flunarizine and Ischemic-Attack--Transient

Topics: Animals; Anticonvulsants; Brain; Calcium Channel Blockers; Cerebral Infarction; Disease Models, Animal; Fatty Acids, Nonesterified; Flunarizine; Humans; Intracranial Aneurysm; Ischemic Attack, Transient; Nimodipine; Piperazines; Verapamil

Twenty-six patients with acute supratentorial brain infarction were randomly allocated to double-blind intravenous treatment with the calcium entry blocker flunarizine (12 patients) or placebo (14 patients) within 24 h. CT scan excluded other significant pathology. Impaired consciousness and gaze deviation were more common in the placebo group. Three patients in the treated group (25%) were either dead or severely disabled after 6 months, whereas this occurred in 8 of the 14 (57%) control patients, a difference of 32%. This difference is not statistically significant and there is an uneven distribution of important prognostic variables, however, the confidence limits of the difference (-4% and +68%) suggest that there may be a clinically important effect.

Topics: Aged; Aged, 80 and over; Calcium Channel Blockers; Cerebrovascular Disorders; Double-Blind Method; Female; Flunarizine; Humans; Ischemic Attack, Transient; Male; Middle Aged

This study was designed to examine the function of cellular prion protein and prion protein-like protein/Doppel, in transient ischemia-related neuronal death in the hippocampus. Two different lines of mice devoid of cellular prion protein, Zrch I Prnp(0/0) and Ngsk Prnp(0/0), were used. The former lacks cellular prion protein whereas the latter ectopically expresses prion protein-like protein/Doppel in the brain in the absence of cellular prion protein. Mice were subjected to 10 min-occlusion of the bilateral common carotid arteries with recovery for 14 days. Less than 10% of the pyramidal neurons in the CA1 subfield were degenerated in male and female wild-type mice. In contrast, more than half of the neurons were lost in male Zrch I Prnp(0/0) and Ngsk Prnp(0/0) mice. Such severe neuronal loss was also observed in female Ngsk Prnp(0/0) mice. However, female Zrch I Prnp(0/0) mice showed mild neuronal loss similar to wild-type mice. Flunarizine, a T- and L-type Ca(2+)-channel antagonist, significantly reduced the neuronal loss in female but not in male Ngsk Prnp(0/0) mice. These results indicate that loss of cellular prion protein renders hippocampal neurons susceptible to ischemic insult specifically in male but not female mice and the ectopic expression of prion protein-like protein/Doppel aggravates the ischemic neuronal death in female prion protein-null mice probably via overloading of Ca(2+)-dependent signaling.

Topics: Amyloid; Animals; Brain; Calcium Channel Blockers; Cell Death; Estradiol; Female; Flunarizine; GPI-Linked Proteins; Hippocampus; In Situ Nick-End Labeling; Ischemic Attack, Transient; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Neuroprotective Agents; Prion Proteins; Prions; Protein Precursors; Sex Characteristics

A series of novel arylpiperidines (4a-d) which have highly potent blocking effects for both neuronal Na+ and T-type Ca2+ channels with extremely low affinity for dopamine D2 receptors were synthesized. Among these compounds, 1-(2-hydroxy-3-phenoxy)propyl-4-(4-phenoxyphenyl)-piperidine hydrochloride (4c; SUN N5030) exhibited remarkable neuroprotective activity in a transient middle cerebral artery occlusion (MCAO) model.

Topics: Animals; Anticonvulsants; Calcium Channel Blockers; Calcium Channels, T-Type; Epilepsy, Reflex; Ischemic Attack, Transient; Mice; Mice, Inbred DBA; Neuroprotective Agents; Phenyl Ethers; Piperidines; Sodium Channel Blockers

Vestibular symptoms frequently occur in patients with migraine headache. The common migraine is defined in neurology as a unilateral, pulsating headache, which may be associated with nausea and vomiting, and lasts one or several days. In the classic form patients have visual prodromal symptoms. Focal neurological signs in the migraine complique include, for example, oculomotor palsy and vestibular abnormalities. This so-called vestibular migraine is different from basilar migraine, which involves the irritation of the cervical sympathetic system, and can cause symptoms that resemble transient brainstem ischemia. In order to evaluate vestibular dysfunction electronystagmography (ENG) was used. Patients frequently had abnormal caloric test responses, especially with a directional preponderance, and most had a spontaneous nystagmus. In the migraine attack the patients are presumed to have hypersensitivity of the labyrinth with nausea and vomiting, while in the headache-free period the ENG was almost normal. At present, we have had a high success rate in treating patients with pyracetam. Diazepam was used to treat basilar migraine and flunarizine to prevent vestibular migraine.

