An automated drug delivery system for focal epilepsy

Stein, Alan G.; Eder, Hans G.; Blum, David; Drachev, A. I.; Fisher, Robert S.

doi:10.1016/s0920-1211(99)00107-2

Cited by 134 publications

(74 citation statements)

References 13 publications

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“…The direct infusion of the neuroactive drug in the precise brain area where it acts may be an appropriate therapeutic option. 24 This possibility has already been explored to treat epilepsy by several authors [25][26][27] who found different effects over the initiation, spread, and behavioral features of seizures, depending on which was the area infused.…”

Section: Intracerebral Infusionmentioning

confidence: 99%

“…For example, local infusion of diacepam was effective to diminish seizures both in models of epilepsy by pilocarpine injection-induced seizures after local cortical cobalt application and in the bicuculline model. 27,33,34 The acute intra-amygdalar injection of muscimol, a GABA-A receptor agonist, or of antagonists of AMPA (␣-amino-3-hidroxi-5-metil-4-isoxazol-propionate, one of the glutamate receptors), also suppresses amygdala-kindled seizures. 35 The local infusion of other drugs or neurotransmitters, such as lidocaine or taurine, the glutamate antagonists, or the serotonin and 2-chloro-adenosine agonists, all of which act through non-GABAergic mechanism, has been effective in models of epilepsy, such as kindling.…”

Section: Intracerebral Infusion In the Epileptic Focusmentioning

confidence: 99%

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Intraventricular and Intracerebral Delivery of Anti-epileptic Drugs in the Kindling Model

Barcia

Gallego

2009

Neurotherapeutics

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Summary:A means to avoid the pharmacokinetic problems affecting the anti-epileptic drugs may be their direct intracerebroventricular (ICV) or intracerebral delivery. This approach may achieve a greater drug concentration at the epileptogenic area while minimizing it in other brain or systemic areas, and thus it could be an interesting therapeutic alternative in drug-resistant epilepsies. The objective of this article is to review a series of experiments, ranging from actute ICV injection to continuous intracerebral infusion of anti-epileptic drugs or grafting of neurotransmitter producing cells, in experimental models, especially in the kindling model of epilepsy in the rat.Acute ICV injection of phenytoin, phenobarbital or carbamacepine is able to diminish the intensity of kindling seizures, but it is also associated with a high neurologic toxicity, especially phenobarbital. Continuous ICV infusion of anti-epileptic drugs can effectively control seizures, but neurologic toxicity is not improved compared with systemic delivery. However, systemic toxicity may be improved, as in the case of valproic acid, whose continuous ICV infusion results in very low plasmatic or hepatic drug concentrations. Continuous intracerebral infusion at the epileptogenic area was studied as an alternative to minimize neurologic toxicity. Thus, intra-amygdalar infusion of gamma-aminobutyric acid (GABA) controls seizures with minimal neurotoxicity in amygdala-kindled rats. Similarly, continuous infusion of GABA into the dorsomedian nucleus of the thalamus improves seizure spread, while not affecting the local epileptogenic activity at the amygdala. Grafting of GABA releasing cells may reduce kindling parameter severity without behavioral side effects.We may conclude that ICV or intracerebral delivery of antiepileptic drugs or neurotransmitters may be a useful technique to modulate epilepsy.

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Section: Intracerebral Infusionmentioning

confidence: 99%

Section: Intracerebral Infusion In the Epileptic Focusmentioning

confidence: 99%

Intraventricular and Intracerebral Delivery of Anti-epileptic Drugs in the Kindling Model

Barcia

Gallego

2009

Neurotherapeutics

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“…Focally administered small-molecule antiepileptic drugs (such as diazepam and carbamazepine) and inhibitory substances (such as adenosine, GABA, and muscimol) have been demonstrated to prevent seizure generation and inhibit ongoing seizures in animal models (Eder et al, 1997;Stein et al, 2000;Anschel et al, 2004;Fisher and Chen, 2006;Ludvig et al, 2010). However, these agents have a short duration of action because they diffuse from the site of delivery or are biologically inactivated.…”

