scholarly journals CYP3A5*3 and C3435T MDR1 Polymorphisms in Prognostication of Drug-Resistant Epilepsy in Children and Adolescents

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Ewa Emich-Widera ◽  
Wirginia Likus ◽  
Beata Kazek ◽  
Paweł Niemiec ◽  
Anna Balcerzyk ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Cytochromes P450 ◽  
Mdr1 Gene ◽  
Drug Resistant ◽  
Pharmacoresistant Epilepsy ◽  
Glycoprotein P ◽  
C3435t Polymorphism ◽  
Transporter Protein ◽  
Drug Resistant Epilepsy

Drug-resistant epilepsies still remain one of the most profound problems of contemporary epileptology. Several mechanisms of drug resistance are possible; among them, genetic factors have a prominent place. Much importance is attached to genes, which encode enzymes that metabolize antiepileptic drugs CYP 3A, which belong to the family of cytochromes P450 and the genome of multidrug resistance, such as multidrug resistance 1 (MDR1) that expresses P-glycoprotein (P-gp), a drug transporter protein. The aim of the study was to assess the relation between polymorphism of gene CYP3A5 and polymorphism C3435T of MDR1 gene with the occurrence of focal, drug-resistant epilepsy in children and youths up to 18 years of age. The study comprised 85 patients, and their age range was from 33 months to 18 years of age, suffering from epilepsy, partly responding well to treatment, partly drug resistant. The polymorphism of both genes has been analysed using the PCR-RFLP method. The study failed to corroborate association between polymorphism CYP3A5*3 and C3435T polymorphism in MDR1 gene and pharmacoresistant epilepsy. The results of our research do not confirm the prognostic value of the polymorphisms examined in the prognostication of drug resistance in epilepsies.

scholarly journals Expressional Study of Permeability glycoprotein (P-gp) and Multidrug Resistance Protein 1 (MRP-1) in Drug-Resistant Mesial Temporal Lobe Epilepsy

2021 ◽  
pp. 1-31
Author(s):  
Mandeep Kaur ◽  
◽  
Tulika Gupta ◽  
Mili Gupta ◽  
Parampreet S. Kharbanda ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Mesial Temporal Lobe Epilepsy ◽  
Efflux Transporters ◽  
P Value ◽  
Drug Efflux ◽  
Drug Resistant ◽  
Glycoprotein P ◽  
Mesial Temporal Lobe ◽  
Drug Efflux Transporters

About 30% of epileptic patients do not react to anti-epileptic drugs leading to refractory seizures. The pathogenesis of drug-resistance in Mesial Temporal Lobe Epilepsy (MTLE) is not completely understood. Increased activity of drug-efflux transporters might be involved, resulting in subclinical concentrations of the drug at the target site. The major drug-efflux transporters are permeability glycoprotein (P-gp) and multidrug-resistance associated protein-1 (MRP-1). The major drawback so far is the expressional analysis of transporters in equal numbers of drug-resistant epileptic tissue and age-matched non-epileptic tissue. We have studied these two transporters in the sclerotic hippocampal tissues resected from the epilepsy surgery (n=15) and compared their expression profile with the tissues resected from non-epileptic autopsy cases (n=15). Statistically significant over expression of both P-gp (p-value <0.0001) and MRP-1 (p-value 0.01) at gene and protein levels was found in the MTLE cases. The fold change of P-gp was more pronounced than MRP-1. Immunohistochemistry of patient group showed increased immunoreactivity of P-gp at blood brain barrier and increased reactivity of MRP-1 in parenchyma. The results were confirmed by confocal immunofluorescence microscopy. The study demonstrated that P-gp in association with MRP-1 might be responsible for the multi-drug resistance in epilepsy

Multidrug Resistance 1 (MDR1) Gene Polymorphisms in Childhood Drug-Resistant Epilepsy

2010 ◽  
Vol 25 (12) ◽  
pp. 1485-1490 ◽  
Author(s):  
Asude Alpman ◽  
Ferda Ozkinay ◽  
Hasan Tekgul ◽  
Sarenur Gokben ◽  
Sacide Pehlivan ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Gene Polymorphisms ◽  
Mdr1 Gene ◽  
Drug Resistant ◽  
Drug Resistant Epilepsy

scholarly journals Association between C3435T polymorphism of MDR1 gene and the incidence of drug-resistant epilepsy in the population of Polish children

2016 ◽  
Vol 12 (1) ◽  
Author(s):  
Mariusz Stasiołek ◽  
Hanna Romanowicz ◽  
Katarzyna Połatyńska ◽  
Maciej Chamielec ◽  
Dominik Skalski ◽  
...  
Keyword(s):  
Mdr1 Gene ◽  
Drug Resistant ◽  
C3435t Polymorphism ◽  
Drug Resistant Epilepsy

scholarly journals Mechanisms of Drug Resistance in the Pathogenesis of Epilepsy: Role of Neuroinflammation. A Literature Review

