cinnarizine and Brain-Ischemia

The efficacy of combined medication which comprised compounds with nootropic (piracetam) and vasoactive (cinnarisin) effects, was studied in patients with cerebral blood flow insufficiency. The main inclusion criterion was a diagnosis of chronic brain ischemia (CI). The study consisted of two stages: (1) a randomized comparative trial in neurological clinic (60 patients) and (2) estimation of the drug efficacy in routine practice (60 patients). The clinical examination was accompanied by neuropsychological tasks, kinetic tests and ultrasound investigation of brain vessels. At the first stage, a positive neurological and neuropsychological dynamics was found after 8 weeks of phezam treatment. Also a statistically significant positive dynamics was observed for a number of blood flow velocity parameters in the middle brain artery. In routine medical practice, a positive effect of phezam was seen after 2 months of the treatment for all but CI main symptoms and confirmed by the data of kinetic investigation. The patients reported good tolerability and convenience of the drug intake (one capsule instead of two tablets of nootropic and vasoactive drugs).

Topics: Aged; Brain; Brain Ischemia; Calcium Channel Blockers; Cerebrovascular Circulation; Chronic Disease; Cinnarizine; Drug Combinations; Female; Humans; Male; Middle Aged; Nootropic Agents; Piracetam

Topics: Brain Ischemia; Cerebral Hemorrhage; Cerebral Infarction; Cinnarizine; Diagnosis, Differential; Electroencephalography; Flicker Fusion; Humans; Reaction Time; Tomography, X-Ray Computed; Ultrasonography; Vincamine; Visual Fields; Xenon Radioisotopes

With the purpose to define the specific activity of substances acting on the cerebral circulation and metabolism, (-)eburnamonine and cinnarizine were compared in a double-blind study carried out in a group of 106 elderly patients suffering from established chronic brain ischemia. The photoscintigraphic and rheoencephalographic studies carried out on some of the patients showed that only (-)eburnamonine had a clear-cut activity on brain circulation. (-)Eburnamonine also showed an activity on kidney circulation. With regard to the clinical picture, a statistical evaluation of the results obtained showed that both drugs improve psychic disturbances and the overall clinical picture. Cinnarizine appears to influence, to a slightly greater extent, some neurological symptoms, while (-)eburnamonine exerts a significantly better action on daily living activities and general psychic efficiency.

Topics: Aged; Brain; Brain Ischemia; Cerebrovascular Circulation; Chronic Disease; Cinnarizine; Clinical Trials as Topic; Double-Blind Method; Drug Evaluation; Female; Humans; Male; Piperazines; Placebos; Vasodilator Agents; Vinca Alkaloids

Topics: Administration, Oral; Atherosclerosis; Brain Ischemia; Calcium Channel Blockers; Carotid Arteries; Cerebrovascular Circulation; Chronic Disease; Cinnarizine; Drug Combinations; Drug Synergism; Female; Follow-Up Studies; Humans; Intracranial Arteriosclerosis; Magnetic Resonance Imaging; Male; Middle Aged; Neuroprotective Agents; Piracetam; Recovery of Function; Treatment Outcome; Ultrasonography, Doppler; Vertebral Artery

Topics: Administration, Oral; Blood Flow Velocity; Brain Ischemia; Cerebral Arteries; Cerebrovascular Circulation; Cinnarizine; Cognition; Drug Combinations; Follow-Up Studies; Humans; Middle Aged; Piracetam; Severity of Illness Index; Treatment Outcome; Ultrasonography, Doppler, Transcranial

The aim of the present work was to perform a morphological assessment of the cerebroprotective action of lanthanum acetate in chronic cerebral ischemia in rats. Chronic ischemia was produced in Wistar rats (weighing 160-180 g) by ligation of both common carotid arteries. Ischemic lesions were corrected by intragastric lanthanum acetate (3 mg/kg per day) throughout the experimental period. Ischemic damage to the cortex was assessed morphometrically on histological sections stained by the Nissl method. Lanthanum acetate was found to suppress the development of ischemic neuron damage in the cerebral cortex, with reductions in the numbers of hyperchromic neurons, cells with focal chromatolysis, and ghost cells, as well as an increase in the number of normochromic cells as compared with controls.

