Phenytoin and Congeners

Kutt, Henn; Harden, Cynthia L.

doi:10.1007/978-3-642-60072-2_9

Cited by 12 publications

(11 citation statements)

References 89 publications

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“…Using female Wistar rats, we have previously shown in the kindling model of TLE that maintenance of plasma PHT concentrations within or above the therapeutic range (10–20 μg/ml; Hvidberg, 1985; Kutt and Harden, 1999) is possible by starting treatment with a loading dose of 75 mg/kg PHT i.p., followed by once daily administration of 50 mg/kg i.p. (Rundfeldt and Löscher, 1993).…”

Section: Resultsmentioning

confidence: 99%

“…PHT has only a relatively narrow therapeutic concentration range. At slightly higher plasma concentrations, acute toxic effects such as ataxia and somnolence may occur (Kutt and Harden, 1999). Furthermore, PHT may exert proconvulsant effect at such toxic concentrations in both patients and laboratory animals, leading to worsening of seizures (Löscher et al, 1998; Perucca et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…1). As with PB, several preliminary experiments were performed with PHT to develop a dosing protocol with maximum tolerated doses, resulting in maintenance of plasma drug concentrations within or above the therapeutic range (10–20 μg/ml; Hvidberg, 1985; Kutt and Harden, 1999) over 24 h/day, 7 days/week. Based on these preliminary experiments in nonepileptic rats (see ), we chose a dosing protocol with an i.p.…”

Section: Methodsmentioning

confidence: 99%

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Resistance to Phenobarbital Extends to Phenytoin in a Rat Model of Temporal Lobe Epilepsy

2007

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Summary:Purpose: Most patients who are resistant to the first antiepileptic drug (AED) treatment are also resistant to a treatment with a second or third AED, indicating that patients who have an inadequate response to initial treatment with AEDs are likely to have refractory epilepsy. Animal models of refractory epilepsy are important tools to study mechanisms of AED resistance and develop new treatment strategies for counteracting resistance. We have recently described a rat model of temporal lobe epilepsy (TLE), in which spontaneous recurrent seizures (SRS) develop after a status epilepticus induced by sustained electrical stimulation of the basolateral amygdala. Prolonged treatment of epileptic rats with phenobarbital (PB) resulted in two subgroups, PB responders and PB nonresponders.Methods: In the present study we examined if rats with PBresistant seizures are also resistant to phenytoin (PHT), using continuous EEG/video recording of spontaneous seizures.Results: First, a new group of 15 epileptic rats was produced and selected by treatment with PB into responders (8 rats) and nonresponders (6 rats), respectively. During subsequent treatment with PHT, the doses of PHT had to be individually adjusted for each rat to avoid toxicity. Treatment with PHT led to complete seizure control in two animals and a >50% reduction of seizure frequency in three other rats, which were considered PHT responders. In nine of the remaining rats, PHT did not exert any clear anticonvulsant effect, so that these rats were considered nonresponders. Plasma levels of PHT did not differ significantly between responders and nonresponders. When comparing the PB and PHT nonresponder groups, five of the six PB-resistant rats (83%) were also resistant to PHT, demonstrating that rats that have an inadequate response to initial treatment with PB are likely to be also resistant to treatment with a second AED.Conclusions: The AED-resistant rats of our model meet the definition of pharmacoresistance in animal models, that is, persistent seizure activity not responding to at least two AEDs at maximum tolerated doses. This new model of pharmacoresistant TLE may be useful in the targeted development of new therapies for refractory epilepsy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Resistance to Phenobarbital Extends to Phenytoin in a Rat Model of Temporal Lobe Epilepsy

2007

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“…Phenytoin is eliminated predominately by CYP2C9‐ and CYP2C19‐dependent hepatic metabolism (4, 18). CYP2C9 handles the major portion (90%) of the dose, and CYP2C19 a minor portion (10%) (19).…”

Section: Discussionmentioning

confidence: 99%

Effect of CYP2C19 genetic polymorphism on pharmacokinetics of phenytoin and phenobarbital in Japanese epileptic patients using Non-linear Mixed Effects Model approach

Yukawa

Mamiya

2006

J Clin Pharm Ther

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“…17 Metabolism of diazepam has been reported to be enhanced as a result of induction of hepatic drug-metabolizing enzymes following phenytoin therapy as shown in an earlier study of Kutt and Harden (1999) 18 and Dhillon and Richens (1981). 10 However, in the present study, the combination of sub-effective doses of phenytoin and diazepam showed synergistic (additive) effect (combination showed 100% protection).…”

Section: Interactions Seen Between Anti-epileptics With Diazepammentioning

confidence: 94%

Study of potential drug-drug interactions between benzodiazepines and four commonly used antiepileptic drugs in mice

Shah

Rana

Patel

2014

Int J Basic Clin Pharmacol

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Phenytoin and Congeners

Cited by 12 publications

References 89 publications

Resistance to Phenobarbital Extends to Phenytoin in a Rat Model of Temporal Lobe Epilepsy

Resistance to Phenobarbital Extends to Phenytoin in a Rat Model of Temporal Lobe Epilepsy

Effect of CYP2C19 genetic polymorphism on pharmacokinetics of phenytoin and phenobarbital in Japanese epileptic patients using Non-linear Mixed Effects Model approach

Study of potential drug-drug interactions between benzodiazepines and four commonly used antiepileptic drugs in mice

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