thromboxane-a2 and Epilepsy

Mild to moderate hypothermia (32-35 degrees C) is the first treatment with proven efficacy for postischemic neurological injury. In recent years important insights have been gained into the mechanisms underlying hypothermia's protective effects; in addition, physiological and pathophysiological changes associated with cooling have become better understood.. To discuss hypothermia's mechanisms of action, to review (patho)physiological changes associated with cooling, and to discuss potential side effects.. Review article.. None.. A myriad of destructive processes unfold in injured tissue following ischemia-reperfusion. These include excitotoxicty, neuroinflammation, apoptosis, free radical production, seizure activity, blood-brain barrier disruption, blood vessel leakage, cerebral thermopooling, and numerous others. The severity of this destructive cascade determines whether injured cells will survive or die. Hypothermia can inhibit or mitigate all of these mechanisms, while stimulating protective systems such as early gene activation. Hypothermia is also effective in mitigating intracranial hypertension and reducing brain edema. Side effects include immunosuppression with increased infection risk, cold diuresis and hypovolemia, electrolyte disorders, insulin resistance, impaired drug clearance, and mild coagulopathy. Targeted interventions are required to effectively manage these side effects. Hypothermia does not decrease myocardial contractility or induce hypotension if hypovolemia is corrected, and preliminary evidence suggests that it can be safely used in patients with cardiac shock. Cardiac output will decrease due to hypothermia-induced bradycardia, but given that metabolic rate also decreases the balance between supply and demand, is usually maintained or improved. In contrast to deep hypothermia (

Topics: Acidosis; Apoptosis; Body Temperature Regulation; Brain Edema; Brain Ischemia; Calpain; Critical Care; Epilepsy; Free Radicals; Genes, Immediate-Early; Humans; Hypothermia, Induced; Infections; Inflammation; Ion Pumps; Mitochondria; Reperfusion Injury; Thrombosis; Thromboxane A2

Valproate (VPA) is an extensively used drug in the therapy of epilepsies. One of the most frequently reported side effects of VPA is hemorrhagic diathesis. Some authors emphasized the decreased platelet count as the basis of VPA-induced hemorrhagic diathesis, but some reports suggested that a significant proportion of patients with normal platelet count may still have an altered platelet function. The mechanism of the VPA-induced platelet dysfunction has not yet been elucidated. A determining element of platelet functions is the arachidonate cascade. Present ex vivo experiments were designed to determine whether a relation exists between the incidence of hemostasis caused by VPA and the effect of this drug on the arachidonate cascade of platelets.. Platelets were isolated from patients receiving long-term VPA treatment (serum level, 36.04+/-16.12 microg/ml; n = 10) or carbamazepine (CBZ) treatment (serum level, 5.24+/-2.67 microg/ml; n = 10) and were labeled with [14C]arachidonic acid. (CBZ-treated patients were chosen as a control group, because CBZ causes blood dyscrasias similar to those elicited by VPA, but there has been no report that CBZ induces a platelet dysfunction.) The 14C-eicosanoids were separated by means of overpressure thin-layer chromatography and determined quantitatively by liquid scintillation.. Even when the mean plasma concentration of the drug was low, VPA treatment reduced the activity of the arachidonate cascade in platelets. VPA effectively inhibited the cyclooxygenase pathway and the synthesis of the strong platelet aggregator thromboxane A2.. Inhibition of the platelet arachidonate cascade may contribute to the platelet-function alterations caused by VPA.

Topics: Adult; Arachidonic Acids; Blood Coagulation Tests; Blood Platelets; Epilepsy; Fasting; Hemorrhagic Disorders; Humans; Male; Platelet Activation; Platelet Aggregation; Thromboxane A2; Valproic Acid