Lacosamide, a novel anti-convulsant drug, shows efficacy with a wide safety margin in rodent models for epilepsy

Koncz

Acta Medica Marisiensis

et al. 2017

Objective: This study evaluated the anticonvulsant action of lacosamide (LCS), a novel drug that was recently approved for the treatment of partial or secondarily generalized seizures, using an animal model of generalized epilepsy induced by repetitive pentylenetetrazole (PTZ) administration in rats. The main goal was to evaluate the behavioral pattern of lacosamide action by classifying seizures according to a modified Racine-scale. Furthermore, the reproducibility of the win-PTZ kindling model of epilepsy, a recently described variant of the standard PTZ-kindling model, was also assessed. Methods: Adult male Wistar rats (n=16) were divided into two groups and underwent the win-PTZkindling protocol in two independent trials. After finishing the kindling procedure, all animals, which presented stage 5 seizures were tested for the anticonvulsant action of lacosamide at three different doses (3, 10, and 30 mg/kg). Results: The maximal severity of seizures decreased and the latency to stage 3-5 seizures increased when the animals were treated with lacosamide at a single dose of 10 mg/kg compared to saline pretreatment (p < 0.05), both parameter reflecting an anticonvulsant action of the drug. Unfortunately, the number of stage 3-5 seizures also increased, but not significantly. The win-PTZ kindling model showed an adequate reproducibility between different trials, however, the number of fully kindled rats was lower than previously reported. Conclusions: Lacosamide showed a convincing anticonvulsant action in the win-PTZ kindling model of epilepsy by preventing the generalization of seizures. The win-PTZ kindling model was proved to be useful for studying epileptogenesis and the anticonvulsant action of drugs.

Section: Discussionmentioning

confidence: 94%

“…Lacosamide was incapable to reduce the clonic seizures induced by PTZ at doses of 85 mg/kg and 70 mg/kg in both mice and rats, respectively. However, it significantly increased the seizure threshold in the intravenous PTZ test, which involved a continuous infusion of a 0.5% solution of PTZ [5].…”

Section: Introductionmentioning

confidence: 99%

Lacosamide Reduces Seizure Severity but Increases Seizure Frequency in PTZ-Kindled Rats

Koncz

Acta Medica Marisiensis

et al. 2017

“…[10] Benzer şekilde bu ilaçlar da klinik olarak anlamlı bir şekilde lakozamidin farmakokinetiğini etkilemez. [11] Yirmi sekiz günlük periyotlarla, nöbet sıklığında %50'den fazla azalmanın değerlendirildiği 418 hasta ile yapılan plasebo kontrollü randomize bir çalışmada, 400 mg/gün ve 600 mg/gün lakozamid ile plaseboya göre istatistiksel olarak anlamlı düzeyde nöbet sıklığında azalma görülmüştür. 200 mg/gün lakozamid ile plasebo arasında ise anlamlı bir fark saptanmamıştır.…”

Section: Bulgularunclassified

The Effectivety, Safety and Tolerability Profile of Lacosamide Therapy in Refractory Epilepsy: Premarketing Experience

