Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations (original) (raw)
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Animal Models for Preclinical Antiepileptic Drug Research
Animal models are essential in preclinical anti eplilptic drug research. These models serve different purposes in epilepsy research and in drug discovery and development of anti epileptic drugs to evaluate efficacy, to determine mechanism of action, used to determine preclinical efficacy of new drugs during chronic administration, to study the mechanism of drug resistance and also used to study whether elileptogenesis alters the adverse effect potential of a given drug. A large number of in vivo animals models are used, some important which can be adapted and acclimatized to institutional laboratory settings discussed.
A Review: Animal Models for Screening Antiepileptic Drugs & Important Unani Anticonvulsant Drugs
Epilepsy is the world's most common serious disorder of the brain according to WHO. It is defined as the occurrence of transient paroxysms of excessive or uncontrolled discharges of neurons due to a number of causes leading to epileptic seizures. The identification of potential therapeutic agents for the treatment of epilepsy requires the use of seizure models. A large number of traditional drugs have been used in epilepsy since centuries. So, screening/investigating these drugs for their anticonvulsant activity to make an effective medicine in the treatment of epilepsy is auspicious. Different types of experimental models have been used to assess the anticonvulsant activity of these drugs such as Maximal electroshock seizure (MES) test, Pentylenetetrazole (PTZ) test, kindling animal model, strychnine model etc. These models can be either in vivo or in vitro, mechanism specific, mechanism independent, or seizure specific. The present article explains the types of experimental models used for screening of anticonvulsant activity of traditional drugs and some important scientifically proved Unani anticonvulsant drugs.
MODELS OF EPILEPSY USED IN ANTIEPILEPTIC DRUG DISCOVERY: A REVIEW Review Article
International journal of Pharmacy and Pharmaceutical Sciences, 2014
This article describes various experimental models of seizure and epilepsy. Epilepsy is characterised by recurrent unprovoked seizures. Antiepileptic drug discovery in animal models starts with the assumption that the experimental seizure model mimics human seizure. Hence a drug which suppresses ictogenesis or inhibits epileptogenesis in animal model is a potential antiepileptic drug for human and it needs further investigation. Phenytoin and Carbamazepine were identified with the help of relatively simple models like Maximal electroshock seizure and the pentylenetetrazole test. Lots of drugs were discovered with the help of these models but a big portion of patients still remains resistant to the available antiepileptic drugs. Again these simple seizure models are increasingly being questioned, are they providing us same type of drugs with same kind of mechanism of action? This question brings the importance of newer animal models that target epileptogenesis, pharmacoresistant epilepsy and models which mimic human epilepsy more closely. There is increased concern on agents for epilepsy disease modification and prevention. To solve these unmet needs, the research scientist must have a thorough knowledge of available animal models of epilepsy so that he can pick up the best model for his research. In this article, we are reviewing the diversity of animal models of epilepsy and their implications in antiepileptic drug discovery.
Animal models for the development of new neuropharmacological therapeutics in the status epilepticus
Current neuropharmacology, 2006
Status epilepticus (SE) is a major medical emergency associated with significant morbidity and mortality. SE is best defined as a continuous, generalized, convulsive seizure lasting > 5 min, or two or more seizures during which the patient does not return to baseline consciousness. The relative efficacy and safety of different drugs in the treatment of human SE should be determined in a prospective, randomized, blinded study. However, complementary animal models of SE are required to answer important questions concerning the treatment of SE because of the obvious difficulties of setting up such studies in clinical emergency conditions. This review offers an overview of the implementation and characteristics of some of the most prevalent animal models of SE currently in use. A description is also provide about how animal models of SE may facilitate the use of neurobiological techniques to successfully address critical questions in the drug treatment of SE. In particular, the exper...
Discovery of antiepileptic drugs
Neurotherapeutics, 2007
Despite the apparent success of the current discovery process, a significant need persists for more efficacious and less toxic antiepileptic drugs (AEDs). This is particularly true for patients whose seizures remain refractory to the currently available AEDs. This chapter will review the current process for AED discovery employed by the Anticonvulsant Drug Development Program at the University of Utah and other laboratories working toward the common goal of discovering better therapeutic options for patients living with epilepsy. It will discuss some of the inherent advantages and limitations of the primary animal models employed, while offering insight into potential future directions as we seek to better understand the pathophysiology underlying acquired epilepsy, therapy resistance, and epileptogenesis.
