJECTIVES: To assess the effects of calcium antagonists for reducing the risk of death or dependency after acute ischemic stroke. We investigated the influence of different drugs, dosages, routes of administration, time intervals after stroke, and trial design on the outcomes. SEARCH METHODS: The evidence is current to 6 February 2018. We searched the Cochrane Stroke Group Trials Register (6 February 2018), Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 2), MEDLINE Ovid (1950 to 6 February 2018), Embase Ovid (1980 to 6 February 2018), and four Chinese databases (6 February 2018): Chinese Biological Medicine Database (CBM-disc), China National Knowledge Infrastructure (CNKI), Chinese Scientific Periodical Database of VIP information, and Wanfang Data. We also searched the following trials registers: ClinicalTrials.gov, EU Clinical Trials Register, Stroke Trials Registry, ISRCTN registry, WHO International Clinical Trials Registry Platform, and Chinese Clinical Trial Registry, and we contacted trialists and researchers. SELECTION CRITERIA: Randomized controlled trials comparing a calcium antagonist versus control in people with acute ischemic stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted data, assessed risk of bias, and applied the GRADE approach to assess the quality of the evidence. We used death or dependency at the end of long-term follow-up (at least three months) in activities of daily living as the primary outcome. We used standard Cochrane methodological procedures. MAIN RESULTS: We included 34 trials involving 7731 participants. All the participants were in the acute stage of ischemic stroke, and their age ranged from 18 to 85 years, with the average age ranging from 52.3 to 74.6 years across different trials. There were more men than women in most trials. Twenty-six trials tested nimodipine, and three trials assessed flunarizine. One trial each used isradipine, nicardipine, PY108-608, fasudil, and lifarizine. More than half of these trials followed participants for at least three months. Calcium antagonists showed no effects on the primary outcome (risk ratio (RR) 1.05; 95% confidence interval (CI) 0.98 to 1.13; 22 trials; 22 studies; 6684 participants; moderate-quality evidence) or on death at the end of follow-up (RR 1.07, 95% CI 0.98 to 1.17; 31 trials; 7483 participants; moderate-quality evidence). Thirteen trials reported adverse events, finding no significant differences between groups. Most trials did not report the allocation process or how they managed missing data, so we considered these at high risk of selection and attrition bias. Most trials reported double-blind methods but did not state who was blinded, and none of the trial protocols were available. AUTHORS' CONCLUSIONS: We found no evidence to support the use of calcium antagonists in people with acute ischemic stroke.

Combination of flunarizine and transcutaneous supraorbital neurostimulation improves migraine prophylaxis.

OBJECTIVE: This study is aimed to access the efficacy and safety of combination therapy of flunarizine plus transcutaneous supraorbital neurostimulation (tSNS) compared with either flunarizine or tSNS alone for migraine prophylaxis. METHODS: Patients with episodic migraine were enrolled and randomized into 3 groups. Flunarizine 5 mg per day, or tSNS for 20 minutes daily or combination of both were prescribed consecutively for 3 months. The primary outcome measures were changes in migraine days and 50% responder rate of monthly migraine days. Secondary outcome measures were the changes in migraine intensity and intake of rescue medication. Finally, satisfaction to treatment and adverse effect were evaluated as well. RESULTS: A total of 154 were randomized and included in the analysis. After 3 months, the monthly migraine days were decreased in 3 groups and more significant in the combination group. The 50% responder rate was significantly higher (78.43%) in the combination therapy than monotherapy of flunarizine (46.15%) or tSNS (39.22%) alone. Greater reduction of migraine intensity and intake of rescue medication was observed in combination group. There was no difference of adverse events between flunarizine group and combination group (P = .89). CONCLUSION: Adding tSNS to flunarizine can improve the therapeutic efficacy of migraine prophylaxis without increasing the adverse effects. In addition, tSNS is effective and safe for migraine treatment and can be a valid option for migraineurs who are reluctant to take oral medications or for patients who experience a low-migraine frequency and/or intensity that prophylactic therapy is not indicated but desire to acquire medical intervention.