Topics: Acetates; Animals; Brain Ischemia; Calcium Channel Blockers; Chronic Disease; Cinnarizine; Female; Lanthanum; Male; Neurons; Neuroprotective Agents; Rats; Rats, Wistar

To explore the relations between anti-apoptotic role of dipfluzine (DIP) and the death signaling transduction pathway initiated by CD95 molecules, and the transcription factor involved in the transcription regulation of CD95 molecules in the hippocampal CA1 region after transient forebrain ischemia.. The rat forebrain transient ischemia model was established through 15 min ischemia followed by 3 days reperfusion by using the four-vessel method. The rats were divided randomly into five groups: sham control group, ischemia/reperfusion (I/R) group, DIP treated groups (20, 40 and 80 mg x kg(-1) body weight, ig, separately). Western blotting and RT-PCR were performed to detect the expression changes of Fas, FasL, caspase 10 p20, caspase 8, I-kappaB-alpha, and p-I-kappaB-alpha molecules in protein and mRNA levels, separately, and immunohistochemistry for molecular localization of Fas and FasL in rat hippocampus.. The expression of Fas, FasL, and caspase 10 p20 in protein and mRNA levels increased after I/R, which was inhibited significantly after treatment with 20 and 40 mg x kg(-1) of DIP (P < 0.01). In 80 mg x kg(-1) of DIP group, the expression of Fas and FasL protein was not significantly different from that of I/R group (P > 0.05). The expression of caspase 8 and I-kappaB-alpha showed no significant differences in all groups (P > 0.05), and no gene expression was observed for p-I-kappaB-alpha protein in the study. DIP significantly affected molecular distribution of Fas and FasL protein in CA1 subregion of hippocampus.. DIP inhibits the death signaling transduction pathway initiated by CD95 molecules in rat hippocampal CA1 subregion, and NF-kappaB transcription factor may not be involved in the transcription regulation of CD95 molecules after transient forebrain ischemia.

Topics: Animals; Apoptosis; Brain Ischemia; Calcium Channel Blockers; Cinnarizine; Fas Ligand Protein; fas Receptor; Female; Hippocampus; Membrane Glycoproteins; Neurons; NF-kappa B; Rats; Rats, Sprague-Dawley; Reperfusion Injury; RNA, Messenger; Signal Transduction; Tumor Necrosis Factors

To evaluate the effects of dipfluzine on the expressions of E-selectin, P-selectin, and ICAM-1 and the infiltration of polymorphonuclear leukocytes in brain ischemia-reperfusion rats.. The model of focal cerebral ischemia was established with the Zea-Longa occluding suture. Dipfluzine (0.25, 0.5 and 1 mg x kg(-1)), flunarizine 0.5 mg x kg(-1) and solvent were injected separately into lingual vein at 30 min after ischemia. The occluding suture was slowly taken away to cause reperfusion at 1 h after ischemia. Rats were decapitated under anesthesia at 24 h after ischemia-reperfusion and brains were immediately removed to do the following procedures. Effects of dipfluzine on morphology of the brain tissue were observed through hematoxylin-eosin (HE) staining. By immunohistochemistry and flow cytometry technique and biochemical method, effects of dipfluzine on P-selectin, E-selectin, ICAM-1 and myeloperoxidase (MPO) were observed.. Dipfluzine could relieve pathological damages in the brain tissue after ischemia-reperfusion, and reduce the expressions of E-selectin, P-selectin and ICAM-1 and activities of MPO in dose-dependent manner.. Dipfluzine depresses the expressions of P-selectin, E-selectin, and ICAM-1, which are correlated with their effects on the activities of MPO, suggesting that dipfluzine has anti-inflammation effect in certain extent and could protect brain tissue from ischemia-reperfusion injury.

