Efficacy Testing of Valproic Acid Compared to Ethosuximide in Monkey Model: II. Seizure, EEG, and Diurnal Variations

Lockard, Joan S.; Congdon, William C.; DuCharme, Larry L.; Patel, Indravadan H.

doi:10.1111/j.1528-1157.1977.tb04468.x

Cited by 31 publications

(12 citation statements)

References 14 publications

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“…Seizure frequency was reduced with high doses of VPA or CZP, even after cessation of the ASM. The enduring effects of VPA after medication discontinuation were first demonstrated in this primate model . These studies established ASM efficacy for seizure prophylaxis and suggest that long‐term risk modification requires high doses.…”

Section: Results: Nonhuman Primate Models Of Epilepsymentioning

confidence: 65%

“…Animals given pharmacologic prophylaxis had only partial seizures, whereas control animals exhibited secondarily generalized tonic‐clonic seizures (GTCS). This model compared the efficacy of valproic acid (VPA) and ethosuximide (ESM) . Low‐dose VPA reduced seizure frequency, duration, and severity but a higher dose was required to attenuate focal motor seizures.…”

Section: Results: Nonhuman Primate Models Of Epilepsymentioning

confidence: 99%

“…The enduring effects of VPA after medication discontinuation were first demonstrated in this primate model. 8 These studies established ASM efficacy for seizure prophylaxis and suggest that long-term risk modification requires high doses. This model was also used to evaluate vagus nerve stimulation (VNS) to treat seizures.…”

Section: The Study Of Potential Seizure Therapies In Experimental Mmentioning

confidence: 99%

“…This model compared the efficacy of valproic acid (VPA) and ethosuximide (ESM). 8 Low-dose VPA reduced seizure frequency, duration, and severity but a higher dose was required to attenuate focal motor seizures. Long-term seizure frequency was reduced with high VPA plasma levels.…”

Section: The Study Of Potential Seizure Therapies In Experimental Mmentioning

confidence: 99%

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Epilepsy in nonhuman primates

Croll¹,

Szabó

Abou‐Madi

et al. 2019

Epilepsia

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Objectives Nonhuman primates (NHPs) are model organisms for understanding the pathophysiology and treatment of epilepsy in humans, while data from human patients informs the diagnosis and treatment of NHP with seizures and epilepsy. We reviewed the literature and surveyed veterinarians at zoos and NHP research centers to (a) better define the range of seizures and epilepsy in NHP, (b) understand how NHPs can inform our knowledge of the pathophysiology and treatment of epilepsy in humans, and (c) identify gaps of knowledge and develop more effective guidelines to treat seizures and epilepsy in NHP. Methods We searched PrimateLit, PubMed, and Google Scholar for studies on experimental models of epilepsy in NHPs and on naturally occurring seizures and epilepsy in NHPs in captivity. In addition, we created a survey to assess methods to diagnose and treat epilepsy in NHPs. This survey was sent to 41 veterinarians at major international zoos and research facilities with NHP populations to study seizure phenomenology, diagnostic criteria for seizures and epilepsy, etiology, and antiseizure therapies in NHPs. Results We summarize the data from experimental and natural models of epilepsy in NHPs and case reports of epilepsy of unknown origin in captive primates. In addition, we present survey data collected from veterinarians at eight zoos and one research facility. Experimental data from NHP epilepsy models is abundant, whereas data from primates who develop epilepsy in the wild or in zoos is very limited, constraining our ability to advance evidence‐based medicine. Significance Characterization of seizure or epilepsy models in NHPs will provide insights into mechanisms and new therapies that cannot be addressed by other animal models. NHP research will better inform species‐specific diagnoses and outcomes.

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Section: Results: Nonhuman Primate Models Of Epilepsymentioning

confidence: 65%

Section: Results: Nonhuman Primate Models Of Epilepsymentioning

confidence: 99%

Section: The Study Of Potential Seizure Therapies In Experimental Mmentioning

confidence: 99%

Section: The Study Of Potential Seizure Therapies In Experimental Mmentioning

confidence: 99%

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Epilepsy in nonhuman primates

Croll¹,

Szabó

Abou‐Madi

et al. 2019

Epilepsia

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“…In addition to different seizure or epilepsy models in rodent species, larger mammalian species, including dogs and rhesus monkeys, have been used by some researchers to evaluate whether tolerance to AEDs develops during prolonged treatment. In an alumina-gel monkey model, Lockard et al (62) reported that VPA was effective in the plasma-level range of 50-150 μg/ml with an immediate but transitory effect of VPA on seizure frequency at low plasma levels, and a more permanent decrease in seizure frequency at the higher plasma levels. These data substantiate that tolerance to VPA occurs in some models, depending on the doses or plasma drug levels being studied.…”

Section: Demonstration Of Tolerance To Aeds In Different Models and Smentioning

confidence: 99%

Experimental and Clinical Evidence for Loss of Effect (Tolerance) during Prolonged Treatment with Antiepileptic Drugs

Löscher

Schmidt²

2006

Epilepsia

213

141

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Summary: Development of tolerance (i.e., the reduction in response to a drug after repeated administration) is an adaptive response of the body to prolonged exposure to the drug, and tolerance to antiepileptic drugs (AEDs) is no exception. Tolerance develops to some drug effects much more rapidly than to others. The extent of tolerance depends on the drug and individual (genetic?) factors. Tolerance may lead to attenuation of side effects but also to loss of efficacy of AEDs and is reversible after discontinuation of drug treatment. Different experimental approaches are used to study tolerance in laboratory animals. Development of tolerance depends on the experimental model, drug, drug dosage, and duration of treatment, so that a battery of experimental protocols is needed to evaluate fully whether tolerance to effect occurs. Two major types of tolerance are known. Pharmacokinetic (metabolic) tolerance, due to induction of AED-metabolizing enzymes has been shown for most firstgeneration AEDs, and is easy to overcome by increasing dosage. Pharmacodynamic (functional) tolerance is due to "adaptation" of AED targets (e.g., by loss of receptor sensitivity) and has been shown experimentally for all AEDs that lose activity during prolonged treatment. Functional tolerance may lead to complete loss of AED activity and cross-tolerance to other AEDs. Convincing experimental evidence indicates that almost all first-, second-, and third-generation AEDs lose their antiepileptic activity during prolonged treatment, although to a different extent. Because of diverse confounding factors, detecting tolerance in patients with epilepsy is more difficult but can be done with careful assessment of decline during long-term individual patient response. After excluding confounding factors, tolerance to antiepileptic effect for most modern and old AEDs can be shown in small subgroups of responders by assessing individual or group response. Development of tolerance to the antiepileptic activity of an AED may be an important reason for failure of drug treatment. Knowledge of tolerance to AED effects as a mechanism of drug resistance in previous responders is important for patients, physicians, and scientists.

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Valproic Acid

Bruni¹

1979

Arch Neurol

120

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Efficacy Testing of Valproic Acid Compared to Ethosuximide in Monkey Model: II. Seizure, EEG, and Diurnal Variations

Cited by 31 publications

References 14 publications

Epilepsy in nonhuman primates

Epilepsy in nonhuman primates

Experimental and Clinical Evidence for Loss of Effect (Tolerance) during Prolonged Treatment with Antiepileptic Drugs

Valproic Acid

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