Genç¹,

Tokuç²,

Akça³

et al. 2014

Epilepsi

SummaryObjectives: Lacosamide is a novel antiepileptic drug used in partial refractory epilepsy patients. Methods: We searched retrospectively 1100 patients who have follow up in Antalya Education and Research Hospital Epilepsy Departmant between August 2011 and December 2014 and evaluated 14 patients with refractory partial epilepsy who have been using lacosamide which has been obtained abroad by the Turkish Pharmacists' Association before placing on the market in Turkey. Reduction in seizure frequancy was divided in two groups as less than 50% and more than 50%. Results: Nine (64.2%) of 14 patients were male and the remainder were female (35.7%). Mean age was 27.14±7.7 (min. 21,max. 47). Patients were being treated for an average of four antiepileptic drugs (min.3, max.5) before the begining of lacosamide. We titrated the dosage of lacosamide from 100mg/day to 400mg/day (mean 323±30.2 mg/day).The patients had been followed up for a mean of 24 months. Lacosamide reduced the seizure frequancy in five (35.7%) patients but not the other nine (64.2%) patients.Side effects observed in five patients dizziness was the most frequent. Conclusion: Lacosamide can be effective and safe in patients with partial refractory epilepsy if it was combined appropriately with the other antiepileptic drugs. We believe that we need prospective, randomised, multicenter and longer follow up studies to evaluate the safety and effectivety profile of lacosamide on seizure control.Key words: Add-on therapy; epilepsy; lacosamide; new antiepileptic drugs. ÖzetAmaç: Lakozamid parsiyel başlangıçlı refrakter epilepsi hastalarında kullanılmaya başlanan yeni bir antiepileptik ilaçtır. Gereç ve Yöntem:Ağustos 2011 ile Aralık 2014 tarihleri arasında Antalya Eğitim ve Araştırma Hastanesi Epilepsi Polikliniği'nde takipli 1100 hasta taranarak henüz Türkiye'ye gelmeden önce Türk Eczacılar Birliği aracılığı ile yurtdışından getirilerek lakozamid tedavisi alan 14 dirençli parsiyel başlangıçlı epilepsi hastası geriye dönük olarak değerlendirildi. Nöbet sıklığındaki azalma %50'den az ve %50'den çok olmak üzere ikiye ayrıldı. Bulgular:On dört hastanın dokuzu (%64.2) erkek, beşi (%35.7) kadın idi. Yaş ortalaması 27.14±7.7 (min. 21, maks. 47) idi. Hastalara lakozamid başlanmadan evvel ortalama dörtlü (min. 3, maks. 5) antiepileptik ilaç kullanıyordu. Lakozamid 100 mg/gün ile başlanıp maksimum 400 mg/ gün'e (ort. 323±30.2 mg/gün) yükseltildi. Hastalar ortalama 24 ay takip edildi. Lakozamid beş (%35.7) hastada nöbet sıklığını azaltırken, dokuz (%64.2) hastada ise etkisizdi. Beş (%35.7) hastada yan etki gözlenmiş olup en sık sersemlik ile karşılaşıldı. Sonuç:Parsiyel epilepsilerde lakozamid uygun kombinasyonlarda kullanıldığında güvenilir efektif bir ilaç olabilir. Fakat yan etki profili ve nö-betsizlik süresi üzerine daha fazla hastanın katıldığı ve daha uzun süreli takibin yapıldığı çok merkezli geniş çaplı çalışmalara ihtiyaç olduğunu düşünmekteyiz.

“…Furthermore, LCM showed efficacy in two models of chemically-induced SE. In the cobalt/homocysteine-induced model, LCM protected against GTC seizures and in the lithium chloride/pilocarpine model neuroprotective effects were seen [Stohr et al 2007;Bialer et al 2007;Stohr et al 2003]. …”

Section: Levetiracetammentioning

confidence: 99%

Review: Recent and future advances in the treatment of status epilepticus

Rosenow

Knake

2008

Ther Adv Neurol Disord

Status epilepticus (SE) is one of the most frequent neurological emergencies with an incidence of 20/100,000 per year and a mortality between 3% and 40% depending on etiology, age, SE type and duration. Generalized convulsive forms of SE (GTCSE), in particular, require aggressive treatment. Presently, only 55-80% of cases of GTCSE are controlled by initial therapy. Therefore, there is a need for new options for the treatment of SE. Here we review the current standard treatment including recent advances and provide a summary of preclinical and clinical data regarding treatment options which may become available in the near future. The initial treatment of SE usually consists of a benzodiazepine (preferably lorazepam 0.1 mg/kg) followed by phenytoin or fosphenytoin or valproic acid (where approved for SE therapy). With intravenous formulations of levetiracetam, available since 2006, and lacosamide, which is expected for autumn of 2008, new treatment options have become available, that should be evaluated in prospective controlled trials. If SE remains refractory, the induction of general anaesthesia using propofol, midazolam, thiopental, or pentobarbital is warranted in GTCSE.