Topics: Adolescent; Adult; Aged; Basilar Artery; Calcium Channel Blockers; Caloric Tests; Child; Diazepam; Ear, Inner; Electronystagmography; Female; Flunarizine; Hearing Loss, Sensorineural; Humans; Ischemic Attack, Transient; Male; Middle Aged; Migraine Disorders; Muscle Relaxants, Central; Nausea; Neuroprotective Agents; Nystagmus, Pathologic; Ophthalmoplegia; Piracetam; Sympathetic Nervous System; Vestibular Diseases; Vomiting

Topics: Animals; Animals, Newborn; Brain; Brain Injuries; Electroencephalography; Fetal Diseases; Flunarizine; G(M1) Ganglioside; gamma-Aminobutyric Acid; Glutamic Acid; Glycine; Ischemic Attack, Transient; Microdialysis; Neuroprotective Agents; Sheep; Spectrophotometry, Infrared

A patient with unusual alternating hemiplegia in childhood is reported. The frequency of hemiplegic episodes was lower than that in other reported patients. Interictal positron emission tomography revealed decreased cerebral blood flow in the left hemisphere. After cerebral angiography, postanesthetic irritability occurred which evolved into coma with hemiplegic episodes. We believe that cerebral angiography in a child with alternating hemiplegia may cause hemiplegic episodes and coma. The episodes disappeared almost completely for 6 years after treatment with flunarizine, thus indicating the benefit of the medication for the treatment of alternating hemiplegia.

Topics: Basal Ganglia; Cerebral Angiography; Cerebral Cortex; Child; Coma; Dominance, Cerebral; Electroencephalography; Epilepsy, Tonic-Clonic; Female; Flunarizine; Follow-Up Studies; Hemiplegia; Humans; Ischemic Attack, Transient; Recurrence; Regional Blood Flow; Status Epilepticus; Tomography, Emission-Computed

In baboons with or without regional cerebral ischaemia (achieved by transorbital clip of the middle cerebral artery), cerebral blood flow (CBF) was measured using the intra-arterial Xenon-133 technique during steady-state, slight hypotension, and hypocapnia before and after administration of various doses of the calcium antagonist flunarizine (0.5 mg kg-1, 1.0 mg kg-1, or 10 micrograms kg-1 min-1 over 30 min). In normal baboons flunarizine did not alter CBF significantly, but at reduced blood pressure it increased CBF by 19.9% owing to exaggerated vasodilatory autoregulation. During hypocapnia flunarizine impaired the physiological reduction in CBF owing to reduced vasoconstriction. In baboons with cerebral ischaemia, CBF measurements were stable and comparable with those in a control group using an arterial clip unless flunarizine was added. In a group of five flunarizine-treated animals, mean CBF after positioning of the clip was higher than in the control group. However, the increase in mean CBF varied significantly between animals, indicating that a secondary reduction in CBF due to postischaemic pathophysiological processes was not prevented consistently.

Topics: Animals; Cerebrovascular Circulation; Female; Flunarizine; Ischemic Attack, Transient; Male; Papio

Pretreatment with MK-801 (an NMDA antagonist) or pentobarbital (a GABAA receptor-effector) ameliorated histopathological neuronal damage to the hippocampal CA1 subfield and to the thalamus following three 2-min forebrain ischemia at 1-h intervals in the gerbil. Flunarizine, a calcium antagonist, failed to prevent the neuronal damage. The results suggest that the excitotoxic mechanism plays a role in the neuronal damage following repeated ischemia.

Topics: Animals; Dibenzocycloheptenes; Dizocilpine Maleate; Flunarizine; Gerbillinae; Ischemic Attack, Transient; Male; Pentobarbital; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter

We studied the protective effects of pentobarbital, vinpocetine, flunarizine, and ifenprodil on delayed neuronal death using Mongolian gerbils. The animals were allowed to survive for 7 days after 5 min of cerebral ischemia induced by bilateral occlusion of the common carotid arteries. Hippocampal cell loss was quantified histologically 7 days following ischemia. Intraperitoneal application of pentobarbital (40 mg/kg) 30 min and vinpocetine (50 and 100 mg/kg) 10 min before ischemia significantly reduced neuronal cell loss in the CA1 sector. However, the intraperitoneal administration of flunarizine (10 and 30 mg/kg) and ifenprodil (10 and 30 mg/kg) 15 min before ischemia was not protective. The results suggest that pentobarbital and vinpocetine prevent ischemic neuronal damage, but not flunarizine and ifenprodil. These findings are of interest in relation to the mechanism of delayed neuronal death.

