flunarizine and Brain-Ischemia

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.. 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.. 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.. Randomized controlled trials comparing a calcium antagonist versus control in people with acute ischemic stroke.. 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.. 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.. We found no evidence to support the use of calcium antagonists in people with acute ischemic stroke.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Brain Ischemia; Calcium; Calcium Channel Blockers; Female; Flunarizine; Humans; Isradipine; Male; Middle Aged; Nimodipine; Randomized Controlled Trials as Topic; Stroke; Vasodilator Agents; Young Adult

Topics: Animals; Brain Ischemia; Calcium Channel Blockers; Calcium Channels; Cerebrovascular Disorders; Dihydropyridines; Flunarizine; Humans; Neuroprotective Agents; Verapamil

The clinical use of calcium antagonists (Ca-antagonists) in neurological diseases focuses on 2 main therapeutic fields: (a) For the therapy of migraine flunarizine is the first choice therapy and nimodipine is a second line treatment. With verapamil cluster headache can be treated successfully, flunarizine shows less impressive clinical efficacy. The therapy with flunarizine may be restricted due to the incidence of extrapyramidal disturbances and depressions as known side effects. (b) The therapy of clinical conditions after subarachnoidal bleeding with nimodipine is well established. In the therapy of acute cerebral ischemia the therapeutic efficacy of nimodipine administered orally is not therapeutically proved until now; the intravenous administration of nimodipine offers the risk of acute hypotensive reactions. At present the usefulness of the administration of ca-antagonists in the so-called cerebrovascular insufficiency or dementia and various others cerebral disorders with vertigo could not be demonstrated.

Topics: Brain Ischemia; Calcium Channel Blockers; Cluster Headache; Flunarizine; Humans; Migraine Disorders; Nifedipine; Nimodipine

Calcium antagonists are of potential value in preventing neuronal death following cerebral ischemia or anoxia. Prevention of calcium influx into neurons, not just preservation of cerebral blood flow, is necessary if these agents are to be protective. To be of value clinically in humans, these agents must be effective even if administered after the ischemic insult has occurred. Experimental studies suggest that flunarizine, which inhibits calcium influx following brain anoxia, prolongs clinical survival and prevents neuronal death even when administered after the ischemic event, has no known significant toxic effects in humans following acute administration, has important potential value in the treatment of stroke, and should be evaluated in controlled clinical trials of patients with acute stroke.

Topics: Brain Ischemia; Calcium; Calcium Channel Blockers; Flunarizine; Humans; Hypoxia, Brain

The present study was designed to investigate the role of flunarizine (a non-selective calcium channel blocker) on cerebral ischemic-reperfusion associated cognitive dysfunction in aged mice. Bilateral carotid artery occlusion of 12min followed by reperfusion for 24h was given to induce cerebral injury in male Swiss mice. The assessment of learning & memory was performed by Morris water maze test; motor in-coordination was evaluated by rota rod, lateral push and inclined beam walking tests; cerebral infarct size was quantified by triphenyltetrazolium chloride staining. In addition, reduced glutathione (GSH), total calcium and acetylcholinesterase (AChE) activity were also estimated in aged brain tissue. Donepezil treated group served as a positive control in this study. Ischemia reperfusion (I/R) injury produced significant increase in cerebral infarct size. A significant loss of memory along with impairment of motor performance was also noted. Further, I/R injury also produced significant increase in levels of total calcium, AChE activity and decrease in GSH levels. Pretreatment of flunarizine significantly attenuated I/R induced infarct size, behavioral and biochemical changes. Hence, it may be concluded that, a non-selective calcium channel blocker can be useful in I/R associated cognitive dysfunction due to its anti-oxidant, anti-infarct and modulatory actions of neurotransmitters & calcium channels.

Topics: Acetylcholinesterase; Aging; Animals; Brain Ischemia; Calcium Channel Blockers; Cognition Disorders; Flunarizine; Male; Maze Learning; Mice; Motor Activity; Reperfusion Injury

To explore the expression of Fas and FasL genes after ischemia-reperfusion in rats and the effect of flunarizine.. Ischemia was induced by four-vessel occlusion for 30 min following reperfusion in rats. The biopsy tissues from brain were immunohistochemically assayed with Fas and FasL genes polyclonal antibody.. The expression of Fas was increased as early as 6 h after the onset of reperfusion. The peak of the expression of Fas occurred 24-48 h after ischemia-reperfusion. The expression of FasL was observed 12 h after ischemia-reperfusion and peaked at 48-72 h. The expression of Fas and FasL gene was quite obvious in the cortex and hippocampus CA1, the more sensitive areas to ischemic injury. Flunarizine i.p. 10 mg.kg-1 and 20 mg.kg-1 obviously inhibited the expression of Fas and FasL in dose-dependent manner.. Expression of Fas and FasL in cerebral cortex and hippocampus can be induced by global ischemia-reperfusion. Flunarizine significantly inhibited the expression of Fas and FasL genes following ischemia-reperfusion.

Topics: Animals; Apoptosis; Brain; Brain Ischemia; Calcium Channel Blockers; Fas Ligand Protein; fas Receptor; Flunarizine; Male; Membrane Glycoproteins; Rats; Rats, Wistar; Reperfusion Injury

We examined whether the anti-ischemic effect of lamotrigine (LTG), which inhibits the presynapic sodium channel, could be enhanced by the calcium channel blocker-flunarizine (FNR) in cerebral ischemia. Global ischemia was induced in Mongolian gerbils for 5 min under the monitoring of scalp temperature. LTG and FNR were administered intraperitoneally 1 h before ischemia. After 7 days, animals were killed and viable neurons in CA1 area were counted. LTG treated group showed significant protective effects compared to control group (P < 0.01). These effects were more prominent in group treated with LTG and FNR (P = 0.01). Combination of two drugs did not increase the mortality rate compared to single-treated group. These results show that a synergistic reduction of neuronal death can be achieved by combination of LTG and FNR without serious adverse reaction.