The Screening models for antiepileptic drugs: A Review
Journal of Drug Delivery and Therapeutics
Considering the prevalence of epilepsy and the problems associated with currently available antiepileptic drugs like side effects, resistance, safety issue and high cost, herbal medicine with fewer complications could be very appropriate alternative. Therefore in the present study, we have examined the antiepileptic properties of ethanolic extract of leaves in mice using maximal electroshock seizers (MES)test, Pentylenetetrazole (PTZ), induced seizures, strychnine induced convulsion, Isoniazid-induced convulsions, Picrotoxin-induced convulsions, Kainic acid (KA) model etc.There is increased concern on agents for epilepsy disease modification and prevention. To solve these unmet needs, the research scientist must have a thorough knowledge of available animal models of epilepsy so that he can pick up the best model for his research. In this article, we are reviewing the diversity of animal models of epilepsy and their implications in antiepileptic drug discovery. Keywords: Epilepsy, a...
Experimental chronic epilepsy in rats: A screening method for antiepileptic drugs
Pharmacological Research Communications, 1983
Rats were rendered epileptic by subpial injection of an FeCI 3 solution. Epileptiform discharges, recorded by chronically implanted extradural electrodes, were evident within 48 h of surgery and persisted for more than 6 months. It is demonstrated that this model is useful for studying new antiepileptic agents since a series of clinically effective drugs (diazepa~, clonazepam, Na phenobarbital, primidone, carbamezepine, ethosuximide, diphenylhydantoin, Na valproate, GABOB) show an activity which is dose-dependent and within a range satisfactorily related to human dosages.
Use of epileptic animals for adverse effect testing
Epilepsy Research, 2002
A crucial parameter deciding the clinical utility of new antiepileptic drugs (AEDs) is the therapeutic index expressing the margin between anticonvulsant and adverse effects. The latter is commonly quantified during preclinical testing in the rotarod test in normal, healthy rodents. However, the validity of using normal animals for adverse effect predictions in epilepsy patients is questionable. Limbic kindling of rodents induced by corneal kindling of mice and amygdala kindling of rats confirm that epileptic animals are more susceptible to the behavioral and cognitive alterations following acute administration of NMDA antagonists and certain established AEDs. This appears to represent a permanent reactivity specific for limbic kindling since it is absent in rats after chemical kindling with pentylenetetrazole. Animal species with inborn epilepsy, including audiogenic and photosensitive animals, are not revealing an enhanced susceptibility to the behavioral alterations induced by NMDA antagonists. In contrast, these induce severe adverse effects in genetic absence epilepsy rats where certain AEDs also are associated with a more marked deterioration of motor function than in normal animals. This appears in line with several complications with AED use in man being linked to an interaction with the dysfunction of the brain imposed by the epileptic condition. Thus, it is important to involve epileptic animals in preclinical adverse effect testing, in particular when evaluating new AED candidates with novel or unknown mechanisms. In that respect, limbic kindling appears to represent a sensitive and relevant approach.
Difficulties in Treatment and Management of Epilepsy and Challenges in New Drug Development
Epilepsy is a serious neurological disorder that affects around 50 million people worldwide. Almost 30% of epileptic patients suffer from pharmacoresistance, which is associated with social isolation, dependent behaviour, low marriage rates, unemployment, psychological issues and reduced quality of life. Currently available antiepileptic drugs have a limited efficacy, and their negative properties limit their use and cause difficulties in patient management. Antiepileptic drugs can provide only symptomatic relief as these drugs suppress seizures but do not have ability to cure epileptogenesis. The long term use of antiepileptic drugs is limited due to their adverse effects, withdrawal symptoms, deleterious interactions with other drugs and economic burden, especially in developing countries. Furthermore, some of the available antiepileptic drugs may even potentiate certain type of seizures. Several in vivo and in vitro animal models have been proposed and many new antiepileptic drugs have been marketed recently, but large numbers of patients are still pharmacoresistant. This review will highlight the difficulties in treatment and management of epilepsy and the limitations of available antiepileptic drugs and animal seizure models.
Iris Publishers LLC, 2018
Epilepsy affects millions of people world-wide with wideranging health and economic consequences [1]. A first-line approach to the control of epilepsy is through the administration of anticonvulsant drugs sometimes referred to as antiepileptics [2]. These medicines help control seizure activity but the evidence for controlling disease progression in patients is not firmly established [3]. There are many antiepileptics approved for clinical use [2] that dampen excitatory neurotransmission through different mechanisms including positive allosteric modulation of GABA (e.g., diazepam, valproic acid) and blockade of ion channels (e.g., gabapentin, lacosamide)