Topics: Animals; Cell Survival; Flunarizine; Gerbillinae; Hippocampus; Ischemic Attack, Transient; Male; Neurons; Pentobarbital; Piperidines; Vinca Alkaloids

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.

Topics: Adult; Aged; Aged, 80 and over; Calcium Channel Blockers; Female; Flunarizine; Humans; Ischemic Attack, Transient; Male; Middle Aged; Subarachnoid Hemorrhage

Isolated perfused rat brains were subjected to complete ischemia. Reperfusion was started 10 min after the negative DC-shift. In control brains, recovery of flow was retarded and, after 10 min of reperfusion, a delayed hypoperfusion developed. In flunarizine-treated brains, recovery of flow was considerably steeper, complete and without reduction during the further course of reperfusion. Additionally, restoration of energy metabolism and mitochondrial function was significantly improved. The effect on the energetic state of the brains was at least partly independent of the improvement of flow. This could be concluded from experiments in which reperfusion was commenced simultaneously with DC-negativation. In these experiments, flow recovery was prompt and complete in control as well as in treated brains. Nevertheless, treated brains exhibited after reperfusion significantly better ratios of ATP to ADP and normalized levels of lactate and succinate.

Topics: Animals; Cerebrovascular Circulation; Energy Metabolism; Flunarizine; In Vitro Techniques; Ischemic Attack, Transient; Perfusion; Rats; Reference Values; Reperfusion

Baroreflex sensitivity assessed by phenylephrine-induced reflex bradycardia was markedly decreased by 5- an 10-min global cerebral ischemia in anesthetized dogs. Flunarizine, 0.1 and 1 mg/kg i.v., administered 5 min prior to 5-min ischemia, completely inhibited the decrease in baroreflex sensitivity while such a protective effect of the latter dose was incomplete against 10-min ischemia. In contrast, papaverine, 0.5 mg/kg per min i.v., infused for 5 min prior to 5-min ischemia, failed to protect the decrease in baroreflex sensitivity. Flunarizine may possess a certain direct cerebroprotective effect in addition to its cerebrocirculatory effect.

Topics: Animals; Blood Pressure; Cerebrovascular Disorders; Dogs; Dose-Response Relationship, Drug; Female; Flunarizine; Heart Rate; Ischemic Attack, Transient; Male; Papaverine; Pressoreceptors; Reflex

The present study was initiated to determine whether pretreatment of gerbils with calcium channel blockers, flunarizine and verapamil would prevent injury to cerebral ATPases following secondary ischemia consisting of 60-min bilateral clamping of the carotids followed by 40 min of reperfusion. The sequence of ischemia produced a deficit in Na+,K+-ATPase activity without influencing Ca++,Mg++- or Mn++-sensitive ATPases. Pretreatment with flunarizine significantly prevented the damage to Na+,K+-ATPase while the effect of verapamil was marginal. Verapamil, along with dimethylsulfoxide (DMSO), reduced the mortality rate of gerbils subjected to the paradigm of ischemia. When added directly to the cerebral fractions in vitro the two calcium channel blockers inhibited Na+,K+-ATPase alone. Flunarizine was more potent in vitro than verapamil.

Topics: Animals; Calcium Channel Blockers; Cerebral Cortex; Female; Flunarizine; Gerbillinae; In Vitro Techniques; Ischemic Attack, Transient; Sodium-Potassium-Exchanging ATPase; Verapamil

To test the effect of flunarizine on cerebral ischaemia, 15 dogs were subjected to ischaemia, using the 'canine model of the completely ischaemic brain regulated with a perfusion method' in which the cerebral blood flow (CBF) can be fully regulated. Five animals served as untreated controls, 10 received flunarizine, a calcium antagonist (1 mg/kg in 5 dogs and 3 mg/kg in 5 dogs), before the ischaemic period. After 1 h CBF was restored and recovery of the electrical activity of the brain and the degree of brain swelling were observed for 3 h. At the end of the experiments, the degree of extravasation of Evans blue was examined. Remarkable recovery of EEG was found in the groups given flunarizine when compared with untreated controls. However, no significant difference was found between untreated controls and flunarizine treated groups for the degree of brain swelling and the degree of extravasation of Evans blue. These results suggest that the treatment of flunarizine is of benefit for functional recovery against cerebral ischaemia, but does not suppress ischaemic brain oedema.