Section: Introductionmentioning

confidence: 99%

Long-Lasting Attenuation of Amygdala-Kindled Seizures after Convection-Enhanced Delivery of Botulinum Neurotoxins A and B into the Amygdala in Rats

Gąsior

Tang

Rogawski

2013

J Pharmacol Exp Ther

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Botulinum neurotoxins (BoNTs) are well recognized to cause potent, selective, and long-lasting neuroparalytic actions by blocking cholinergic neurotransmission to muscles and glands. There is evidence that BoNT isoforms can also inhibit neurotransmission in the brain. In this study, we examined whether locally delivered BoNT/A and BoNT/B can attenuate kindling measures in amygdala-kindled rats. Male rats were implanted with a combination infusion cannula-stimulating electrode assembly into the right basolateral amygdala. Fully kindled animals received a single infusion of vehicle or BoNT/A or BoNT/B at doses of 1, 3.2, or 10 ng over a 20-minute period by convectionenhanced delivery. Electrographic (EEG) and behavioral kindling measures were determined at selected times during the 3-to 64-day period after the infusion. BoNT/B produced a dose-dependent elevation in after-discharge threshold and duration and a reduction in the seizure stage and duration of behavioral seizures that lasted for up to 50 days after infusion. BoNT/A had similar effects on EEG measures; behavioral seizure measures were also reduced, but the effect did not reach statistical significance. The effects of both toxins on EEG and behavioral measures progressively resolved during the latter half of the observation period. Animals gained weight normally, maintained normal body temperature, and did not show altered behavior. This study demonstrates for the first time that locally delivered BoNTs can produce prolonged inhibition of brain excitability, indicating that they could be useful for the treatment of brain disorders, including epilepsy, that would benefit from long-lasting suppression of neurotransmission within a circumscribed brain region.

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“…One therapeutic approach currently under investigation in animal models is the delivery of antiepileptic medication directly into the seizure focus in the brain (Kubek et al, 1998;Stein et al, 2000;Kohane et al, 2002;Tamargo et al, 2002). This strategy has the advantage of avoiding problems of whole-brain and systemic toxicity but requires that the action of the antiepileptic compound be long-lasting to prevent seizures for an extended period of time.…”

Section: Introductionmentioning

confidence: 99%

Antiepileptic Effects of Botulinum Neurotoxin E

Costantin¹,

Bozzi²,

Richichi³

et al. 2005

J. Neurosci.

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Experimental studies suggest that the delivery of antiepileptic agents into the seizure focus might be of potential utility for the treatment of focal-onset epilepsies. Botulinum neurotoxin E (BoNT/E) causes a prolonged inhibition of neurotransmitter release after its specific cleavage of the synaptic protein synaptosomal-associated protein of 25 kDa (SNAP-25). Here, we show that BoNT/E injected into the rat hippocampus inhibits glutamate release and blocks spike activity of pyramidal neurons. BoNT/E effects persist for at least 3 weeks, as determined by immunodetection of cleaved SNAP-25 and loss of intact SNAP-25. The delivery of BoNT/E to the rat hippocampus dramatically reduces both focal and generalized kainic acid-induced seizures as documented by behavioral and electrographic analysis. BoNT/E treatment also prevents neuronal loss and long-term cognitive deficits associated with kainic acid seizures. Moreover, BoNT/Einjected rats require 50% more electrical stimulations to reach stage 5 of kindling, thus indicating a delayed epileptogenesis. We conclude that BoNT/E delivery to the hippocampus is both antiictal and antiepileptogenic in experimental models of epilepsy.

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An automated drug delivery system for focal epilepsy

Cited by 134 publications

References 13 publications

Intraventricular and Intracerebral Delivery of Anti-epileptic Drugs in the Kindling Model

Intraventricular and Intracerebral Delivery of Anti-epileptic Drugs in the Kindling Model

Long-Lasting Attenuation of Amygdala-Kindled Seizures after Convection-Enhanced Delivery of Botulinum Neurotoxins A and B into the Amygdala in Rats

Antiepileptic Effects of Botulinum Neurotoxin E

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