Topics: Animals; Brain; Brain Chemistry; Brain Ischemia; Calcium Channel Blockers; Cerebral Infarction; Drug Synergism; Flunarizine; Gerbillinae; Lamotrigine; Male; Neuroprotective Agents; Sodium Channels; Triazines

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.

Topics: Animals; Brain; Brain Ischemia; Calcium Channel Blockers; Carotid Arteries; Cell Death; Cerebrovascular Circulation; Fetus; Flunarizine; Injections, Intravenous; Neurons; Rats; Sheep

Hypoxic-ischemic encephalopathy is still a very important cause of neonatal mortality and morbidity. Recently, platelet-activating factor (PAF) has been accused of being responsible for the neuronal damage in hypoxic-ischemic brain. We investigated tissue PAF concentrations in hypoxic-ischemic brain injury in immature rats. Endogenous PAF concentration in brain tissue showed a marked increase in hypoxic-ischemic pups (85.6 +/- 15.5 pg/mg protein) when compared to that of control (9.05 +/- 3.1 pg/mg protein). In addition, we examined the effects of flunarizine, a selective calcium channel blocker, and Ginkgo biloba extract (EGb 761) on endogenous PAF concentration in hypoxic-ischemic brain injury. Endogenous PAF concentrations in both flunarizine-pretreated (16.6 +/- 4.8 pg/mg protein) and EGb 761-pretreated (33.5 +/- 8.9 pg/mg protein) pups were significantly lower than the untreated group. These results indicate that PAF is an important mediator in immature rat model of cerebral hypoxic-ischemic injury. The suppressor effect of flunarizine and EGb 761 on PAF production may open new insight into the treatment of hypoxic-ischemic brain injury.

Topics: Animals; Brain; Brain Ischemia; Calcium Channel Blockers; Female; Flunarizine; Ginkgo biloba; Hypoxia, Brain; Male; Plant Extracts; Plants, Medicinal; Platelet Activating Factor; Rats; Rats, Wistar

Photochemical induction of a thrombosis produces lesions of the cortex of reproducible area and depth, and it has been suggested that this may provide a relatively noninvasive model of the human condition of stroke. The cognitive effects of photothrombotic lesions centred at two different positions were assessed in rats using the Morris water maze test for spatial learning and memory, and it was demonstrated that profound deficits in acquisition of this task were produced by bilateral lesions of the frontal cortex. These effects were in the absence of overt motor deficits, and there was no significant correlation between lesion volume and functional deficits. Flunarizine (2 mg/kg) did not attenuate this ischaemic damage and had no effect on the functional deficits. This model has distinct advantages over more invasive global models of ischaemia and may also provide greater understanding of the functional role of the mammalian neocortex.

Topics: Animals; Brain Ischemia; Cerebral Cortex; Flunarizine; Frontal Lobe; Intracranial Embolism and Thrombosis; Light; Male; Maze Learning; Necrosis; Neuroprotective Agents; Parietal Lobe; Rats; Spatial Behavior

Calcium is involved in the physiopathology of cerebral ischemia. Calcium antagonists might prevent the calcium overload and death of cells from ischemically compromised tissue. We compare the neuroprotective effect of various doses (0.2, 0.5 and 1 mg/kg) of two dihydropyridines, nimodipine and the novel 1,4-dihydropyridine derivative PCA50938, and flunarizine in the gerbil model of global ischemia. Improvements in morbidity were observed 2 h after the end of carotid occlusion (McGraw's scale) with 0.5 mg/kg of flunarizine, all doses of PCA50938 and 0.2 mg/kg nimodipine. Neuronal loss in the CA1 sector of the hippocampus was examined. The animals treated with 0.5 mg/kg flunarizine and those treated with 1 mg/kg PCA50938 showed a significant reduction in the percentage of damaged neurons in the hippocampal CA1 area, 72 h after transient ischemia. None of the animals treated with 0.5 mg/kg flunarizine had more than 80% of the evaluated neurons altered. We conclude that PCA50938 and flunarizine may act as neuroprotective drugs with different patterns of dose-response and neuroprotective-morbidity-mortality relationships, in the model of global cerebral ischemia in the gerbil. Flunarizine has a narrow therapeutic range.

Topics: Animals; Brain Ischemia; Calcium Channel Blockers; Dihydropyridines; Female; Flunarizine; Gerbillinae; Male; Neuroprotective Agents; Nimodipine

To study whether regional brain calcium change would be an important factor for ischemic neuranal damage and whether calcium antagonist would exert protective effects on cerebral ischemia.. OCPC autoanalyzer method, was used to measure the regional brain calcium and observe the influence of flunarizine (FNZ) 48 hours after the rabbit middle cerebral artery occlusion (MCAO).. 48 hours after MCAO, the calcium in the ischemic middle cerebral artery territory was 10.8 times as much as that in the pseudo-occluded controls, and FNZ could significantly decrease the ischemic brain calcium (P < 0.05) and the ischemic cerebral edema (P < 0.01).. Caoverload was animportant factor leading to ischemic neuronal death, and FNZ has protective effects on cerebral ischemia.

