flunarizine and Ischemia

94 patients with Stage II obliterating arteriopathy of the lower extremities, treated with Flunarizine (10-20 mg per diem), were checked every two months for a 6 month period. Of the 76 patients reaching the final check up, 58 had received no previous treatment and 18 had ischemias secondary to reconstructive vascular surgery. Clinical improvement in terms of increased independent mobility and improved Doppler flowmeter pressure readings were noted in both groups. In view of its beneficial effects on blood vessel function in other areas, Flunarizine is felt to be a valuable drug for the treatment of peripheral arteriopathies, both initially and in cases of ischaemia following vascular surgery.

Topics: Aged; Arterial Occlusive Diseases; Chronic Disease; Cinnarizine; Clinical Trials as Topic; Female; Flunarizine; Humans; Ischemia; Leg; Male; Middle Aged; Piperazines; Regional Blood Flow; Rheology; Time Factors; Ultrasonography; Vasodilator Agents

A series of novel 4-arylpiperidines and 4-aryl-4-piperidinols (2a-f, 3a-f and 4a-f) was synthesized and evaluated for blocking effects on both neuronal Na(+) and T-type Ca(2+) channels and binding affinity for dopamine D(2) receptors. Most of the compounds blockaded both ion channels with potency greater than or equal to flunarizine 1a which was adopted as a reference standard. In addition, these compounds had significantly reduced affinity for dopamine D(2) receptors which is common in this class of structure. Compounds 2a-f, 3a-f and 4a-f exhibited potent anticonvulsant effects following systemic (ip) administration on audiogenic seizures in DBA/2 mice, indicating their excellent brain permeability. The neuroprotective activity of 2a, 3a and 4a was also assessed in a transient middle cerebral artery occlusion (MCAO) model. These compounds significantly reduced neuronal damage without affecting ischemic hyperthemia, while flunarizine 1a produced only minor reductions. In particular, 4a had 1.7-fold the potency in this MCAO model but only 1/20 the affinity for dopamine D(2) receptors of 1a. The superposition of 2a, 3a and 4a on the basis of analyses of systematic conformation and similar structure has revealed that the cinnamyl, phenacyl and phenoxypropanol groups are likely to be structurally and biologically equivalent. Moreover, the superposition of 2a and 2f shows that diphenyl ether and biphenyl groups occupy a similar space, suggesting that both groups act as a bioisostere for the blockade of ion channels; however, this is not the case for dopamine D(2) receptors since only biphenyl compounds such as 2f had high affinity similar to flunarizine 1a. Compound 4a (SUN N5030) has a good pharmacological profile and may be useful in the alleviation and treatment of ischemic diseases.

Topics: Animals; Biochemistry; Calcium Channel Blockers; Cerebral Cortex; Drug Evaluation, Preclinical; Female; Flunarizine; Ischemia; Male; Mice; Mice, Inbred DBA; Neuroprotective Agents; Phenyl Ethers; Piperidines; Rats; Rats, Wistar; Receptors, Dopamine D2; Seizures; Sodium Channel Blockers; Structure-Activity Relationship

Topics: Animals; Blood Flow Velocity; Calcium Channel Blockers; Cochlea; Flunarizine; Guinea Pigs; Humans; Ischemia; Laser-Doppler Flowmetry; Pentoxifylline; Vasodilator Agents; Vestibule, Labyrinth

Using the model of the isolated perfused rat liver, we investigated the influence of the two pharmacologically different calcium channel blockers, verapamil and flunarizine, on changes of ion homeostasis, liver weights, pH deviations and enzyme activities during warm ischemia (37 degrees C) and reperfusion. The LDH and GLDH activities were determined and the calcium, potassium, and sodium concentrations were measured in the effluent. Warm ischemia (180 min) caused an increased enzyme release, a high influx of calcium and sodium into the liver and a massive potassium efflux current. Normoxic reperfusion led to a further increase in hepatic enzyme release and although the loss of potassium ceased, the calcium influx into the liver continued. By the end of reperfusion the liver weight had increased significantly (P < 0.01) in the control group. The two calcium entry blockers were added to the perfusate in various concentrations. Both substances protected the liver against warm ischemia and normoxic reperfusion damage, but they did not inhibit calcium inflow. However, the potassium efflux was significantly reduced by all concentration tasted (P < 0.001). After reperfusion the liver weights were significantly lower in the treated groups (P < 0.001) than in control animals. Thus, the calcium entry blockers verapamil and flunarizine protect liver cells against damage caused by warm ischemia and reperfusion. Furthermore, they prevent the disruption of intracellular potassium homeostasis, which seems to be related to improved volume regulation of liver cells.

