The Course of Seizure Disorders in Patients With Malignant Gliomas

Moots, Paul L.; Maciunas, Robert J.; Eisert, Donald R.; Parker, Robert A.; LaPorte, K.; Abou‐Khalil, Bassel

doi:10.1001/archneur.1995.00540310091021

Cited by 214 publications

(162 citation statements)

References 13 publications

Supporting

Mentioning

149

Contrasting

Unclassified

Order By: Relevance

“…In humans, PHY is predominantly metabolized by the cytochrome P450 2C isozymes (ϳ80% by CYP2C9 and 20% by CYP2C19) and is a recognized inducer of CYP2B6, CYP2C9, and CYP3A4 (34 -36). Because more than 40% of patients with brain tumors experience disease-related seizures (37,38), drugdrug interactions between anticancer agents and antiepileptic drugs such as PHY can have significant clinical consequences (39). It has been reported that PHY induction of CYP2B6 results in altered pharmacokinetics of the antineoplastics cyclophosphamide and ifosfamide, which are frequently co-administered with PHY (40,41).…”

Section: Phy Activates and Translocates Hcar In Vivo Inmentioning

confidence: 99%

Human Constitutive Androstane Receptor Mediates Induction of CYP2B6 Gene Expression by Phenytoin

Wang

Faucette

Moore

et al. 2004

Journal of Biological Chemistry

139

100

View full text Add to dashboard Cite

Compared with its rodent orthologs, little is known about the chemical specificity of human constitutive androstane receptor (hCAR) and its regulation of hepatic enzyme expression. Phenytoin (PHY), a widely used antiepileptic drug, is a potent inducer of CYP2B6 in primary human hepatocytes, but does not activate human pregnane X receptor (PXR) significantly in cellbased transfection assays at the same concentrations associated with potent induction of CYP2B6. Based on this observation, we hypothesized that PHY may be a selective activator of hCAR. In primary human hepatocytes, expression of CYP2B6 reporter genes containing phenobarbital-responsive enhancer module (PBREM) or PBREM/xenobiotic-responsive enhancer module (XREM) response elements were activated up to 14-and 28-fold, respectively, by 50 M PHY. By contrast, parallel experiments in HepG2 cell lines co-transfected with an hPXR expression vector did not show increased reporter activity. These results indicated that a PXR-independent pathway, which is retained in primary hepatocytes, is responsible for PHY induction of CYP2B6. Further experiments revealed that PHY effectively translocates hCAR from the cytoplasm into the nucleus in both primary human hepatocytes and CAR ؊/؊ mice. Compared with vehicle controls, PHY administration significantly increased CYP2B6 reporter gene expression, when this reporter construct was delivered together with hCAR expression vector into CAR ؊/؊ mice. However, PHY did not increase reporter gene expression in CAR ؊/؊ mice in the absence of hCAR vector, implying that CAR is essential for mediating PHY induction of CYP2B6 gene expression. Taken together, these observations demonstrate that, in contrast to most of the known CYP2B6 inducers, PHY is a selective activator of CAR in humans.Induction of cytochrome P450 2B (CYP2B) 1 expression by xenobiotics, including clinically used drugs, is mediated by activation of the nuclear receptors constitutive androstane receptor (CAR) and/or pregnane X receptor (PXR) through response elements located in the promoter region of CYP2B genes. In contrast to rodent CYP2B genes, mounting evidence suggests that human PXR (hPXR) may be a key receptor in the regulation of human CYP2B6 gene expression (1-3). hPXR ligands, including rifampicin (RIF), phenobarbital (PB), troglitazone, clotrimazole (CLZ), and SR12813 have been reported to induce CYP2B6 gene expression (1, 4 -7). Recently, fourteen commercially available compounds, including weak, moderate, and strong inducers of CYP2B6 and CYP3A4, were used to compare the potency and magnitude of CYP2B6 and CYP3A4 induction and activation of hPXR in primary cultured hepatocytes and hepatoma cell-based reporter gene assays, respectively. Results from these studies indicate that CYP2B6 induction is highly correlated with the activation of hPXR for most compounds (3). Among the efficacious CYP2B6 inducers evaluated, most activate hPXR but not hCAR, such as RIF and CLZ (CLZ was even reported as a hCAR deactivator by Moore et al. (8)), whereas others can a...

show abstract

Section: Phy Activates and Translocates Hcar In Vivo Inmentioning

confidence: 99%

Human Constitutive Androstane Receptor Mediates Induction of CYP2B6 Gene Expression by Phenytoin

Wang

Faucette

Moore

et al. 2004

Journal of Biological Chemistry

139

100

View full text Add to dashboard Cite

show abstract

“…Most patients with a suspected brain tumor then need to undergo a neurosurgical procedure, which is in itself associated with an increased risk of seizures. Thus, the control of seizures in the perioperative phase is an important goal in brain tumor management (4, 5,11,13,20,25,29).…”