Topics: Animals; Brain; Brain Ischemia; Calcium; Calcium Channel Blockers; Flunarizine; Rabbits; Random Allocation

The anti-ischemic and anti-anoxic effects of efonidipine, a dihydropyridine calcium antagonist, were studied in several models for cerebral ischemia and anoxia in mice and rats, and the effects were compared with those of nicardipine and flunarizine. Both efonidipine and flunarizine showed protective effects in the models of KCN-induced anoxia and complete ischemia induced by decapitation in mice 6 hr after the treatment, while nicardipine did not show such a long-lasting effect. Efonidipine (1 mg/kg, i.p.), but not nicardipine and flunarizine, prolonged the tolerance times in the asphyxic anoxia model. In mice, efonidipine (4 mg/kg, i.p.) significantly reduced the cumulative mortality rate after bilateral carotid artery ligation. The survival rates at 20 hr after bilateral carotid artery ligation were 33% in the group treated with efonidipine, significantly higher than that in the control group, 0%. On the other hand, the treatment with nicardipine or flunarizine did not increase the rates at 20 hr after the ligation. Moreover, efonidipine attenuated the disturbance of cerebral energy metabolism induced by decapitation in rats. These effects of efonidipine observed in this study were on the whole superior to those of the reference drugs, strongly suggesting the improving effect of efonidipine on cerebral ischemia and anoxia.

Topics: Animals; Brain Ischemia; Calcium Channel Blockers; Dihydropyridines; Flunarizine; Hypoxia; Male; Mice; Mice, Inbred ICR; Nicardipine; Nitrophenols; Organophosphorus Compounds; Rats; Rats, Wistar

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.

Topics: Animals; Brain Diseases; Brain Ischemia; Calcium Channel Blockers; Disease Models, Animal; Female; Fetal Hypoxia; Flunarizine; Hypotension; Hypoxia, Brain; Pregnancy; Sheep

Several diphenylmethylpiperazine derivatives are potential therapeutic agents for prevention of ischemic injuries in the heart and brain, because of their ability to block Ca2+ currents and their antioxidant activity. In this study, the current lead compound, U-92032 ((7-((bis-4-fluorophenyl)methyl)-1-piperazinyl)-2-(2-hydroxyethylamin o)- 4-(1-methylethyl)-2,4,6-cycloheptatrien-1-one), has been compared with flunarizine and nifedipine (well-known T- and L-type Ca2+ channel antagonists, respectively) for their effects on Ca2+ channels in a mouse neuronal cell line, N1E-115 cells, and their ability to preserve the phenomenon of long-term potentiation and to improve neurological symptoms in gerbil ischemic models. U-92032, like flunarizine, blocked transient Ba2+ currents (IBa) through T-type Ca2+ channels with no effect on nifedipine-sensitive non-inactivating currents. Transient IBa was reduced by U-92032 at a constant rate, the magnitude of which depended on the drug concentration, probably because of a time-dependent accumulation of the lipophilic drug in the membrane phase. For instance, the drug at 6 microM reduced IBa by 21% per min and abolished it in less than 5 min, about 3 times faster than flunarizine at the same concentration. Otherwise, U-92032 behaved like flunarizine, showing a use-dependent block without noticeable effects on the current-voltage relationship for transient IBa. Oral administration of U-92032 (1 and 25 mg/kg) or flunarizine (25 mg/kg), but not nifedipine (50 mg/kg), to gerbils 1 h prior to bilateral carotid artery occlusion, preserved long-term potentiation in hippocampal CA1 neurons, which were largely abolished by ischemia without the drug treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antioxidants; Brain Ischemia; Calcium Channel Blockers; Flunarizine; Gerbillinae; Hippocampus; Lipid Peroxidation; Long-Term Potentiation; Malondialdehyde; Mice; Neuroblastoma; Neurons; Piperazines; Rats; Tropolone; Tumor Cells, Cultured

Neuroprotective properties of the calcium channel blocker flunarizine have been reported after hypoxic-ischemic insults in immature, infant, and adult rats. However, its effect on fetal regional cerebral blood flow (rCBF) and systemic blood pressure after severe asphyxia is not known. In 15 fetal lambs (3 to 5 d after surgery; gestational age at the experiment, 123.2 +/- 2.5 d), arterial oxygen content was progressively reduced to 30% by restriction of uterine blood flow with an inflatable balloon occluder around the maternal common internal iliac artery. The rCBF was measured with radioactive microspheres at baseline condition, after 1 h of severe asphyxia, and at 30 and 120 min in the recovery phase. Immediately after the end of the occlusion period, fetuses randomly received either flunarizine or its solvent (0.5 mg/kg estimated fetal weight). No differences in rCBF changes between groups were observed during and after asphyxia. Changes in arterial blood pressure or fetal heart rate due to flunarizine could not be demonstrated either. Only five fetuses (33%) survived this degree of asphyxia longer than 24 h: four of the flunarizine-treated group and one of the control group. It is unlikely that this possible protective property of the drug is caused by its influence on rCBF, arterial blood pressure, or fetal heart rate in the phase immediately after asphyxia.

Topics: Acid-Base Imbalance; Animals; Blood Pressure; Brain Ischemia; Cerebrovascular Circulation; Female; Fetal Hypoxia; Flunarizine; Gestational Age; Pregnancy; Sheep

This study was designed to determine whether flunarizine enhances the rate of brain recovery as measured by electroencephalography after cerebral ischemia and whether these effects are attributable to changes in brain temperature.. Male gerbils (n = 81) were treated with either 10 mg/kg flunarizine or its vehicle, beta-cyclodextrin, intraperitoneally, 60 minutes before bilateral carotid occlusion of either 4 or 6 minutes' duration. The electroencephalogram was continuously recorded in the preischemic, ischemic, and postischemic stages of the experiment and rated for the time necessary for the return of 4-6, 7-10, and 11-15 Hz activity. In a second set of experiments, intracerebral temperature was monitored for 60 minutes before ischemia, during 10 minutes of carotid occlusion, and for 60 minutes after ischemia.. Flunarizine pretreatment resulted in significantly more rapid return of electroencephalographic activity in each of the three frequency categories monitored when compared with those animals pretreated with vehicle alone (p less than 0.001). Flunarizine had no effect on brain temperature before, during, or up to 60 minutes after termination of ischemia.. Flunarizine, which has been of efficacy in reducing neuronal death, mortality, and functional impairment when administered after ischemic insults, may have prophylactic value in accelerating brain recovery from ischemia, but does not have this effect as a result of altered brain temperature.