Induction of late LTP-like plasticity in the human motor cortex by repeated non-invasive brain stimulation.

BACKGROUND: Non-invasive brain stimulation enables the induction of neuroplasticity in humans, however, with so far restricted duration of the respective cortical excitability modifications. Conventional anodal transcranial direct current stimulation (tDCS) protocols including one stimulation session induce NMDA receptor-dependent excitability enhancements lasting for about 1 h. OBJECTIVE: We aimed to extend the duration of tDCS effects by periodic stimulation, consisting of two stimulation sessions, since periodic stimulation protocols are able to induce neuroplastic excitability alterations stable for days or weeks, termed late phase long term potentiation (l-LTP), in animal slice preparations. Since both, l-LTP and long term memory formation, require gene expression and protein synthesis, and glutamatergic receptor activity modifications, l-LTP might be a candidate mechanism for the formation of long term memory. METHODS: The impact of two consecutive tDCS sessions on cortical excitability was probed in the motor cortex of healthy humans, and compared to that of a single tDCS session. The second stimulation was applied without an interval (temporally contiguous tDCS), during the after-effects of the first stimulation (during after-effects; 3, or 20 min interval), or after the after-effects of the first stimulation had vanished (post after-effects; 3 or 24 h interval). RESULTS: The during after-effects condition resulted in an initially reduced, but then relevantly prolonged excitability enhancement, which was blocked by an NMDA receptor antagonist. The other conditions resulted in an abolishment, or a calcium channel-dependent reversal of neuroplasticity. CONCLUSION: Repeated tDCS within a specific time window is able to induce l-LTP-like plasticity in the human motor cortex.

[Effects of acupuncture preventive treatment on the quality of life in patients of no-aura migraine].

OBJECTIVE: To assess the therapeutic effects on acupuncture preventive treatment of no-aura migraine and its influence on the QOL (quality of life) of the patients. METHODS: Randomized controlled, double-blind and double-dummy research methods were adopted, 60 cases were randomly divided into an observation group and a control group, 30 cases in each group. The observation group was treated with acupuncture combined with oral administration of Flunarizine Hydrochloride vacuity capsules, and Baihui (GV 20), Shenting (GV 24) and Benshen (GB 13) were selected as main points. The control group was treated with oral administration of Flunarizine Hydrochloride capsules combined with acupuncture at placebo-points, thrice each week, for 4 weeks. The SF-36 QOL Scale and effective rate were used for assessment of therapeutic effects before treatment, after treatment and 3 months later. RESULTS: There were significant differences in each dimension scores of SF-36 at 3 time points between the two groups (all P < 0.05). The dimension of the physiological function in the observation group was superior to that of the control group after treatment (P < 0.05), and there was no significant difference in other 7 dimensions between the two groups (all P > 0.05). After treatment and 3 months later, the effective rates were 68.0%, 68.0% in the observation group and 24.0%, 32.0% in the control group, respectively, with significant differences between the two groups (all P < 0.05). CONCLUSION: Acupuncture preventive treatment can effectively improve the life quality of the patients with migraine and reduce the migraine attack. There is no significant difference in improving the physical and psychological health of the migraine patients between acupuncture and Flunarizine Hydrochloride, and acupuncture is more effective in reducing the migraine attack days.

[Acupuncture at points of the liver and gallbladder meridians for treatment of migraine: a multi-center randomized and controlled study].

