flunarizine and Brain-Edema

A series of 11-[4-(cinnamyl)-1-piperazinyl]-6,11-dihydrodibenz[b,e] oxepins and related compounds were synthesized and evaluated for their protective activities against complete ischemia, normobaric hypoxia, lipidperoxidation and convulsion. Structure-activity relationship studies of this series led to the finding of (E)-1-(3-fluoro-6,11-dihydrodibenz[b,e]oxepin-11-yl)-4-(3- phenyl-2-propenyl)piperazine dimaleate (50), AJ-3941 with the most appropriate property for combined pharmacological activities. Compound 50 also shows an inhibitory effect against cerebral edema as well when orally given to rats.

Topics: Animals; Benzothiepins; Benzoxepins; Brain Edema; Brain Ischemia; Cerebrovascular Disorders; Flunarizine; Hypoxia, Brain; Mice; Piperazines; Rats; Structure-Activity Relationship

Acute ischemia of the brain induces a cascade of biochemical and physiological events. The final consequences depend on the fact whether ischemia is of transient or permanent, total or partial nature. Alteration of extracellular potassium concentration, intracellular calcium and potassium concentration, development of cytotoxic and vasogenic edema, postischemic hyperfusion and no-reflow phenomenon are important factors which decide about the final fate of functional capacity. CO2 reactivity, autoregulation and hemorheology must be considered when therapeutic approaches are used to influence basic flow during ischemic condition. At present there exists no therapy which has been fully accepted and is able to guarantee benefit to the hypoperfused tissue. Since the calcium metabolism is altered by ischemic processes, substances which act on this metabolism might be of value in the treatment of ischemia and its consequences. However, their beneficial effect on cerebral infarction has not been proven yet. In subarachnoid hemorrhage and migraine calcium antagonists are used to prevent and treat ischemia. In epilepsia calcium overload blockers have been tried by one group with promising results.

Topics: Acute Disease; Brain Edema; Brain Ischemia; Calcium Channel Blockers; Cerebrovascular Disorders; Epilepsy; Flunarizine; Humans; Migraine Disorders; Rheology; Subarachnoid Hemorrhage