Topics: Animals; Body Temperature; Brain; Brain Ischemia; Electroencephalography; Flunarizine; Gerbillinae; Male

Prolonged inhibition of protein synthesis precedes delayed neuronal death in the CA1 sector of the hippocampus after transient cerebral ischemia. Organic calcium antagonists have been recommended for alleviation of ischemic neuronal damage. The present study was undertaken to investigate whether these drugs improve the recovery of protein biosynthesis after interruption of cerebral blood flow.. Cerebral protein synthesis was measured biochemically and autoradiographically in gerbils submitted to 5 minutes of bilateral occlusion of the common carotid arteries followed by 2 hours or 2 days of recirculation. Flunarizine (25 mg/kg) or nimodipine (1.5 mg/kg) were applied intraperitoneally shortly after ischemia.. Treatment with either calcium antagonist did not markedly influence postischemic recovery of protein synthesis in the resistant regions of the brain and did not prevent the persisting inhibition in the vulnerable stratum pyramidale of the CA1 sector of the hippocampus.. The postischemic application of the organic calcium antagonists nimodipine and flunarizine does not promote postischemic recovery of protein synthesis. The beneficial effects of these drugs must, therefore, be based on other mechanisms.

Topics: Amino Acids; Animals; Brain Ischemia; Calcium Channel Blockers; Cerebrovascular Circulation; Flunarizine; Gerbillinae; Hippocampus; Male; Nerve Tissue Proteins; Nimodipine

Topics: Adenosine Triphosphate; Brain Ischemia; Cerebral Infarction; Cerebrovascular Circulation; Flunarizine; Humans; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Time Factors

A series of 11-[4-(cinnamyl)-1-piperazinyl]-6,11-dihydrodibenz[b,e] oxepins and related compounds were synthesized and evaluated for their protective activities against complete ischemia, normobaric hypoxia, lipidperoxidation and convulsion. Structure-activity relationship studies of this series led to the finding of (E)-1-(3-fluoro-6,11-dihydrodibenz[b,e]oxepin-11-yl)-4-(3- phenyl-2-propenyl)piperazine dimaleate (50), AJ-3941 with the most appropriate property for combined pharmacological activities. Compound 50 also shows an inhibitory effect against cerebral edema as well when orally given to rats.

Topics: Animals; Benzothiepins; Benzoxepins; Brain Edema; Brain Ischemia; Cerebrovascular Disorders; Flunarizine; Hypoxia, Brain; Mice; Piperazines; Rats; Structure-Activity Relationship

21-day-old rats were subjected to unilateral carotid ligation, then, after 2 h of recovery, to 2 h of 8% hypoxia. Immediately following the insult they were treated with either flunarizine (30 mg/kg, i.p.) or with an equal volume of diluent. We have previously shown similar doses of flunarizine to be neuroprotective when given preinsult. After 5 days they were sacrificed for histological analysis. Cerebral injury was almost entirely confined to the ligated side. Full-thickness cortical infarction was noted in 55% of controls (n = 29) versus 36% of flunarizine-treated rats (n = 28; p = 0.14). Mean damage scores for all areas assessed including cortex, striatum, and hippocampus were not significantly different. These observations suggest that flunarizine is not significantly neuroprotective when given immediately after severe hypoxia-ischemia.

Topics: Animals; Animals, Newborn; Brain Ischemia; Cerebral Infarction; Dose-Response Relationship, Drug; Flunarizine; Hypoxia; Prosencephalon; Rats; Rats, Wistar

The purpose of the present study was to investigate the influence of ischemia on postischemic metabolic activity of the brain. Furthermore, the effect of preischemic application of neuroprotective agents such as flunarizine or phencyclidine on postischemic local cerebral glucose utilization (LCGU) was examined. Forebrain ischemia in the rat was performed for 10 min with bilateral carotid clamping, administration of trimethaphan and blood withdrawal to obtain a mean arterial blood pressure of 40 mm Hg. LCGU was determined 7 days after ischemia by injecting 14C-deoxy-D-glucose in saline solution. A significant increase in LCGU in the CA1 subfield of the hippocampus was found 7 days after ischemia, whereas preischemic administration of flunarizine or phencyclidine inhibited this increase. Alterations in LCGU of other brain regions were insignificant.

Topics: Animals; Blood Glucose; Blood Pressure; Brain Ischemia; Deoxyglucose; Flunarizine; Glucose; Hippocampus; Male; Phencyclidine; Rats; Rats, Inbred Strains; Time Factors

Baroreflex sensitivity assessed from the phenylephrine-induced reflex bradycardia was significantly decreased following 5 min global incomplete cerebral ischemia in pentobarbitalized dogs. Although bilateral vagotomy in the cervical region decreased baroreflex sensitivity by about 50% in sham-operated animals, it hardly affected the baroreflex in animals subjected to ischemia. The extent of the decrease in the influence of vagotomy on the baroreflex was dependent on the severity of ischemia in the dorsal medulla oblongata. In animals vagotomized before ischemia, no significant decrease in baroreflex sensitivity was observed following ischemia. Pretreatment with ifenprodil or flunarizine, 1 mg/kg i.v., 5 min prior to ischemia prevented the post-ischemic decrease in baroreflex sensitivity. Vagotomy decreased baroreflex sensitivity during the reperfusion period in these treated animals. These results suggest that the post-ischemic attenuation of reflex bradycardia may be due to a selective dysfunction of the vagal component of baroreflex, which can be prevented by the cerebroprotective agents.