2021 ◽  
Vol 11 (5) ◽  
pp. 663
Author(s):  
Elena D. Bazhanova ◽  
Alexander A. Kozlov ◽  
Anastasia V. Litovchenko
Keyword(s):  
Drug Resistance ◽  
Premature Death ◽  
Resistance Mechanisms ◽  
Biomedical Literature ◽  
Drug Resistant ◽  
Psychological Consequences ◽  
Text Documents ◽  
Neural Connections ◽  
Inflammatory Processes ◽  
Drug Resistant Epilepsy

Epilepsy is a chronic neurological disorder characterized by recurring spontaneous seizures. Drug resistance appears in 30% of patients and it can lead to premature death, brain damage or a reduced quality of life. The purpose of the study was to analyze the drug resistance mechanisms, especially neuroinflammation, in the epileptogenesis. The information bases of biomedical literature Scopus, PubMed, Google Scholar and SciVerse were used. To obtain full-text documents, electronic resources of PubMed Central and Research Gate were used. The article examines the recent research of the mechanisms of drug resistance in epilepsy and discusses the hypotheses of drug resistance development (genetic, epigenetic, target hypothesis, etc.). Drug-resistant epilepsy is associated with neuroinflammatory, autoimmune and neurodegenerative processes. Neuroinflammation causes immune, pathophysiological, biochemical and psychological consequences. Focal or systemic unregulated inflammatory processes lead to the formation of aberrant neural connections and hyperexcitable neural networks. Inflammatory mediators affect the endothelium of cerebral vessels, destroy contacts between endothelial cells and induce abnormal angiogenesis (the formation of “leaky” vessels), thereby affecting the blood–brain barrier permeability. Thus, the analysis of pro-inflammatory and other components of epileptogenesis can contribute to the further development of the therapeutic treatment of drug-resistant epilepsy.

scholarly journals Gene transfer of multidrug resistance into a factor-dependent human hematopoietic progenitor cell line: in vivo model for genetically transferred chemoprotection

Blood ◽  
1996 ◽  
Vol 87 (7) ◽  
pp. 2723-2731 ◽  
Author(s):  
P Schwarzenberger ◽  
S Spence ◽  
N Lohrey ◽  
T Kmiecik ◽  
DL Longo ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Gene Transfer ◽  
Hematopoietic Progenitor Cells ◽  
Mdr1 Gene ◽  
In Vivo Model ◽  
Hematopoietic Progenitor ◽  
Human Dna

To develop a rapid preclinical in vivo model to study gene transfer into human hematopoietic progenitor cells, MO-7e cells (CD-34+, c-kit+) were infected with multidrug resistance (MDR1)-containing retroviruses and then transplanted into nonobese diabetic severe combined immunodeficient mice (NOD SCID). MO-7e cells infected with a retrovirus encoding the human MDR1 cDNA showed integration, transcription, and expression of the transfered MDR1 gene. This resulted in a 20-fold increase in the resistance of MO-7e cells to paclitaxel in vitro. The expression of the MDR1 gene product was stable over a 6-month period in vitro without selection in colchicine. MO-7e and MDR1-infected MO-7e cells were transplanted into NOD SCID mice to determine whether MDR1 could confer drug resistance in vivo. A sensitive polymerase chain reaction method specific for human sequences was developed to quantitate the level of human cell engraftment in NOD SCID bone marrow (BM) cells. The percentage of human DNA in BM cells from MO-7e- transplanted mice was 10.9% and decreased to 0.7% in mice treated with paclitaxel. The percentage of human DNA in infected-MO-7e transplanted mice was 7.6% and that level was unchanged in mice treated with paclitaxel. These results show that expression of the MDR1 gene in human hematopoietic progenitor cells can confer functional drug resistance in an in vivo model.

scholarly journals The ILAE definition of drug resistant epilepsy and its clinical applicability compared with “older” established definitions

2015 ◽  
Vol 23 (1) ◽  
pp. 39-44
Author(s):  
Alexandra Rohracher ◽  
Judith Dobesberger ◽  
Claudia A. Granbichler ◽  
Julia Höfler ◽  
Giorgi Kuchukhidze ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Epilepsy Surgery ◽  
Treatment Process ◽  
Drug Resistant ◽  
Course Of Disease ◽  
Clinical Applicability ◽  
Specialized Center ◽  
Drug Resistant Epilepsy ◽  
Definition Of ◽  
Mean Time