Topics: Animals; Brain Ischemia; Cerebral Cortex; Cinnarizine; Dose-Response Relationship, Drug; E-Selectin; Infarction, Middle Cerebral Artery; Intercellular Adhesion Molecule-1; Male; Neuroprotective Agents; P-Selectin; Peroxidase; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Topics: Animals; Brain Ischemia; Calcium Channel Blockers; Cerebrovascular Circulation; Chronic Disease; Cinnarizine; Female; Male; Rats; Sodium Chloride; Vitamins

Topics: Adjuvants, Immunologic; Animals; Brain; Brain Ischemia; Calcium Channel Blockers; Chronic Disease; Cinnarizine; Disease Models, Animal; Hemodynamics; Interferon beta-1b; Interferon-beta; Proprioception; Rats; Vestibule, Labyrinth

To examine the effect of dipfluzine (Dip), a novel calcium channel blocker first developed in China, on acute ischemic brain edema.. One hundred and thirty gerbils, 65 males and 65 females, weighing 68 +/- 10 g, were used. Eighty gerbils randomly divided into four groups of 20 animals: sham operation group, Dip 25 mg/kg group, and Dip 50 mg/kg group. All of the 120 gerbils were injected with solution or Dip at different concentrations intraperitoneally. The skin of neck was incised one hour after injection. Except in the sham operation group, bilateral carotid artery ligation (BCAL) was performed in the other 70 gerbils to cause brain edema. Another 10 gerbils were used as normal controls without undergoing injection and operation. One hour after the operation, all of the animals were killed and the whole brain tissue was taken to detect the water and Na(+) and K(+) contents. The brain tissues of other 50 gerbils were used to produce homogenate to determine the Na(+), K(+)-ATPase activity.. The water and Na(+) contents in hippocampus of model control group were 77.4% and 279 +/- 22 micro mol/g dry tissue respectively, significantly higher than those in sham operation group (74.8% and 220 +/- 22 micro mol/g dry tissue). The K(+) content in the hippocampus of the model control group was 381 +/- 28 micro mol/g dry tissue respectively, significantly lower than that in the sham operation group (430 +/- 30 micro mol/g dry tissue). The Na(+), K(+)-ATPase activity in the plasmalemma of brain cells in model control group was 179 +/- 62 micro mol pi/mg protein/min, significantly lower than that in sham operation group (1006 +/- 130 micro mol pi/mg protein/min, P < 0.01). The water contents of hippocampus in Dip 25 mg/kg group and Dip 50 mg/kg group were 75.4 +/- 0.5% and 74.8 +/- 0.9% respectively, significantly lower than that in model control group (all P < 0.01). The Na(+) contents in hippocampus of Dip 25 mg/kg group and Dip 50 mg/kg group were 235 +/- 39 micro mol/g dry tissue and 223 +/- 36 micro mol/g dry tissue respectively, significantly lower than that in model control group (279 +/- 22 micro mol/g dry tissue, all P < 0.01). The K(+) content in hippocampus of Dip 25 mg/kg group and Dip 50 mg/kg group were 427 +/- 32 micro mol/g dry tissue and 434 +/- 29 micro mol/g dry tissue respectively, significantly higher than that in model control group (P < 0.05 and P < 0.01). The Na(+), K(+)-ATPase activity in the plasmalemma of brain cells in Dip 25 mg/kg group and Dip 50 mg/kg group was 649 +/- 45 and 1 198 +/- 218 micro mol pi/mg protein/min respectively, significantly higher than that in model control group (r = 0.9981, P < 0.01). The correlation between brain water content and Na(+), K(+)-ATPase activity was significant (r = -0.999 7, P < 0.01).. Dip attenuates dose-dependently the increased H(2)O and Na(+) contents, prevents the decrease in potassium level, and accelerates the restoration of lowered Na(+), K(+)-ATPase activity resulted from cerebral ischemia, thus preventing ischemic brain edema.