Topics: Animals; Blood Pressure; Brain Ischemia; Cerebrovascular Circulation; Dogs; Female; Flunarizine; Heart Rate; Male; Piperidines; Pressoreceptors; Reflex; Vagotomy; Vagus Nerve; Vasodilator Agents

To provide evidence to support the calcium hypothesis of cerebral ischemia, we examined the effects of extracellular calcium and calcium antagonists (verapamil, flunarizine, nicardipine) on in vitro 'ischemia' using guinea pig hippocampal slices. As a model of in vivo ischemia we used a state of both glucose and oxygen deprivation. Recovery of dentate antidromic field response and histological changes were used as indices of cell damage. After 10 min of deprivation in standard Krebs-Ringer solution, the field potentials exhibited minimum recovery and dentate neurons were severely damaged. Damaged neurons had pyknotic nuclei and swollen cytoplasms. Drugs were added and the calcium concentration was changed during 30 min of pre-deprivation and during deprivation. In the first experiment we demonstrated that pre-treated calcium antagonists protect the dentate granule cells against glucose and oxygen deprivation. The order of the protective potency was flunarizine greater than verapamil much greater than nicardipine. In the second experiment we also showed that neuronal damage caused by deprivation is dependent on the extracellular concentration of calcium. Our data show that extracellular calcium is partially responsible for 'ischemic' neuronal injury in the hippocampal slice. Both low calcium and voltage-gated calcium channel blockers can preserve an antidromic population spike. Conversely, high calcium in the bath can worsen the damage caused by in vitro 'ischemia' to hippocampal slices.

Topics: Action Potentials; Animals; Brain Ischemia; Calcium; Calcium Channel Blockers; Disease Models, Animal; Flunarizine; Glucose; Guinea Pigs; Hippocampus; Hypoxia, Brain; In Vitro Techniques; Male; Nicardipine; Verapamil

Cultured neurons of chick cerebral embryo hemispheres were used to study drug effects against neuronal damage caused by hypoxia during long-term recovery. Sodium cyanide (NaCN, 1 mmol/l) induces hypoxia-like conditions by inhibiting oxydative phosphorylation. The sensitivity of the cultured neurons against this type of hypoxia was determined after 3, 4, 5 and 6 days of cultivation followed by 4, 3, 2 days and 1 day of recovery, respectively. The ATP level and the viability of cells as well as the total cell number and the protein content of the cultures were used to characterize the extent of posthypoxic neuronal damage. A hypoxic period of 30 min after 4 days of cultivation followed by 3 days of recovery seemed to be appropriate for determining protective drug effects. The drug effects obtained were comparable to those from in vivo models of cerebral ischemia or hypoxia. The results suggest that cultured neurons exposed to hypoxia and to long-term recovery could be suitable for studying post-hypoxic neuronal damage as well as neuroprotective drug effects.

Topics: Adenosine Triphosphate; Animals; Anticonvulsants; Brain Ischemia; Cell Count; Cell Survival; Cells, Cultured; Chick Embryo; Clonazepam; Diazepam; Dibenzocycloheptenes; Dizocilpine Maleate; Flunarizine; Haloperidol; Imipramine; Ketamine; Lidocaine; Nafronyl; Neurons; Pyrithioxin; Telencephalon

One postulated final common pathway leading to neuronal death after hypoxic-ischemic insults is an increase in intracellular calcium concentrations. We examined the effect of pretreatment with flunarizine, a calcium channel antagonist known to pass the blood brain barrier, on the behavioral and histologic changes after an hypoxic-ischemic insult in the infant rat. The 21-d-old rats were subjected to unilateral carotid ligation, then to 2 h of hypoxia. They were pretreated with either flunarizine (30 mg/kg, intraperitoneally) or with an equal volume of diluent. After 5 days of observation they were killed for histology. Acute behavioral abnormalities were observed in more controls than treatment animals, 52 vs 11% (p less than 0.002). Cerebral injury was almost entirely confined to the ligated side and was significantly worse in the control rats. Full thickness cortical infarction was noted in 56% of controls (n = 27) vs 4% of flunarizine-treated rats (n = 24), (p less than 0.001). Mean and maximum damage scores for all areas assessed including cortex, corpus striatum, thalamus, amygdala, and hippocampus were improved markedly in treatment rats (p less than 0.005). These observations confirm that flunarizine, when given prophylactically, has a neuroprotective effect against hypoxic-ischemic injury in the developing brain.

Topics: Animals; Animals, Newborn; Brain Diseases; Brain Ischemia; Flunarizine; Hypoxia; Rats

Temporary cerebral ischemia (15 min) produced by "four-vessel occlusion" in the rat causes neurological disorders, changes in behavior (locomotor hyperactivity), and neuronal damage in the neocortex, striatum, and especially the CA1 zone of the hippocampus. We have studied the effects of two calcium overload blockers, flunarizine (50 mg/kg p.o. twice a day) and cinnarizine (100 mg/kg p.o. twice a day), on these alterations. Cinnarizine markedly improved the functional abnormalities of ischemia but had little or no effect upon the neuronal damage. In contrast, flunarizine provided far greater neuronal protection but with less obvious effects upon behavioral parameters. However, there was evidence of sedation 2 h after treating animals with this dose of flunarizine that might have masked any positive effect of the drug on behavior. We conclude that under the present experimental conditions, there is no correlation between the early and late behavioral changes observed following a temporary cerebral ischemic episode and the histological damage observed in certain vulnerable neurons, particularly in the hippocampus, 72 h after the insult.