SUMMARY Background. Early identification of potential epilepsy surgery candidates is essential to the treatment process. Aim. To evaluate the clinical applicability of the ILAE definition of drug resistant epilepsy and its potential in identifying surgical candidates earlier compared to three established “older” definitions of drug resistant epilepsy. Material and Methods. Retrospective analysis of 174 patients who underwent epilepsy surgery between 1998 and 2009. Clinical factors and course of disease were extracted from patients' charts. Drug resistant epilepsy was classified according to four definitions and the time until fulfillment of criteria compared. Results. Mean time to fulfillment of criteria of drug resistant epilepsy ranged from 11.8 (standard deviation (SD) 9.8) to 15.6 years (SD 11.3). Time to drug resistance was significantly longer applying the only definition, requiring failure of three antiepileptic drugs (AEDs) (Canada definition), whereas time to fulfillment of all other definitions did not differ. Fifty percent of all patients experienced a seizure free period of ≥1 year prior to being classified as drug resistant, 13% entered another 1-year remission after fulfilling any criteria for drug resistance. Conclusion. We conclude that the ILAE definition identifies drug resistant epilepsy, with similar latency like two of three formerly used definitions. It is an easy applicable tool to minimize the delay of referral to a specialized center. Intermittent remissions delay assessment of drug resistance for all definitions and 13% of patients enter a remission despite established drug resistance.

scholarly journals The Pharmacoresistant Epilepsy: An Overview on Existant and New Emerging Therapies

2021 ◽  
Vol 12 ◽  
Author(s):  
Antonella Fattorusso ◽  
Sara Matricardi ◽  
Elisabetta Mencaroni ◽  
Giovanni Battista Dell'Isola ◽  
Giuseppe Di Cara ◽  
...  
Keyword(s):  
Treatment Options ◽  
Current Evidence ◽  
Seizure Freedom ◽  
Symptomatic Therapy ◽  
Drug Resistant ◽  
Drug Trials ◽  
Pharmacoresistant Epilepsy ◽  
Emerging Therapies ◽  
Chronic Disorders ◽  
Drug Resistant Epilepsy

Epilepsy is one of the most common neurological chronic disorders, with an estimated prevalence of 0. 5 – 1%. Currently, treatment options for epilepsy are predominantly based on the administration of symptomatic therapy. Most patients are able to achieve seizure freedom by the first two appropriate drug trials. Thus, patients who cannot reach a satisfactory response after that are defined as pharmacoresistant. However, despite the availability of more than 20 antiseizure medications (ASMs), about one-third of epilepsies remain drug-resistant. The heterogeneity of seizures and epilepsies, the coexistence of comorbidities, and the broad spectrum of efficacy, safety, and tolerability related to the ASMs, make the management of these patients actually challenging. In this review, we analyze the most relevant clinical and pathogenetic issues related to drug-resistant epilepsy, and then we discuss the current evidence about the use of available ASMs and the alternative non-pharmacological approaches.

scholarly journals Drug Resistant Epilepsy Among Patients Attended The Neurosciences Hospital

2019 ◽  
Vol 13 (1) ◽  
pp. 108-115
Author(s):  
Nael Husain Zaer
Keyword(s):  
Drug Resistance ◽  
Medical History ◽  
Refractory Epilepsy ◽  
Seizure Freedom ◽  
Drug Resistant ◽  
Past Medical History ◽  
Number Of Patients ◽  
Drug Resistant Epilepsy ◽  
Patients With Epilepsy

Background: Drug resistant epilepsy is defined as failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules to achieve sustained seizure freedom. Up to 30% of patients referred to clinics with a diagnosis of pharmaco-resistant epilepsy may have been misdiagnosed, and many can be helped by optimizing their treatment.Pseudoresistance, in which seizures persist because the underlying disorder has not been adequately or appropriately treated, must be ruled out or corrected before drug treatment can be considered to have failed. Objectives: The objectives of this study were to determine the causes of drug failure in patients with epilepsy and to differentiate between drug resistant epilepsy and pseudoresistant epilepsy. Type of the study: This is a retrospective study. Method: It is conducted in Baghdad governorate at the epilepsy clinic in the neurosciences hospital during the period from the 1st of February through July 2013. Two hundred patients with refractory epilepsy were involved. These patients attended the epilepsy clinic during 2011 and 2012. The data was collected from the files of the patients including age, gender, weight, history of presenting illness, type of seizure, drugs used, duration of disease, EEG and imaging findings, compliance and follow up. Results: Drug resistance epilepsy constituted a prevalence of 24% (128) as the total number of patients with epilepsy attending the hospital during the same period was 527.The mean age of patients with refractory epilepsy was 25 years. Male were 56.5% (113/200) and urban residents were 70.5% (141/200). The study revealed that 64% (128/200) of refractory epilepsy was attributed to drug resistance; while the remaining proportion was pseudoresistance 36% (72/200). The main cause of pseudoresistance was poor compliance 36.1% (26/72).The most common type of seizure in the sampled patients was generalized tonic clonic seizures in 51.5% (103/200).Compliance was found to be statistically associated with abnormal EEG finding, past medical history (hypertension, cardiac diseases, encephalitis, diabetes mellitus and any significant history) and quality of follow up. The follow-up was found to be statistically associated with the family history, past medical history( encephalitis and hypertension) and compliance of patient. Conclusion:A considerable number of patientsdiagnosed as cases of drug resistant epilepsy had another explanation causing drug failure.The study recommends the application of consensus definition for drug resistant epilepsy and periodic evaluation of patients with drug resistant epilepsy to exclude pseudoresistance.

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