OBJECTIVE: To investigate the therapeutic effect and safety of acupuncture at points of The Liver and Gallbladder Meridians for treatment of migraine. METHODS: Multi-central, randomized and controlled trial was used and 253 cases of migraine were divided into an acupuncture group and a western medicine group. The acupuncture group was treated with acupuncture at points of The Liver and Gallbladder Channels with Taichong (LR 3), Yang-lingquan (GB 34), Fengchi (GB 20), Ququan (LR 8) selected as main points, and the western medicine group with oral administration of Flunarizine tablets for 4 therapeutic courses. The total therapeutic effects 3 and 6 months after the treatment, the scores of various symptoms of migraine before and after treatment, and the stability of therapeutic effect in one-year following-up survey were observed in the two groups. RESULTS: After treatment, mean times and duration of the headache attack were significantly improved in the two groups (all P < 0.01) with the acupuncture group better than the western medicine group (P < 0.05). The total effective rates for stopping pain after treatment, 3 months and 6 months after treatment in the acupuncture group were 93.0%, 93.0% and 87.7%, respectively, which were better than 85.6%, 86.5% and 69.2% in the western medication group (all P < 0.01). One year later, the stability of the therapeutic effect in the acupuncture group was better than that in the western medicine group (P < 0.05); the adverse reaction and the compliance in the acupuncture group were significantly superior to those in the western medicine group. CONCLUSION: Acupuncture at points of The Liver and Gallbladder Meridians for treatment of migraine is safe, effective, and with stable long-term therapeutic effect.

Atypical antipsychotic profile of flunarizine in animal models.

RATIONALE: Flunarizine is known as a calcium channel blocker commonly used in many countries to treat migraine and vertigo. Parkinsonism has been described as one of its side-effects in the elderly, which is in agreement with its recently characterized moderate D2 receptor antagonism. OBJECTIVES: To perform a pre-clinical evaluation of flunarizine as a potential antipsychotic. METHODS: We evaluated the action of orally administered flunarizine in mice against hyperlocomotion induced by amphetamine and dizocilpine (MK-801) as pharmacological models of schizophrenia, induction of catalepsy as a measure for extrapyramidal symptoms and impairment induced by dizocilpine on the delayed alternation task for working memory. RESULTS: Flunarizine robustly inhibited hyperlocomotion induced by both amphetamine and dizocilpine at doses that do not reduce spontaneous locomotion (3-30 mg/kg). Mild catalepsy was observed at 30 mg/kg, being more pronounced at 50 mg/kg and 100 mg/kg. Flunarizine (30 mg/kg) improved dizocilpine-induced impairment on the delayed alternation test. CONCLUSIONS: These results suggest a profile comparable to atypical antipsychotics. The low cost, good tolerability and long half-life (over 2 weeks) of flunarizine are possible advantages for its use as an atypical antipsychotic. These results warrant clinical trials with flunarizine for the treatment of schizophrenia.

[Treatment of idiopathic headache in childhood - recommendations of the German Migraine and Headache Society (DMKG)]. / Therapie idiopathischer Kopfschmerzen im Kindesalter. Empfehlungen der Deutschen Migräne-und Kopfschmerzgesellschaft (DMKG).

According to the principles of evidence-based medicine, the controlled studies on the treatment of idiopathic headache in childhood have been analysed and compiled to treatment recommendations. For the acute treatment of migraine attacks or tension-type headache, ibuprofen (10 mg per kg body weight) or acetaminophen (15 mg per kg body weight) are recommended with highest evidence, intranasal sumatriptan (10 to 20 mg) can be given as second choice. For the prophylaxis of migraine, betablockers (propranolol and metoprolol), flunarizine, and valproic acid are recommended. Flunarizine is the drug of first choice in the treatment of migraine-related disorders. No controlled studies are available for the treatment of further headache types. First line methods for the non-drug treatment of headache in childhood are relaxation therapies, biofeedback, and specific training schedules.

Dolor de cabeza en niños: una revisión / Children's headache: a revision

El dolor de cabeza en niños es un tema hoy por fin considerado, tras haber estado relegado por muchos años. Su importancia se recobra desde la psicología, a partir del estudio y abordaje del dolor recuperando un gran esplendor en los úllttimos diez años. El presente trabajo recopila la información más relevante existente sobre este tema, centrándose en las cefaleas funcionales infantiles: concepto, epidemiología, consideraciones evolutivas, sintomatología, factores asociados, evaluación y tratamiento, para finalizar se establecen algunas conclusiones al respeccto. (AU)

Flunarizine pretreatment attenuates hyperthermia-induced extravasation in rats.