Topics: Animals; Behavior, Animal; Brain; Brain Ischemia; Calcium; Cinnarizine; Flunarizine; Male; Motor Activity; Nervous System; Rats; Rats, Inbred Strains

The effects of flunarizine on local cerebral blood flow, cortical energy metabolism and neuronal necrosis were evaluated in a rat model of forebrain ischemia. The application of flunarizine (2 X 40 mg/kg p.o.) at 24 and 4 h before ischemia accelerated the restoration of cortical high-energy phosphates during early post-ischemic recirculation and also increased the flow in cortical but not in hippocampal areas. Neuronal necrosis was reduced in the hippocampal CA 1 sector but unchanged in the cortex. It is concluded that flunarizine reduces ischemic damage mainly via a direct effect on brain tissue.

Topics: Animals; Brain Ischemia; Cerebral Cortex; Cerebrovascular Circulation; Energy Metabolism; Flunarizine; Hippocampus; Male; Neurons; Phosphates; Rats; Rats, Inbred Strains

From 6 months of age on this girl experienced frequent episodes of hemiplegia involving both sides of the body and lasting up to 8 days. The attacks were often precipitated by tonic deviation of the head and/or the eyes to one side and nystagmus. At this stage the girl used to cry. Squinting, tonic stiffening of body and extremities, and dystonic posturing also occurred. Autonomic dysfunctions such as paleness of the skin, sweating, respiratory embarrassment, tachycardia, and mydriasis were associated features of the attacks. Motor and mental development of the girl is delayed. Improvement concerning severity, duration and frequency of the attacks has been achieved by permanent treatment with flunarizine in combination with acetazolamide and acetylsalicylic acid. If the child falls asleep immediately after rectal application of chloral hydrate at the onset of an attack there is no hemiplegia after awakening.

Topics: Acetazolamide; Aspirin; Brain Ischemia; Cerebral Cortex; Child, Preschool; Chloral Hydrate; Drug Therapy, Combination; Female; Flunarizine; Hemiplegia; Humans; Migraine Disorders; Tomography, Emission-Computed

Topics: Arterial Occlusive Diseases; Brain Ischemia; Child, Preschool; Female; Flunarizine; Humans; Moyamoya Disease

1. Morphological changes characterizing delayed neuronal death (DND) of selectively vulnerable CA1 pyramidal cells in the hippocampus of the Mongolian gerbil brain occurred 72 h after transient (5 min) bilateral occlusion of the common carotid arteries. 2. Different groups of animals were treated 15 min before carotid artery occlusion and twice daily during the 72 h post-ischaemia period with either saline alone, nicardipine, flunarizine, lidoflazine or nimodipine at doses of 500 micrograms kg-1 intraperitoneally. 3. At 72 h the animals were killed and their brains examined histologically. Absolute cell counts were made from 5 sites distributed linearly throughout the hippocampal CA1 subfield in each hemisphere to determine the percentage DND in each group. Normal brains and those of sham-operated animals were included in the study for comparison. 4. Features of DND were distributed evenly throughout the CA1 subfield in both hemispheres in all groups of gerbils. Nicardipine, lidoflazine and flunarizine, but not nimodipine, were protective. This protection extended linearly throughout the hippocampus without altering the pattern of neuronal damage. 5. Compared to saline-treated (78.3 +/- 2.9% DND) and nimodipine-treated (76.5 +/- 3.4% DND) gerbils, the overall protection afforded by nicardipine (41.8 +/- 3.8% DND) was statistically significant. The effects of lidoflazine (53.6 +/- 7.1%) and flunarizine (55.8 +/- 3.9% DND) were of borderline significance. 6. Abnormal neurones appeared in normal and sham-operated brains to the extent of 4.5 +/- 1.0% and 4.6 +/- 0.4%, respectively. Such changes can be attributed to fixation artefacts. 7. The results demonstrate that overall protection is conferred on ischaemic hippocampal CA1 neurones by nicardipine and to a lesser extent by flunarizine and lidoflazine, but not by nimodipine.

Topics: Animals; Brain Ischemia; Calcium Channel Blockers; Cerebrovascular Circulation; Female; Flunarizine; Gerbillinae; Hippocampus; Lidoflazine; Male; Nicardipine; Nimodipine

The effects of flunarizine, a calcium antagonist, were evaluated in an experimental model of global brain ischemia produced by 15 min of cardiac arrest followed by resuscitation and reperfusion. One group of dogs received flunarizine (0.1 mg/kg intravenously during a 10-min period) at the onset of resuscitation. Another group of dogs underwent cardiac arrest, resuscitation, and reperfusion but did not receive flunarizine. A third group served as nonischemic control. In situ-fixed brains of all animals (nonischemic controls and the postischemic dogs after 8 h of reperfusion) were examined for anoxic ischemic injury. Quantitation of the ischemic neurons was carried out in parietal cortex, hippocampus, and cerebellum by using an image analysis system. Significant difference in the number of necrotic neurons between the flunarizine-treated group and the ischemic controls was noted in the hippocampus only; the mean percentage of necrotic neurons in the two groups being 14.8 +/- 9.6 and 29.3 +/- 12.1, respectively (P less than 0.05). These results indicate that flunarizine has an ameliorating effect on neuronal injury in the hippocampus that follows cardiac arrest in this experimental model of global brain ischemia. However, flunarizine was not found to be effective in reducing the ischemic neuronal damage in the cortex or the cerebellum.