Topics: Animals; Calcium Channel Blockers; Dogs; Dose-Response Relationship, Drug; Electroencephalography; Flunarizine; Ischemic Attack, Transient

Local cerebral blood flow (lCBF) was measured autoradiographically 60 min after 15 min of forebrain ischaemia in rats treated with flunarizine (0.1 mg/kg b.w.), lidoflazine (1.0 mg/kg b.w.) or Mg2+ (600 mumol/kg b.w.) before or at the end of the ischaemic period. Incomplete forebrain ischaemia was produced by a combination of common carotid artery occlusion and bleeding to a mean arterial blood pressure of 50 mmHg. During ischaemia lCBFs in cortical areas were less than 1% of preischaemic values. Neither flunarizine, lidoflazine nor Mg2+ influenced lCBF during ischaemia. Sixty minutes after the start of recirculation lCBFs were decreased to between 40 and 60% of the values found in control animals. None of the instituted treatments improved postischaemic cerebral blood flow. The results do not lend support to the view that calcium plays an essential role in the pathogenesis of delayed postischaemic hypoperfusion in the brain in this model.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Circulation; Flunarizine; Frontal Lobe; Heart Rate; Ischemic Attack, Transient; Lidoflazine; Magnesium; Male; Piperazines; Rats; Rats, Inbred Strains

It has been previously established that prolonged bilateral carotid occlusion followed by recirculation produces damage to the synaptic enzyme adenylate cyclase in the frontal cortex of the gerbil. Since calcium entrance into the brain may account in part for the deleterious consequences of stroke, the present study examined whether pretreatment with calcium channel blockers would modify the effects of 60 min of bilateral ischemia plus 40 min of reflow on various parameters of cortical adenylate cyclase activation. In this context activation of cerebral homogenates by norepinephrine with or without 5'-guanylyl imidodiphosphate was preserved by pretreatment of ischemic gerbils with verapamil but worsened by flunarizine. In contrast, in particulate fractions (treated with EGTA to reduce metallic ion levels) the damage to the Mn2+-sensitive catalytic site of adenylate cyclase was prevented only by flunarizine. Pretreatment with the two calcium channel blockers resulted in an elevated basal activity of the enzyme, thereby reducing the response in the homogenate preparation to forskolin. Gerbils pretreated with verapamil tended to have an increased ability for survival resulting from the ischemic episode. Under in vitro conditions the enzyme preparations were not markedly influenced by either drug.

Topics: Adenylyl Cyclases; Animals; Calcium Channel Blockers; Disease Models, Animal; Female; Flunarizine; Gerbillinae; Ischemic Attack, Transient; Manganese; Verapamil

In order to study the role of platelets in migraine and cerebrovascular disease, beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) plasma levels, indices of in vivo platelet activation, were assayed in two groups of patients suffering from migraine (common/classic and classic/complicated migraine, respectively) and in one group suffering from transitory ischemic attacks (TIAs). Plasma determinations were carried out in the absence of treatment and during the administration of aspirin (50 mg/daily) and flunarizine (10 mg/daily). Platelet activation was found in patients suffering from TIA; patients affected by classic and complicated migraine showed a high incidence of activation, in comparison with common migraine sufferers, also in headache-free periods. Administration of aspirin (ASA) was more effective than flunarizine in inducing a decrease in beta-TG and PF4 plasma levels in migraineurs. Aspirin, however, did not affect platelet activation in subjects suffering from ischemic attack even though we did not observe any relapse after one year of treatment. The different effect of ASA in TIAs and migraine indicates that the platelet activation in TIA patients is due not only to cyclo-oxygenase pathway but also to other in vivo pathways.

Topics: Adult; Aged; Aspirin; beta-Thromboglobulin; Cinnarizine; Female; Flunarizine; Humans; Ischemic Attack, Transient; Male; Middle Aged; Migraine Disorders; Piperazines; Platelet Aggregation; Platelet Factor 4; Vasodilator Agents

Topics: Animals; Brain; Calcium; Cinnarizine; Dogs; Flunarizine; Hypoxia, Brain; Ischemic Attack, Transient; Muscle, Smooth