Double-Blind Placebo-Controlled Trial with Flunarizine in Therapy-Resistant Epileptic Patients

Fröscher, W.; Bülau, P.; Burr, W.; Penin, H.; Rao, Madhusudhan; Beukelaar, F. de

doi:10.1097/00002826-198806000-00005

Cited by 21 publications

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“…[21] and Froscher et al . [22] also found significant seizure frequency reduction in patients with flunarizine as add-on therapy in double-blind placebo-controlled trials. Starreveld et al .…”

Section: Discussionmentioning

confidence: 99%

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

2011

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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.

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Section: Discussionmentioning

confidence: 99%

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

2011

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“…For example, a FNR dose of 15-20 mg/day in patients receiving other AEDs results in plasma levels similar to a daily dose of 10 mg in patients receiving FNR monotherapy. Although FNR is more than 99% protein-bound, it does not appear to alter protein binding of concomitant medications (Froscher et al, 1988).…”

Section: Kunarizine Flunarizine (Fnr) (E)-mentioning

confidence: 94%

Antiepileptic Drugs in Development: Prospects for the Near Future

Leppik

1994

Epilepsia

102

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Among some 14 new antiepileptic drugs (AEDs), those most extensively tested in humans include felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OCBZ), vigabatrin (VGB), and zonisamide (ZNS). All are currently marketed in some but not all countries. Although no large, comparative studies on efficacy have been conducted, all of these new AEDs are effective in adult localization-related epilepsies, and some have activity in specific syndromes. Although these drugs all have some CNS side effects, especially when administered in combination with other AEDs, they also all have low toxicity profiles. The availability of AEDs with different mechanisms of action may facilitate rational polytherapy. FBM is not teratogenic in animals. Half-life of FBM in humans is 11-28 h. Daily FBM dosages are 15-45 mg/kg in children and 2,400-4,800 mg in adults. Side effects include insomnia and anorexia, with weight loss. FBM increases phenytoin (PHT) and valproate (VPA) concentrations, and FBM concentration may be affected by other drugs. It is available in the United States for treatment of Lennox-Gastaut syndrome and partial seizures in adults. GBP is very water soluble. Half-life of GBP in humans is 5-7 h and daily dosages range from 900 to 2,400 mg in adults. Few side effects have been observed. GBP is not metabolized by the liver and has no drug interactions. It is available in the United Kingdom and the United States. LTG has no teratogenicity in animal models. Half-life of LTG in humans depends on co-medication: with enzyme inducers it is 15-24 h, and with VPA it is approximately 60 h. LTG dosages are 100-600 mg/day in adults. LTG is available in Europe. OCBZ is rapidly metabolized to 10,11-dihydro-10-hydroxy-carbazepine (MHD), the active compound. Animal studies have shown similar efficacy but superior toxicity to carbamazepine (CBZ) in animal models. For MHD, half-life ranges from 10 to 15 h in patients. OCBZ dosages range from 300 to 1,800 mg/day. VGB is a potent, irreversible inhibitor of GABA transaminase which elevates GABA levels in the CNS. Daily dosages of 2,000-4,000 mg of VGB are needed in adults. Although intramyelinic edema has developed in rats and dogs, it has not yet presented in other mammals or humans. ZNS is a sulfonamide effective in animal models of epilepsy. Half-life of ZNS is 27-36 h. ZNS daily dosage is 400-600 mg. ZNS has been effective in some cases of Baltic myoclonic epilepsy.

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“…2 Glutamate is the major excitatory neurotransmitter acting through the N-methyl-D-aspartate (NMDA) receptors in the vestibular nerve fibers. [3][4][5] M2 cholinergic receptors are involved with dizziness. 6 Gamma-aminobutyric acid (GABA) an inhibitory neurotransmitter is found in the vestibular neurons leading to stimulation of GABA-A and GABA-B receptors.…”

Section: Introductionmentioning

confidence: 99%

Current Perspectives in the Pharmacotherapy of Vertigo

Singh¹,

Singh²

2012

An International Journal of Otorhinolaryngology Clinics

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Vertigo is a symptom encountered very commonly in clinical practice due to a disorder in the vestibular system. In addition to dizziness it is very often accompanied by nausea and vomiting. Pharmacotherapy plays an important role in the management of vertigo. Vestibular suppressants and drugs to control nausea and vomiting constitute the mainstay of the pharmacotherapy of vertigo. Specific drug therapy can be given in patients where the underlying disease process causing the vertigo has been identified. Despite the availability of many classes of drugs, there are no definitive, universally accepted guidelines for the treatment of vertigo which makes it even more difficult to follow first-, second-and third-line therapies when treating patients. It is difficult to establish guidelines or a generally acceptable consensus in the treatment of vertigo due to the complexity of vertigo and lack of adequate randomized clinical studies.

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Double-Blind Placebo-Controlled Trial with Flunarizine in Therapy-Resistant Epileptic Patients

Cited by 21 publications

References 0 publications

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

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

Antiepileptic Drugs in Development: Prospects for the Near Future

Current Perspectives in the Pharmacotherapy of Vertigo

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