Topics: Animals; Calcium; Female; Flunarizine; Glutamate Dehydrogenase; Homeostasis; Hot Temperature; Hydrogen-Ion Concentration; Ischemia; L-Lactate Dehydrogenase; Liver; Organ Size; Perfusion; Potassium; Rats; Rats, Wistar; Reperfusion Injury; Verapamil

The lipophilic calcium channel antagonist flunarizine has been demonstrated to be neuroprotective in several models of cerebral ischemia. Ischemic spinal cord injury may have a similar pathophysiology and hence may respond in a similar fashion. This study was designed to investigate the effects of pretreatment with flunarizine on systemic hemodynamics, spinal cord blood flow, and neurological recovery in a rabbit model of ischemic spinal cord injury.. New Zealand White rabbits were anesthetized with ketamine and xylazine and instrumented for systemic blood pressure monitoring and spinal cord blood flow measurements using the microsphere method. After pretreatment with flunarizine or vehicle, ischemic spinal cord injury was created selectively in the caudal regions of the spinal cord by cross-clamping the abdominal aorta for a period of 25 minutes. Spinal cord blood flow was measured before, during, and 15 minutes after cross-clamp removal. Animals were allowed to recover and were graded neurologically at 18 and 24 hours after ischemia.. Flunarizine injection was associated with hypotension that was both transient and dose related. Animals pretreated with flunarizine 0.4 mg/kg had significantly improved neurological recovery scores at 18 hours after ischemia (P = .017) compared with vehicle controls. At 24 hours this effect was lessened (P = .095); however, 60% of flunarizine-treated animals retained their ability to hop, whereas all of the vehicle-treated animals were nonambulatory.. Flunarizine has a protective effect on neurological recovery after experimental ischemic spinal cord injury. The therapeutic window is narrow, and dosing is limited by untoward hypotension. The mechanism of protection likely involves inhibition of pathological cytosolic calcium accumulation rather than a direct effect on vascular smooth muscle.

Topics: Animals; Flunarizine; Ischemia; Male; Motor Activity; Nervous System Diseases; Rabbits; Regional Blood Flow; Spinal Cord

Intracellular calcium overload has been implicated to be a major factor in triggering cell death after ischemic neuronal injury. We investigated the effects of flunarizine hydrochloride, a calcium-overload blocker, on pressure-induced retinal ischemia in a rat model. Retinal ischemia was induced in intraocular pressure to 110 mm Hg for 45 minutes. Two regimens of treatment with flunarizine were examined: (1) prophylactic treatment, in which flunarizine was administered before ischemia and in the early phase of reperfusion; and (2) postischemic treatment, in which flunarizine was administered only in the early phase of reperfusion. Injury was evaluated morphologically and morphometrically by measuring the thickness of the inner retinal layers on plastic-embedded retinal sections and by counting the retinal ganglion cells on retinal flat preparations. By morphologic and morphometric criteria, a significant but partial protection of the inner retinal layers was noted in the groups given either regimen. This protective effect of flunarizine suggests that elevated intracellular calcium concentration may play an important role in ischemic retinal injury.

Topics: Animals; Cell Count; Disease Models, Animal; Flunarizine; Image Processing, Computer-Assisted; Injections, Intraperitoneal; Intraocular Pressure; Ischemia; Male; Rats; Rats, Inbred Lew; Retinal Ganglion Cells; Retinal Vessels

Infrarenal aortic occlusion in rabbits to produce paraplegia is possible in large series and can be achieved without any side-effects of anesthetic drugs. This model was tested for its suitability to investigate the use of calcium-channel blockers, which potentially reduce or prevent ischemic spinal cord damage. In a pilot study 26 rabbits were treated with 0.1 mg/kg Flunarizine i.v. prior to occlusion and 38 animals served as control. Groups were compared where the aorta was occluded for 10, 15, 20, 25 or 30 min. No reduction of paraplegia in the Flunarizine groups was observed, apart from in the 15-min occlusion subset: here the number of unaffected animals was significantly greater (p less than 0.05). At histopathological examination the number of ischemic spinal cord segments was reduced (p less than 0.03). It is concluded that Flunarizine could not reduce the cellular damage of the spinal-cord due to complete and global ischemia after an aortic occlusion interval exceeding 15 min. The narrow interval between potential recovery (15 min) and definite paraplegia (20 min) makes this rabbit paraplegia model less appropriate for testing of calcium-channel blockers which are presumed to have a moderate effect on the reduction of spinal cord ischemia.

Topics: Animals; Aorta, Abdominal; Constriction; Disease Models, Animal; Flunarizine; Ischemia; Paraplegia; Rabbits; Spinal Cord; Time Factors

In anesthetized rats, global complete ischaemia lasting for 9 min was induced by controlled hydraulic compression of the chest. A neurological score, based on cranial and spinal reflexes, postural tone, gait, movement and limb placement, was determined at 2 hr and 1, 2, 3, 7, 14, 21 and 28 days after resuscitation. Three doses of three calcium antagonists, flunarizine, verapamil and nimodipine and their respective solvents, were given intravenously during the resuscitation. The total neurological score was significantly better than solvent with 0.16 and 0.63 mg/kg of flunarizine and 0.04 and 0.16 mg/kg of verapamil; it was significantly better with solvent (10% ethanol) than with 0.04 and 0.16 mg/kg of nimodipine. The deficiency in tactile placing reactions of the hindpaws was the most resistant to therapy. This non-invasive model of global ischaemia in rats seems useful for the evaluation of drugs, since it requires minimal anesthesia and allows assessment of neurological recovery over an extended period of time.

