Experimental re-evaluation of flunarizine as add-on antiepileptic therapy

Abstract

Background:Experimental studies have found several calcium channel blockers with anticonvulsant property. Flunarizine is one of the most potent calcium channel blockers, which has shown anticonvulsant effect against pentylenetetrazole (PTZ) and maximal electroshock (MES)-induced seizures. However, further experimental and clinical trials have shown varied results. We conducted a PTZ model experimental study to re-evaluate the potential of flunarizine for add-on therapy in the management of refractory epilepsy.Materials and Methods:Experiments were conducted in PTZ model involving Swiss strain mice. Doses producing seizures in 50% and 99% mice, i.e. CD50 and CD99 values of PTZ were obtained from the dose-response study. Animals received graded, single dose of sodium valproate (100–300 mg/kg), lamotrigine (3–12 mg/kg) and flunarizine (5–20 mg/kg), and then each group of mice was injected with CD99 dose of PTZ (65mg/kg i.p.). Another group of mice received single ED50 dose (dose producing seizure protection in 50% mice) of sodium valproate and flunarizine separately in left and right side of abdomen. Results were analysed by Kruskal–Wallis ANOVA on Ranks test.Results:As compared to control, sodium valproate at 250 mg/kg and 300 mg/kg produced statistical significant seizure protection. At none of the pre-treatment dose levels of lamotrigine, the seizure score with PTZ differed significantly from that observed in the vehicle-treated group. Pre-treatment with flunarizine demonstrated dose-dependent decrease in the seizure score to PTZ administration. As compared to control group, flunarizine at 20 mg/kg produced statistical significant seizure protection.Conclusion:As combined use of sodium valproate and flunarizine has shown significant seizure protection in PTZ model, flunarizine has a potential for add-on therapy in refractory cases of partial seizures. It is therefore, we conclude that further experimental studies and multicenter clinical trials involving large sample size are needed to establish flunarizine as add-on therapy in refractory epilepsy.

Phenothiazine‐Derived Antipsychotic Drugs Inhibit Dynamin and Clathrin‐Mediated Endocytosis

“…However, our finding that calmidazolium potently inhibits dynamin I and II GTPase activity challenges this proposed role of calmodulin in SVE. Similarly, flunarizine is a potent Na + -and Ca 2+ -channel blocker that is effective against neurological disorders, such as epilepsy and migraine (59,60). Our finding that it is a potent dynamin inhibitor challenges the conclusion that it blocks SVE through Ca 2+ channel blockade (61).…”

Tacrine derivatives as dual topoisomerase I and II catalytic inhibitors

“…DNA topoisomerases are essential enzymes that play an important role in DNA transcription and replication as well as in chromosome segregation and recombination [2,4,5,53]. Topoisomerases cut DNA transiently to allow the unwinding of the supercoiled plasmid into both partially relaxed forms and the fully relaxed form [26].…”

“…A large percentage of chemotherapeutic anticancer drugs are compounds which either interact directly with DNA or which prevent the proper relaxation of DNA through the inhibition of topoisomerases [1][2][3][4][5][6]. They are widely occurring enzymes that can solve the topological problems in eukaryotic and prokaryotic cells associated with DNA which emerge during key cellular processes [7,8].…”

“…Topo I acts by creating a transient break in one strand of DNA, whereas Topoisomerase II (Topo II) introduces transient doublestrand breaks [11]. Topo II has been the focus of extensive study and is the target of a wide variety of drugs which can be divided into two main categories: DNA intercalators and non-intercalators [1,2,4,[12][13][14][15][16].…”

C5-curcuminoid-4-aminoquinoline based molecular hybrids: design, synthesis and mechanistic investigation of anticancer activity

“…1,2 It is well established that there is no single treatment for cancer and patients often receive a combination of therapies and palliative care, such as surgery, radiation, immunotherapy, chemotherapy or gene therapy, depending on the type and stage of cancer, the health status, age and personal characteristics. 3 Anticancer drugs such as alkylating agents, [4][5][6][7][8] antimetabolites, [9][10][11] plant alkaloids, [12][13][14][15] topoisomerase inhibitors 16,17 and cytotoxic antibiotics 18 have been used extensively in chemotherapy. Among these, natural products show good promise in the development of anticancer molecules 19,20 and curcumin is one such natural product which has been extensively studied over the past few decades.…”