Topics: Acute Disease; Animals; Brain; Brain Edema; Brain Ischemia; Cinnarizine; Dose-Response Relationship, Drug; Female; Gerbillinae; Hippocampus; Male; Potassium; Sodium; Sodium-Potassium-Exchanging ATPase; Water

To evaluate the effects of dipfluzine ¿1-diphenyl-methyl-4-[3-(4-fluorobenzoyl)]-piperazine, Dip¿ on the intra- and extra-cellular contents of the amino acids in brain and the cortical somatosensory evoked potentials (SEP) in rats with cerebral ischemia.. Amino acids in micro-dialysates and brain tissue homogenates in female Wistar rats with bilateral carotid artery ligation (BCAL) were measured by HPLC and SEP was measured by the electrophysiological technique.. Dip 50 mg.kg-1 i.p. prevented SEP from prolonging of the latency and overactivity of lowered amplitude, markedly lowered the elevation in extracellular level of glutamate (Glu), aspartate (Asp), and glycine (Gly) in intracerebral microdialysates, and alleviated the decrement of intracellular contents of Glu, Asp, Gly, taurine (Tau), and GABA in brain tissue.. Dip reduced the disturbance of cortical function and the imbalance between excitatory and inhibitory amino acids in ischemic brain, therefore provided a further evidence for its protective effect on ischemic cerebral damage.

Topics: Animals; Brain; Brain Ischemia; Calcium Channel Blockers; Cinnarizine; Evoked Potentials, Somatosensory; Excitatory Amino Acids; Female; Rats; Rats, Wistar

The effects of dipfluzine (1-diphenylmethyl-4-(3-(4-fluorobenzoyl))-piperazine, Dip), a new calcium antagonist developed in China, on experimental brain edema in female Wistar rats with bilateral carotid artery ligation were compared with those of cinnarizine (Cin). Dip 25-100 mg.kg-1 i.p. protected the rats against the characteristic signs of global cerebral ischemia that correlate well with the development of brain edema. Its effects were more potent than those of Cin; and the effects of both drugs were more potent by both pretreatment and posttreatment than those by posttreatment alone. Dip 50 mg.kg-1 i.p. attenuated the reduction in cerebral blood flow (CBF) and the infarct size after occlusion, but did not alter CBF before ischemia. These findings suggested that Dip may be potentially useful to treat ischemic brain edema in part by preserving CBF in the ischemic zone.

Topics: Animals; Brain Edema; Brain Ischemia; Calcium Channel Blockers; Cerebrovascular Circulation; Cinnarizine; Female; Male; Rats; Rats, Sprague-Dawley; Rats, Wistar

The central effects of endothelin-1 (ET-1) and their modification by the calcium entry blocker cinnarizine have been investigated using CNS and hypoxia/ischemia tests. CNS tests comprised behavior, horizontal and vertical motor activity and hot plate test. Hypoxia/ischemia tests used were hypobaric hypoxia and complete ischemia by decapitation. ET-1 was injected intracerebroventricularly (i.c.v.) in a volume of 0.01 ml at doses of 1.25, 2.5 and 5 pmol/mouse 15 min before the tests. Cinnarizine (10 mg/kg, i.p.) was administered 60 min prior to ET-1. The i.c.v. ET-1 at all the doses used decreased horizontal and vertical motor activity and produced barrel-rolling. Survival/gasping time of mice subjected to hypoxia/ischemia increased dose-dependently. ET-1 showed an antinociceptive effect. Cinnarizine attenuated the appearance of barrel-rolling, did not antagonize disturbances in motor activity and reversed the antinociceptive effect of ET-1. In hypobaric hypoxia and decapitation cinnarizine antagonized the effects of 5 pmol/mouse ET-1 and potentiated that of 1.25 pmol/mouse. The pharmacological modification of the ET-1 effects by cinnarizine strongly suggests that the CNS actions of ET-1 might be due to multiple mechanisms triggered by an increased influx of extracellular Ca2+ into the brain cells.

Topics: Air Pressure; Animals; Behavior, Animal; Brain Ischemia; Central Nervous System; Cinnarizine; Endothelins; Hypoxia, Brain; Injections, Intraventricular; Male; Mice; Motor Activity; Pain Measurement

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

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

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

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

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