Topics: Anesthesia; Animals; Behavior, Animal; Disease Models, Animal; Electroencephalography; Electromyography; Flunarizine; Injections, Intravenous; Ischemia; Male; Nimodipine; Rats; Reflex; Resuscitation; Verapamil

The effect of flunarizine, a calcium antagonist, on experimentally induced facial nerve injury in guinea pigs was studied electron microscopically. In flunarizine-untreated animals, intra-axonal accumulation of cell organelles and degradation of myelin sheaths were observed. In flunarizine-treated animals, these changes were not observed, but a knob-like protrusion of myelin sheaths and a structure resembling the myelin sheath in Schwann cell cytoplasm was occasionally observed.

Topics: Animals; Axons; Facial Nerve; Facial Paralysis; Flunarizine; Guinea Pigs; Ischemia; Male; Microscopy, Electron; Myelin Sheath

The effects of three chemically dissimilar calcium-blocking drugs were studied in experimental post-ischaemic renal failure, in the rat. After 45 min unilateral clamping and contralateral nephrectomy, post-ischaemic verapamil administration protected renal function (p less than 0.025), but flunarizine, either before or after ischaemia, was not beneficial. Following 60 min bilateral renal pedicle clamping, nifedipine administration was not beneficial. Verapamil was the only calcium-blocking drug which attenuated the post-ischaemic renal dysfunction. Calcium blockers which differ in their modes of action, differ in their ability to protect the kidney from ischaemia.

Topics: Acute Kidney Injury; Animals; Calcium Channel Blockers; Flunarizine; Ischemia; Kidney; Male; Nifedipine; Rats; Rats, Inbred Strains; Verapamil

Perfusion of the cerebral cortex during closed chest CPR in dogs, generating systolic pressures of 60 to 70 mmHg, is only 10% of pre-arrest blood flow. In contrast, internal cardiac massage produces normal cortical perfusion rates. Following a 20-min perfusion arrest, during pressure controlled reperfusion, cortical flow rates decay to less than 20% normal after 90 min of reperfusion. This appears to be due to increasing cerebral vascular resistance, and is not due to rising intracranial pressure. The post-arrest cortical hypoperfusion syndrome is prolonged with cortical flow remaining below 20% normal up to 18 hr post arrest. The use of a variety of calcium antagonists, including flunarizine, lidoflazine, verapamil, and Mg2+, immediately post-resuscitation maintains cerebral vascular resistance and cortical perfusion at normal levels. A prospective blind trial of the calcium antagonist lidoflazine following a 15-min cardiac arrest in dogs and resuscitation by internal massage, demonstrates amelioration of neurologic deficit in the early postresuscitation period.

Topics: Adenosine Triphosphate; Animals; Brain; Calcium; Cell Membrane; Cerebral Cortex; Cerebrovascular Circulation; Cinnarizine; Dogs; Fatty Acids, Nonesterified; Flunarizine; Heart Arrest; Heart Massage; Hypoxia, Brain; Ischemia; Lidoflazine; Nervous System Diseases; Resuscitation

In 48 cases with well-documented retinal vasculopathy, the therapeutic effect of cinnarizine and flunarizine over a period of several months to 3 years has been clinically evaluated. Objective measurements comprised determination of visual field and acuity, funduscopy, three-mirror funduscopy, and fluorangiography with determination of capillary leakage and circulation time. The most prominent features were disappearance of cotton wool nodules, improvement of visual function and capillary perfusion, inhibition of capillary leakage, and a positive hemokinetic effect in arteriolar, capillary, and venous beds. Degeneration of post-ganglionic fibers was partly restored. In some patients with glaucoma, the aspect of the optic disc was normalized. It is concluded that selective calcium-entry-blockers clearly improve tissue perfusion in ischemic areas.

Topics: Adult; Arterioles; Autonomic Fibers, Postganglionic; Calcium Channel Blockers; Capillaries; Cinnarizine; Diabetic Retinopathy; Female; Flunarizine; Fluorescein Angiography; Humans; Hypertension; Ischemia; Male; Middle Aged; Optic Disk; Retinal Artery; Retinal Vein; Venules

Topics: Blood Viscosity; Cinnarizine; Double-Blind Method; Flunarizine; Humans; Ischemia; Meniere Disease; Physical Exertion; Piperazines; Vasodilator Agents