Differences between the concentrations of antiepileptic drugs in normal and pathological human brain

Sironi, V. A.; Ravagnati, L.; Ettorre, G; Cabrini, G; Marossero, F

doi:10.1007/bf00542551

Cited by 8 publications

(3 citation statements)

References 13 publications

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“…Unfortunately the orders of B/S ratios reported in literature are not equivocal. Sironi et al (17,18) The fact that Rambeck et al, who studied autopsy ma-terial, found higher B/S ratios for PHT than any of the other authors coincides with their remarkable observation that the protein free fractions of PHTin the serum of the deceased patients was generally much higher (ca 15'/0) than that in the usual routine samples (7-1 0%).…”

Section: Measurements In Extracts Of Human Brain Have Beenmentioning

confidence: 74%

“…On the average the relationship found between drug concentrations in brain tissue and serum (B/S ratio) werenotfarfromunity (between 0.7and 1.7)forphenytoin, phenobarbital, primidone and carbamazepine. The authors which have compared grey and white matter (12,15,17,18) always found higher concentrations in white matter than in the less lipoid grey substance. This can be related to the lipophilic character of the drugs mentioned.…”

Section: Measurements In Extracts Of Human Brain Have Beenmentioning

confidence: 97%

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A Pharmacokineticist's Criticism

2009

Acta Neurologica Scandinavica

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Section: Measurements In Extracts Of Human Brain Have Beenmentioning

confidence: 74%

Section: Measurements In Extracts Of Human Brain Have Beenmentioning

confidence: 97%

A Pharmacokineticist's Criticism

2009

Acta Neurologica Scandinavica

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“…Possible explanations include the following: The regional differences in PHT effect may be caused by regional differences of PHT brain levels. PHT brain levels, however, have been reported to be almost equal between the individual areas in the gray matter of the neocortex (Firemark et al, 1963), and the brain level in the hippocampus was higher than in the neocortex (Sironi et al, 1982).…”

Section: Discussionmentioning

confidence: 96%

Antiepileptic Effects Under Steady State of Phenytoin Serum Levels Produced in Acute Experiments

et al. 1987

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The antiepileptic effects of phenytoin (PHT) were examined during steady-state serum levels. Experiments were conducted on 69 adult male rabbits weighing 2.5-3.5 kg. A steady state of one or two different PHT serum levels per rabbit was produced with intravenous (i.v.) injections of loading and infusion doses. A train of focal and generalized seizure discharges (SDs) induced by electrical stimulation was compared before and after dosing with PHT. The results showed that PHT levels of 10-40 micrograms/ml induce inhibitory effects, shortening the duration of neocortical focal SDs. The inhibitory effects paralleled the PHT levels and were proportionally related to epileptogenicity in individual neocortical areas. At serum levels under approximately 5-10 micrograms/ml, the spread of secondarily generalized SDs originating from neocortical focal SDs was suppressed more than the shortening of the duration of the primary focus. On the other hand, PHT showed no effects or only slight inhibitory effects on hippocampal SDs, and the SDs spread from them even at levels of 15-40 micrograms/ml. Electroshock (ES)-induced generalized SDs were slightly suppressed in duration at levels of 20-30 micrograms/ml. Moreover, both the focal and the generalized SDs were greatly prolonged at high serum levels (greater than 40 micrograms/ml), although such facilitative effects were rare. The clinical contributions of these results to PHT treatment in human epilepsy are discussed.

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Phenytoin reduces 5-aminolevulinic acid-induced protoporphyrin IX accumulation in malignant glioma cells

2012

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Epileptic seizures are among the presenting clinical signs of malignant glioma patients, frequently necessitating treatment with antiepileptic drugs (AEDs). The efficacy of 5-aminolevulinic acid (5-ALA)-based intraoperative fluorescence-guided surgery and photodynamic therapy (PDT) in glioblastoma multiforme (GBM) patients depends on the specific accumulation and total amount of intracellularly synthesized protoporphyrin IX (PpIX) in tumour cells. In this study, we investigated the effect of the AEDs phenytoin (PHY) and levetiracetam (LEVE) on 5-ALA-induced PpIX accumulation in two glioma cell lines (U373 MG and U-87 MG) and primary GBM cells isolated from a human biopsy. After treatment with PHY and LEVE for three days cells were incubated with 1 mM: 5-ALA for 4 h and PpIX accumulation was determined by fluorescence measurement. We observed a decrease in PpIX synthesis of up to 55 ± 12 % in primary GBM cells after incubation with phenytoin. This reduction was dose-dependent for all tested cell lines and primary GBM cells. LEVE on the other hand did not alter PpIX concentration in GBM cells. PDT was performed in vitro by irradiating the GBM cells with light doses from 0.5 to 10 J cm(-2) at 627 nm after AED and 5-ALA treatment. Although less PpIX accumulated in PHY-treated cells, efficacy of PDT was not affected. We assume that damage to the mitochondrial membrane by PHY inhibits PpIX synthesis in vitro, because we showed mitochondrial dysfunction as a result of reduced mitochondrial membrane potential in PHY-treated cells. No change in glutathione status was observed. To evaluate further the effect of PHY on PpIX fluorescence, and to establish its significance in clinical practice, animal and clinical studies are required, because the results presented here imply PHY may reduce intracellular accumulation of PpIX in patients with high-grade gliomas.

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Differences between the concentrations of antiepileptic drugs in normal and pathological human brain

Cited by 8 publications

References 13 publications

A Pharmacokineticist's Criticism

A Pharmacokineticist's Criticism

Antiepileptic Effects Under Steady State of Phenytoin Serum Levels Produced in Acute Experiments

Phenytoin reduces 5-aminolevulinic acid-induced protoporphyrin IX accumulation in malignant glioma cells

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