Previous work has established that there is an increase in endothelial permeability in hyperthermic rats. This work assessed the potential of the calcium channel blocker (E)-1-bis(4-fluorophenyl)methyl-4-(3-phenyl-2-propenyl)piperazine dihydrochloride (flunarizine) as a pretreatment to ameliorate this extravasation. Five groups of male rats (n=12 rats per group, 400-500 g) were given 0, 0.3, 1, 2, or 3 mg/kg flunarizine (FL0, FL0.3, FL1, FL2, and FL3, respectively) by gavage 30 min prior to induction of hyperthermia. Hyperthermia was achieved by placing unrestrained animals in their own cages in a chamber maintained at 41.5 degrees C until a core temperature (Tc) of 42.6 degrees C was attained. Then, 25 mg/kg of Evans blue in saline was administered via a jugular cannula. After 15 min the animals were anesthetized, exsanguinated, tissues removed and washed in saline, and Evans blue extracted with formamide. As the dose of flunarizine was increased, there was a significant (P<0.05) reduction of Evans blue recovered from the liver, kidney, lung, spleen, and intestinal tissue. Endurance time in the heat to reach a Tc of 42.6 degrees C increased significantly from 194+/-39 min (mean+/-SD) with FL0 to 275+/-33 min with FL1, but decreased again with FL2 (206+/-42) and FL3 (199+/-60). Thus, flunarizine pretreatment attenuated hyperthermia-induced extravasation, and 1 mg/kg flunarizine markedly increased the tolerance time to heat exposure.

Low dose flunarizine protects the fetal brain from ischemic injury in sheep.

Flunarizine, a calcium channel blocker, reduced cerebral damage caused by hypoxic-ischemic insults in neonatal rats and in fetal sheep near term. However, the high dose regimen used in these studies produced cardiovascular side effects that might have counteracted the neuroprotective properties of flunarizine. Therefore, the neuroprotective effect was tested in a low dose protocol (1 mg/kg estimated body weight). Twelve fetal sheep near term were instrumented chronically. Six fetuses were pretreated with 1 mg of flunarizine per kg of estimated body weight 1 h before ischemia, whereas the remainder (n=6) received solvent. Cerebral ischemia was induced by occluding both carotid arteries for 30 min. To exclude the possibility that the neuroprotective effects of flunarizine were caused by cerebrovascular alterations we measured cerebral blood flow by injecting radiolabeled microspheres before (-1 h), during (3 min and 27 min) and after (40 min, 3 h, and 72 h) cerebral ischemia. At the end of the experiment (72 h) the ewe was given a lethal dose of sodium pentobarbitone and saturated potassium chloride i.v., and the fetal brain was perfused with formalin. Neuronal cell damage was assessed in various brain structures by light microscopy after cresyl violet/fuchsin staining using a scoring system: 1, 0-5% damage; 2, 5-50% damage; 3, 50-95% damage; 4, 95-99% damage; and 5, 100% damage. In 10 other fetal sheep effects of low dose flunarizine on circulatory centralization caused by acute asphyxia could be excluded. In the treated group neuronal cell damage was reduced significantly in many cerebral areas to varying degrees (range for control group, 1.03-2.14 versus range for treated group, 1.00-1.13; p < 0.05 to p < 0.001, respectively). There were only minor differences in blood flow to the various brain structures between groups. We conclude that pretreatment with low dose flunarizine protects the brain of fetal sheep near term from ischemic injury. This neuroprotective effect is not mediated by changes in cerebral blood flow. We further conclude that low dose flunarizine may be clinically useful as a treatment providing fetal neuroprotection, particularly because the fetal cardiovascular side effects are minimal.

Long-term follow-up after flunarizine or nimodipine discontinuation in migraine patients.