Topics: Animals; Brain; Brain Ischemia; Dogs; Flunarizine; Heart Arrest, Induced

Topics: Animals; Brain Ischemia; Cats; Cerebral Angiography; Cerebral Arteries; Cerebrovascular Circulation; Constriction; Flunarizine; Fluorescein Angiography; Humans

Recently there is the hypothesis proposing that ischemic brain damage is associated with intracellular accumulation of calcium (Ca++). Therefore a variety of experiments have been carried out to investigate whether a Ca++-entry blocker was able to protect against brain damage caused by ischemia. The purpose of the present experiment is to study the protective effects of a Ca++ antagonist, flunarizine, on cerebral ischemia. In this experiment fifteen dogs were subjected to ischemia, using the "canine model of the completely ischemic brain regulated with a perfusion method" in which the cerebral blood flow (CBF) can be fully regulated. Five animals served as untreated controls, ten received treatment with flunarizine (1 mg/kg in five dogs and 3 mg/kg in five dogs, respectively). This agent was administered intravenously 20 minutes prior to the production of ischemia, when cerebral blood flow was reduced to one-tenth its normal value while monitoring CBF by means of a laser-Doppler flow meter. After one hour CBF was restored and the recovery of electrical activity of the brain and the degree of brain swelling were observed for three hours. At the end of the experiments, the degree of extravasation of Evans blue in the excised brain was examined. With regard to the recovery of EEG, no recovery of EEG was seen subsequent to recirculation except one dog in the control group. Whereas in the groups treated with flunarizine, remarkable recovery of EEG was found following recirculation in a dose dependent fasion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain Ischemia; Calcium Channel Blockers; Dogs; Electroencephalography; Flunarizine

Topics: Animals; Brain Ischemia; Calcium; Calcium Channel Blockers; Cinnarizine; Flunarizine; Humans; Ion Channels

Topics: Brain Ischemia; Calcium Channel Blockers; Cerebrovascular Circulation; Cinnarizine; Flunarizine; Humans

Alterations of regional cerebral blood flow (rCBF) are at least epiphenomena of common and complicated migraine, but may lead to serious clinical complications. Since flunarizine seems to be effective in migraine prevention it may exert a beneficial influence on rCBF in migraine as well. rCBF was assessed using the 133Xe inhalation method in 5 patients with common and 8 patients with complicated migraine. Measurements were done interictally prior and after therapy with 15 mg flunarizine p.o. daily over a period of 4 weeks. Major abnormalities of grey matter flow were observed even interictally. Significant improvement of rCBF in initially hypoemic regions may be attributed to flunarizine therapy. These preliminary data suggest that calcium entry blockers may prevent the ischemic complications of migraine.

Topics: Brain; Brain Ischemia; Carbon Dioxide; Flunarizine; Humans; Migraine Disorders; Prospective Studies; Regional Blood Flow

In dogs global cerebral ischemia was produced by clamping reversibly the left subclavian and brachiocephalic arteries, supplying the head. The intercostal arteries were ligated permanently. Cerebral blood flow (CBF) was measured discontinuously using a hydrogen saturation-desaturation technique. Clamping of the former two vessels caused an increase in systemic blood pressure. When this increase was not blunted by previous splenectomy and blood withdrawal a still important CBF remained during the clamp. However, if this rise in blood pressure was impaired, CBF decreased to 9 +/- 8% (mean +/- S.D., n = 14) of the pre-ischemic value. Flunarizine is known to have anti-hypoxic/ischemic properties. The influence of this drug (0.1 mg/kg i.v.), injected 10 min after the beginning of a 30-min ischemia period, on the post-ischemic CBF was investigated. Two-three hour after ischemia CBF was significantly lower in the solvent-treated animals than in the flunarizine-treated group, in which CBF approached the preischemic values. Changes in CBF were also followed continuously by measurement of the variations of brain versus aortic temperature. It was analyzed what information this can provide on CBF.

Topics: Animals; Body Temperature; Brain Ischemia; Cerebral Cortex; Cerebrovascular Circulation; Cinnarizine; Dogs; Female; Flunarizine; Hydrogen; Male; Potassium Chloride; Time Factors

Acute ischemia of the brain induces a cascade of biochemical and physiological events. The final consequences depend on the fact whether ischemia is of transient or permanent, total or partial nature. Alteration of extracellular potassium concentration, intracellular calcium and potassium concentration, development of cytotoxic and vasogenic edema, postischemic hyperfusion and no-reflow phenomenon are important factors which decide about the final fate of functional capacity. CO2 reactivity, autoregulation and hemorheology must be considered when therapeutic approaches are used to influence basic flow during ischemic condition. At present there exists no therapy which has been fully accepted and is able to guarantee benefit to the hypoperfused tissue. Since the calcium metabolism is altered by ischemic processes, substances which act on this metabolism might be of value in the treatment of ischemia and its consequences. However, their beneficial effect on cerebral infarction has not been proven yet. In subarachnoid hemorrhage and migraine calcium antagonists are used to prevent and treat ischemia. In epilepsia calcium overload blockers have been tried by one group with promising results.