Section: Introductionmentioning

confidence: 99%

Intravenous and oral levetiracetam in patients with a suspected primary brain tumor and symptomatic seizures undergoing neurosurgery: the HELLO trial

et al. 2011

View full text Add to dashboard Cite

BACKGROUND: Levetiracetam (LEV) is a newer anticonvulsant with a favorable safety profile. There seem to be no relevant drug interactions, and an intravenous formulation is available. Therefore, LEV might be a suitable drug for the perioperative anticonvulsive therapy of patients with suspected brain tumors undergoing neurosurgery. METHODS: In this prospective study (NCT00571155) patients with suspected primary brain tumors and tumor-related seizures were perioperatively treated with oral and intravenous LEV up to 4 weeks before and until 4 weeks after a planned neurosurgical procedure. FINDINGS: Thirty patients with brain tumor-related seizures and intended neurosurgery were included. Three patients did not undergo the scheduled surgery after enrollment, and two patients were lost to follow-up. Therefore, 25 patients were fully evaluable. After initiation of therapy with LEV, 100% of the patients were seizure-free in the pre-surgery phase (3 days up to 4 weeks before surgery), 88% in the 48 h post-surgery phase and 84% in the early follow-up phase (48 h to 4 weeks post surgery). Treatment failure even after dose escalation to 3,000 mg/day occurred in three patients. No serious adverse events related to the treatment with LEV occurred. CONCLUSION: Our data show the feasibility and safety of oral and intravenous LEV in the perioperative treatment of tumor-related seizures. Although this was a single arm study, the efficacy of LEV appears promising. Considering the side effects and interactions of other anticonvulsants, LEV seems to be a favorable option in the perioperative treatment of brain tumor-related seizures.

show abstract

“…[50][51][52] Twenty to 40% of all brain tumor patients have experienced a seizure by the time their brain tumor is diagnosed. 3,4,11,12,[14][15][16][53][54][55][56][57][58][59][60][61] In these patients, the need for anticonvulsant medication is clear. Patients who have not experienced a seizure remain at risk, however, and at least 20 to 45% more (depending on factors such as tumor histology, location, age, and treatment) will ultimately develop seizures.…”

mentioning

confidence: 99%

Practice parameter: Anticonvulsant prophylaxis in patients with newly diagnosed brain tumors [RETIRED]

et al. 2000

View full text Add to dashboard Cite

Overview. The Quality Standards Subcommittee seeks to develop scientifically sound, clinically relevant practice parameters for the practice of neurology. Practice parameters are strategies for patient management that assist physicians in clinical decision making. A practice parameter is one or more specific recommendations based on analysis of evidence on a specific clinical problem. These might include diagnosis, symptoms, treatment, or procedure evaluation. American Academy of Neurology (AAN) members have requested the publication of a practice parameter on the use of prophylactic anticonvulsants in patients with primary and metastatic brain tumors.Justification. Physicians often administer anticonvulsant medication prophylactically to patients with brain tumors, despite the lack of definitive evidence that prophylactic anticonvulsant therapy is effective in preventing first seizures. [1][2][3][4] If anticonvulsant medications were free of side effects, their prophylactic use might be attractive even without such evidence. However, discomfort, expense, and inconvenience result from drug treatment and periodic monitoring of serum drug concentrations. Typical anticonvulsant-induced side effects, including cognitive impairment, myelosuppression, liver dysfunction, and dermatologic reactions (ranging from minor rashes to life-threatening Stevens-Johnson syndrome), appear to occur more frequently in patients with brain tumors than in other patient groups, 3,5-16 although direct comparison studies have not been published. A spectrum of side effects unique to patients with brain tumors must also be considered. Phenytoin, carbamazepine, and phenobarbital reduce the efficacy of corticosteroids, 17-21 which are administered almost universally to brain tumor patients. In addition, the ability of these anticonvulsants to stimulate the cytochrome P450 enzyme system results in markedly accelerated metabolism of a wide spectrum of chemotherapeutic agents including nitrosoureas, paclitaxel, cyclophosphamide, topotecan, irinotecan, thiotepa, 9-aminocampo-thecin, adriamycin, and methotrexate.22-34 As a result, inadequate chemotherapeutic dosing of brain tumor patients has been identified recently as a widespread and critically important problem. 35 Conversely, corticosteroids and many chemotherapeutic agents alter the metabolism of anticonvulsants, making anticonvulsant under-and overdosing more common. [35][36][37][38][39][40][41][42][43][44][45] The potential immunosuppressive effect of anticonvulsant medications represents an additional risk to this already immunocompromised patient population. [46][47][48][49] In 1998, more than 170,000 patients were diagnosed with brain metastases, and more than 34,000 developed primary brain tumors. [50][51][52] Twenty to 40% of all brain tumor patients have experienced a seizure by the time their brain tumor is diagnosed. 3,4,11,12,[14][15][16][53][54][55][56][57][58][59][60][61] In these patients, the need for anticonvulsant medication is clear. Patients who have not experienced a seiz...

show abstract

The Course of Seizure Disorders in Patients With Malignant Gliomas

Cited by 214 publications

References 13 publications

Human Constitutive Androstane Receptor Mediates Induction of CYP2B6 Gene Expression by Phenytoin

Human Constitutive Androstane Receptor Mediates Induction of CYP2B6 Gene Expression by Phenytoin

Intravenous and oral levetiracetam in patients with a suspected primary brain tumor and symptomatic seizures undergoing neurosurgery: the HELLO trial

Practice parameter: Anticonvulsant prophylaxis in patients with newly diagnosed brain tumors [RETIRED]

Contact Info

Product

Resources

About