flunarizine and Necrosis

We report a 27-year-old woman, a known case of classical migraine headache, on oral contraceptive pills. She had a severe episode of migraine with visual aura attack, which continued late into the night. The next early morning, her headache persisted and she developed abrupt onset of dysarthria, right hemiparaesthesias. She attributed symptoms to her long-standing headache problem, and hence did not seek medical help for the next two weeks. The symptoms persisted despite her headache subsiding over the next 24 hours. She worsened 2 weeks later during another such episode of headache. This time, she developed right hemiparesis. The patient was admitted with provisional diagnosis of stroke. MRI of the brain showed left temporoparietal lesion and was radiologically compatible with cortical laminar necrosis.Extensive work-up was done to rule out other causes of young stroke. The patient improved with antiplatelets, antimigraine prophylaxis and stroke rehabilitation therapy.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Aspirin; Cerebral Cortex; Cerebral Infarction; Diagnosis, Differential; Female; Flunarizine; Fructose; Humans; Magnetic Resonance Imaging; Migraine with Aura; Naproxen; Necrosis; Stroke Rehabilitation; Topiramate

The abundance of dead macrophages in close proximity to HOCl-modified proteins in advanced atherosclerotic plaques implicates HOCl in the killing of macrophages and the formation of the necrotic core region. The mechanism of HOCl mediated death of macrophages was unknown, so using human monocyte derived macrophages (HMDM) we here have shown that HOCl causes a rapid necrotic cell death characterized by loss of MTT reduction, cellular ATP and cell lysis without caspase-3 activation in HMDM cells. The HOCl causes a rise in cytosolic calcium level via the plasma membrane L- and T-type calcium channels and endoplasmic reticulum RyR channel. Blocking of the calcium channels or the addition of calpain inhibitors prevents the HOCl mediated loss of mitochondrial potential, lysosome failure and HMDM cell death. Blocking MPT-pore formation with cyclosporin A also prevents the loss of mitochondrial membrane potential, lysosomal destabilization and HMDM cell death. Blocking the calcium mitochondrial uniporter with ruthenium red also blocks the loss of mitochondrial potential but only at high concentrations. HOCl appears to cause HMDM cell death through destabilization of cytosolic calcium control resulting in the failure of both the mitochondria and lysosomes.

Topics: Calcimycin; Calcium; Calcium Channel Blockers; Calcium Ionophores; Calpain; Caspase 3; Cyclosporine; Dantrolene; Enzyme Inhibitors; Flunarizine; Humans; Hypochlorous Acid; Lysosomes; Macrophages; Membrane Potential, Mitochondrial; Muscle Relaxants, Central; Necrosis; Nifedipine; Verapamil

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

Plasma thromboxane concentrations were found to be significantly elevated in acute necrotizing pancreatitis in rats, whereas prostaglandin I2 levels were not. The significance of these alterations was investigated. Pancreatitis was induced by injecting 5% sodium taurocholate into the pancreatic duct. Iloprost (ZK 36374, a stable analog of prostaglandin I2, 25 ng/kg body weight) decreased the mortality rate from 100% to 50%. When treatment with iloprost was combined with simultaneous administration of either Sibelium (flunarizine R 14,950, 0.2 mg/kg body weight) or dazmegrel (UK 38,485, 50 mg/kg body weight) an additional decrease in the mortality rate was recorded. Dazmegrel is a selective thromboxane A2 synthetase inhibitor and flunarizine (a calcium entry blocker) also inhibits the effects of elevated thromboxane A2 levels. With flunarizine and iloprost the mortality rate was 40% (P less than 0.05); with dazmegrel and iloprost it was 10% (P less than 0.01). The results of the present study suggest that thromboxane A2 and prostaglandin I2 play a role in the course of acute necrotizing pancreatitis.

Topics: Acute Disease; Animals; Epoprostenol; Flunarizine; Iloprost; Imidazoles; Male; Necrosis; Pancreas; Pancreatitis; Rats; Rats, Inbred Strains; Thromboxane A2; Vasodilator Agents

Acute necrotising pancreatitis in rats was induced by injecting 5% sodium taurocholate into the pancreatic duct. Prostaglandin E2 (100 micrograms/kg subcutaneously twice) decreased the mortality rate from 100% to 60% (NS). When treatment with prostaglandin E2 was combined with simultaneous administration of either dazmegrel (UK 38,485, 50 mg/kg bodyweight) or Sibelium (Flunarizine R 14,950, 0.2 mg/kg body weight) a significant decrease in the mortality rate (p less than 0.05) was recorded. Dazmegrel is a selective thromboxane A2 synthetase inhibitor and prevents the formation of thromboxane A2. Flunarizine (a calcium entry blocker) decreases thromboxane A2 formation and also inhibits the effects of raised thromboxane A2 concentrations. As plasma thromboxane B2 (the stable metabolite of thromboxane A2) concentrations increase and the plasma prostaglandin E2 concentrations decrease in acute necrotising pancreatitis in rats, the results of the present study indicate that these prostaglandins play a role in the pathophysiology of the disease. It is suggested that restoration of the balance in prostanoid concentrations will have a beneficial effect on the course of acute necrotising pancreatitis.

Topics: Acute Disease; Animals; Dinoprostone; Drug Therapy, Combination; Flunarizine; Imidazoles; Male; Necrosis; Pancreas; Pancreatitis; Rats; Thromboxane-A Synthase

The possible role of thromboxane A2 (TXA2) in acute necrotizing pancreatitis (ANP) was investigated in rats. After ANP was induced by injecting sodium taurocholate (5% w/v) into the pancreatic duct, the thromboxane B2 (TXB2) levels in plasma increased significantly. The effects of indomethacin, a general blocker of prostaglandin synthesis, on survival time and on plasma TXB2 levels were compared with those of dazoxiben, a more specific blocker of TXA2 synthesis, and Flunarizine, a calcium entry blocker known to inhibit the effects of TXA2. In a test group without any treatment, all animals died within 30 h of ANP induction. Although TXB2 levels were lowered by the administration of indomethacin, dazoxiben, and Flunarizine, survival times were not significantly altered. Indomethacin pretreatment had no beneficial effect, whereas 30% and 40% of the animals survived for 36 h after treatment with Flunarizine and dazoxiben, respectively. The results of the present study indicate that inhibition of TXA2 synthesis alone does not dramatically alter survival time. However, a potential role for other arachidonate metabolites in ANP cannot be ruled out by this study.

Topics: Acute Disease; Animals; Flunarizine; Imidazoles; Indomethacin; Male; Necrosis; Pancreatitis; Rats; Rats, Inbred Strains; Thromboxane A2; Thromboxane B2

The influence of flunarizine on flap necrosis has been studied in rats by means of an abdominal neurovascular island skin flap model. Four groups of six rats were treated in a pretreatment phase of one week and a medication phase of four weeks with either flunarizine (2.5 mg/kg) or a placebo. Rats with flunarizine treatment over the whole period showed a significantly faster healing and less necrosis than the placebo group. The group without flunarizine pretreatment showed similar results as the control group at the first week after surgery, but from the second week on, the flunarizine effect became manifest. The skin graft model clearly demonstrates the beneficial effects of flunarizine in the prevention of tissue necrosis.

Topics: Animals; Cinnarizine; Flunarizine; Graft Survival; Male; Necrosis; Rats; Rats, Inbred Strains; Surgical Flaps; Vasodilator Agents; Wound Healing

Topics: Animals; Cinnarizine; Drug Antagonism; Female; Flunarizine; Heart; Isoproterenol; Lidoflazine; Myocardium; Necrosis; Piperazines; Rats