Various open and controlled studies have confirmed the antimigraine action of flunarizine, while the antimigraine properties of nimodipine are still open to controversy. Moreover, only a few studies include an additional follow-up after discontinuation of migraine prophylaxis with either drug. We carried out a single blind evaluation of the efficacy and tolerance of flunarizine (25 patients) in comparison with nimodipine (25 patients) and the long-term effect after discontinuation of a 6-month treatment. Both medications significantly reduced migraine frequently and severity. Flunarizine was more efficacious than nimodipine in reducing migraine frequency (p < 0.001), pain severity (p < 0.05), migraine index (p < 0.05) and corrected migraine index (p < 0.05). The positive effect lasted 8.4 +/- 4.0 months after discontinuation of flunarizine and 4.9 +/- 3.5 months after nimodipine (p < 0.05). Our results suggest that flunarizine is more effective than nimodipine in the prophylactic treatment of migraine. The positive effect after drug discontinuation lasts longer with flunarizine, compared to nimodipine.

Flunarizine in stroke treatment (FIST): a double-blind, placebo-controlled trial in Scandinavia and the Netherlands.

INTRODUCTION: An international, multicenter trial was conducted in 331 patients to determine the effect of a large dose of flunarizine (a calcium entry blocker) in the treatment of acute ischemic stroke in the territory of the Middle cerebral artery. METHODS: The administration of the trial medication should start within 24 h after the initial symptoms of stroke. According to a random schedule, the patients were assigned to a 4-weeks double-blind treatment with either flunarizine (n = 166) or placebo (n = 165): one week intravenous administration (50 mg daily), followed by 3 weeks oral treatment (week 2, 21 mg daily; week 3-4, 7 mg daily). All patients had to be investigated by computerized tomography (CT) within 7 days after stroke onset; 36 patients were secundarily excluded because the CT showed another pathology. During the treatment period, other "stroke therapies" were not allowed. Patients were followed up for 24 weeks. RESULTS: After the 24 weeks trial period, the percentage of patients who were dead or pendent (modified Rankin score 3-5) was similar in both treatment groups (flunarizine 67%, placebo 65%). During the trial, the scores for handicap severity (modified Rankin scale), neurological status (Orgogozo) and activities of daily living (modified Barthel index) strongly improved in both treatment groups, but no differences were found between the treatment groups. In this trial, the administration of trial treatment started relatively late after stroke onset (flunarizine group: mean time interval 13.5 h; placebo 12.3 h). A subgroup of patients received trial medication within 6 h after stroke onset (flunarizine n = 31; placebo n = 29). Also in this subgroup, no differences were found between the flunarizine and placebo group. CONCLUSION: Flunarizine did not improve neurologic and functional outcome in patients with acute ischemic stroke.

Flunarizine, a calcium channel antagonist, is partially prophylactically neuroprotective in hypoxic-ischemic encephalopathy in the fetal sheep.

Calcium antagonist therapy has been reported to reduce neuronal death after hypoxia-ischemia; however, its potential use in prenatal hypoxic-ischemic events has received little attention. We examined the effect of pretreatment with flunarizine in chronically instrumented late gestation fetal sheep subjected to 30 min of cerebral ischemia. Eight fetuses were given 0.11 mmol (45 mg) of flunarizine over 2 h preischemia (high dose), 10 were given 0.07 mmol (30 mg) over 3 h preischemia (low dose), 17 were given nothing (ischemia controls), and 5 received neither the ischemic insult nor any treatment (sham controls). The fetal electrocorticogram was monitored for 3 d postinsult. Histologic outcome was quantified after 72 h. Low-dose, but not high-dose, flunarizine therapy was associated with an overall reduction in cerebral damage (p < 0.01), a greater final electrocorticogram intensity, and a reduction in the incidence of seizures (p < 0.02) compared with ischemia controls. High-dose, but not low-dose, flunarizine was associated with a significant acute mortality and a decrease in fetal blood pressure (p < 0.05) at the time of occlusion, although there was no effect on the initial hypertensive response to occlusion. These observations suggest that flunarizine is partially neuroprotective when given before severe global ischemia in utero, but that its hypotensive effects make it unsuitable for prophylactic administration in utero.