Topics: Acute Disease; Brain Edema; Brain Ischemia; Calcium Channel Blockers; Cerebrovascular Disorders; Epilepsy; Flunarizine; Humans; Migraine Disorders; Rheology; Subarachnoid Hemorrhage

The effects of flunarizine, a calcium entry blocker, were evaluated in a long-term survival model of ischemia in rats. One group of animals received the drug orally at 24 and 4 h prior to the insult (40 mg X kg-1 X dose-1). Another group was given flunarizine following the insult, intravenously at 5 min (0.1 mg X kg-1), and orally at 8 and 24 h (40 mg X kg-1 X dose-1). A third group received the solvent for the oral suspension on the same schedule as the pretreated group. Six animals from each group were subjected to 9 min ischemia and recovery of 7 days, at which time the brains were harvested for histologic study. In another six animals from each group, cortical metabolites and fatty acids were determined during early recirculation. Local cerebral blood flow was measured at 60 min recirculation in a third set of animals. Flunarizine significantly improved histological outcome (fewer irreversibly damaged cells) in both treatment groups. This amelioration was not related to improvement of cerebral blood flow during the period of delayed hypoperfusion, nor the postischemic levels of high-energy phosphates or free fatty acids.

Topics: Animals; Brain; Brain Ischemia; Calcium Channel Blockers; Cerebrovascular Circulation; Cinnarizine; Fatty Acids, Nonesterified; Flunarizine; Male; Mathematics; Rats; Regional Blood Flow; Time Factors

The effect of flunarizine, a calcium entry blocker, on ischaemic damage was investigated using a new model of forebrain ischaemia. Fasted rats were subjected to nine minutes ischaemia and one week recovery. One group served as control; a second was pretreated orally with flunarizine; a third group received postischaemic flunarizine treatment. Focussing on the hippocampus, an area of high susceptibility to ischaemic damage, we report that flunarizine treatment significantly reduced neuronal necrosis. Importantly, the amelioration of necrosis was also observed when flunarizine was administered 5 min following resumption of cerebral perfusion.

Topics: Animals; Brain Ischemia; Cinnarizine; Flunarizine; Hippocampus; Male; Piperazines; Rats; Rats, Inbred Strains

Two animal models were used for the morphologic study of hypoxic or ischemic cerebral injury. In the first model ("Levine preparation") rats were subjected to a unilateral carotid artery ligation, followed by intermittent exposure to pure nitrogen. Damage, which was examined 24 h after this bypoxic insult, was largely restricted to the ipsilateral cerebral cortex. In the second model ("Pulsinelli preparation") severe bilateral transient ischemia was induced by permanent occlusion of both vertebral arteries, followed by temporary ligation of both carotid arteries. Damage was examined after short recirculation times and after a 3-day survival period. Injury was largely confined to the CA1 layer of the hippocampus. In both experimental models two types of cell change were prominent: coagulative cell change which was restricted to neurons, and edematous cell change which was largely confined to astrocytes. Studies on cerebral microcirculation revealed a close relationship between areas of reduced flow and areas with structural damage. Cytochemical demonstration of subcellular calcium indicated an early and important redistribution of this cation, indicative for toxic calcium overload in the cytosol. Data on therapeutic intervention with Ca2+-overload blocker flunarizine are included.

Topics: Animals; Astrocytes; Brain; Brain Ischemia; Calcium; Calcium Channel Blockers; Cinnarizine; Flunarizine; Hypoxia, Brain; Neurons; Rats

Topics: Animals; Body Temperature; Brain; Brain Ischemia; Calcium Channel Blockers; Cinnarizine; Computers; Dogs; Electroencephalography; Etomidate; Female; Flunarizine; Imidazoles; Male; Pentobarbital; Piperazines; Thiopental

Topics: Animals; Blood Glucose; Brain Ischemia; Calcium; Calcium Channel Blockers; Cats; Cerebrovascular Circulation; Cinnarizine; Electroencephalography; Energy Metabolism; Evoked Potentials; Female; Flunarizine; Male

Energy depletion and lactate are at plateau levels within five minutes of complete ischemic-anoxia in the brain; however, irreversible brain injury has not occurred in this time. Brain free fatty acids (FFA) rise sharply during the first five minutes of ischemic-anoxia, but then continue to rise during the following hour without plateauing. Barbiturate anesthesia preischemia attenuates the FFA rise. Other agents which also attenuate the FFA increase include, among others, phenytoin and Innovar. The Ca2+ antagonists flunarizine and gallopamil also attenuated FFA rise, but were not as effective as pentobarbital during ischemia. Protective effects of Ca2+ antagonists may be more important during recirculation than during ischemia.

Topics: Animals; Brain Ischemia; Cinnarizine; Fatty Acids, Nonesterified; Flunarizine; Gallopamil; Hypoxia, Brain; Pentobarbital; Rodentia; Sodium Chloride

The protective effect of flunarizine against cerebral cortical damage was evaluated in the "Levine preparation" after 24 hr of a combined hypoxic-ischaemic insult. Ligation of the right carotid artery, followed by intermittent exposure of the rats to pure nitrogen resulted in two major types of cellular damage in the ipsilateral hemisphere: coagulative necrosis of neurones (ischaemic cell change) and extreme cellular swelling (severe cell change). Quantification of the degree of damage was obtained by calculating the number of both types of cell change per mm3 of cortex. Flunarizine given orally at doses of 20 mg/kg and 10 mg/kg 5 hr before mild hypoxia and at doses of 40 mg/kg and 10 mg/kg 5 hr before severe hypoxia, led to a significant reduction of ischaemic and severe cell change. The calcium entry blocking properties of flunarizine are held responsible for these beneficial effects.

Topics: Animals; Brain; Brain Ischemia; Calcium; Calcium Channel Blockers; Cerebral Cortex; Cinnarizine; Flunarizine; Hypoxia, Brain; Male; Piperazines; Rats; Rats, Inbred Strains

Topics: Aged; Brain Ischemia; Cerebrovascular Disorders; Cinnarizine; Female; Flunarizine; Humans; Male; Piperazines; Vasodilator Agents