[Calcium channel blockers and prevention of migraine]. / Médicaments anticalciques et prophylaxie de la migraine.

Calcium antagonists have been proposed for the prophylactic treatment of migraine because of their putative vasodilating antispasmodic effect and of their action against the cellular consequences of brain hypoxia. Published reports of controlled double-blind studies of calcium antagonists for the prophylactic treatment of migraine are reviewed herein. The effectiveness of verapamil, diltiazem, and nifedipine in this indication cannot be considered as firmly demonstrated, when problems with trial design and the amount of available data are taken into account. Nimodipine failed to demonstrate significant effectiveness in migraine with or without an aura. In contrast, the ability of a diphenylpiperazine, flunarizine, to decrease the incidence of migraine attacks in patients with common or classical migraine has been firmly demonstrated, although there is less evidence of this agent's effectiveness on the duration and severity of attacks. The percentage of patients who respond to flunarizine seems comparable to the percentages of propranolol or pizotifen responders. However, flunarizine is associated with unpleasant (weight gain) or severe (extrapyramidal or depressive symptoms) adverse effects which limit its place to that of a second-line drug. Lastly, the analysis of these studies failed to disclose a correlation between calcium movements across the cell membrane and effectiveness for the prevention of migraine attacks. Flunarizine's effect in migraine probably involves monoamine mechanisms which bear no relation to calcium.

Long-term treatment with different calcium- and calmodulin-antagonists induces changes in rat brain alpha-adrenoceptors.

1. The binding characteristics (Bmax and Kd) of the alpha-adrenoceptor radioligand [3H] WB4101 in crude membrane fraction (fraction P2) from cerebral cortex were studied after 13-day oral treatment of male Wistar rats with the Ca(2+)-antagonists nifedipine (20 mg/kg), verapamil (50 mg/kg), flunarizine (10 mg/kg) and with the calmodulin-antagonist trifluoperazine (TFP) (3 mg/kg). 2. A significant reduction of the binding sites (Bmax) for [3H] WB4101 was established after the three Ca(2+)-antagonists as well as after TFP treatment. 3. Different changes in the affinity constant (Kd) of brain adrenoceptors were observed depending on the type of the Ca2+ or CaM-antagonist used: nifedipine did not change the Kd value, verapamil and TFP decreased whereas flunarizine increased the Kd value. 4. Relationships between Ca ions and alpha-adrenoceptor functions are suggested.

[Use of flunarizine in mild-to-severe senile cerebral deterioration]. / Studio sull'impiego della flunarizina nel deterioramento cerebrale senile di grado medio-lieve.

Within the framework of multifactorial etiology the use of calcium entry blockers as a complementary measure in the management of moderate-to-severe senile brain deterioration has been studied. Clinical study of twelve flunarizine-treated patients has yielded promising evidence in favor of vasoactive drugs as adjuvants to treatment with psychoactive drugs. Further studies should lend support to this hypothesis.

Treatment with an i.v. calcium overload blocker (flunarizine) in acute stroke. A pilot study.

In an open pilot study 55 patients suffering from acute stroke were treated with Flunarizine, a calcium overload blocker, in addition to standard therapy including diet, physiotherapy, adequate management of accompanying disorders, and hemodilution. The initial high-dose i.v. treatment (2 X 25 mg Flunarizine/day) and the subsequent oral regimen were well-tolerated. The main side effect was slight transient weariness. No adverse effects regarding blood pressure, heart rate, enzymes, blood analysis, renal function and, especially, no extrapyramidal motor symptoms or depression were detected. Flunarizine may be regarded as a relatively safe drug in acute stroke. The probable beneficial effect on the patient's recovery will be evaluated in a multicenter double-blind study.