A Novel Approach to Refractory Epilepsy by Targeting Pgp peripherally and centrally: Therapeutic targets and Future perspectives

2020 ◽  
Vol 19 ◽  
Author(s):  
Urvashi Langeh ◽  
Pooja Chawla ◽  
Ghanshyam Das Gupta ◽  
Shamsher Singh
Keyword(s):  
Drug Resistance ◽  
Refractory Epilepsy ◽  
Present Review ◽  
Management Approach ◽  
Channel Blockers ◽  
Drug Efflux ◽  
Drug Resistant ◽  
P Glycoprotein ◽  
Novel Approach ◽  
Drug Resistant Epilepsy

Abstract:: Refractory epilepsy is a type of epilepsy involving seizures uncontrolled by first or second-line anticonvulsant drugs at a regular therapeutic dose. Despite considerable growth in epileptic pharmacotherapy, one-third of the patients are resistant to current therapies. In this, the mechanisms responsible for resistant epilepsy are either increased expulsion of an-tiepileptic drugs (AEDs) by multidrug resistance (MDR) transporters from the epileptogenic tissue or reduced sensitivity of drug in epileptogenic brain tissue. The difficulty to treat refractory epilepsy is because of drug resistance due to cellular drug efflux, use of drug monotherapy, and subtherapeutic dose administration. Increased expression of Pgp is also responsible for resistance epilepsy or refractory epilepsy. Increase glutamate expression via inhibition of cyclooxygenase-II (COX-II) en-zyme also upregulate P-glycoprotein (Pgp) expression and augment instance of recurrent seizures. Peripheral and central in-hibition of Pgp is a powerful tool to control this drug resistance epilepsy. Drug resistance primarily involves multidrug re-sistance (MDR1) gene which is responsible for encoding P-glycoprotein (PgP1 or MDR1). Currently, there is no drug under clinical practice which inhibits MDR1. The present review cites some drugs like calcium channel blockers, COX-II inhibi-tors, and glutamate receptors antagonists that inhibit P-gp. The exploitation of these targets may emerge as a beneficial ap-proach for patients with drug-resistant epilepsy. The present review further highlights the mechanistic role of Pgp in drug-resistant epilepsy, glutamate role in drug efflux, and management approach.

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.

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 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.

Potential Role of Dual NF-κB and Oxidative Stress Pathway Inhibitor, OT-304 as a Novel Drug Resistance-Reversing Agent.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4211-4211
Author(s):  
Shaker A. Mousa ◽  
Ghanshyam Patil ◽  
Abdelhadi Rebbaa
Keyword(s):  
Oxidative Stress ◽  
Drug Resistance ◽  
Tumor Cells ◽  
Genetic Alterations ◽  
Potential Candidate ◽  
Drug Resistant ◽  
P Glycoprotein ◽  
And Oxidative Stress

Abstract The development of resistance to chemotherapy represents an adaptive biological response by tumor cells that leads to treatment failure and patient relapse. During the course of their evolution (intrinsic resistance) or in response to chemotherapy (acquired resistance), tumor cells may undergo genetic alterations to possess a drug resistant phenotype. Dysregulation of membrane transport proteins and cellular enzymes, as well as altered susceptibility to commit to apoptosis are among the mechanisms that contribute to the genesis of acquired drug resistance. Recently, the development of approaches to prevent and/or to reverse this phenomenon has attracted special interest and a number of drug candidates have been identified. Despite strong effects observed for these candidates in vitro, however, most of them fail in vivo. In the present study, we have identified a novel small molecule inhibitor of dual NF-κB and oxidative stress pathways, OT-304, as a potential candidate to reverse drug resistance. Initial investigations indicate that this compound effectively inhibits proliferation of doxorubicin-sensitive and doxorubicin-resistant cells to the same extent, suggesting that it is capable of bypassing the development of drug resistance. Additional experiments reveal that OT-304 enhances cancer cell sensitivity to doxorubicin and to etoposide, particularly in cells characterized by the over-expression of the drug transporter P-glycoprotein. These findings suggest that either the expression/and or the function of P-glycoprotein could be affected by OT-304. In vivo studies using tumor xenografts in nude mice showed that OT-304 is also capable of preventing the growth of drug resistant cancer cells. This later finding further confirms the role of OT-304 as a drug resistance-reversing agent and warrants further pre-clinical and clinical investigation to determine its efficacy in treating aggressive tumors.

scholarly journals Potentially Pathological Alpha-Pattern as a Variant of Vigilance EEG in Drug-Resistant Epilepsy

2017 ◽  
Vol 8 (4) ◽  
pp. 48-56
Author(s):  
Aleksandr A. Chukhlovin ◽  
Mikhail V. Aleksandrov ◽  
Sergey A. Lytaev ◽  
Vugar R. Kasumov ◽  
Marina E. Pavlovskaya ◽  
...  
Keyword(s):  
Alpha Rhythm ◽  
Refractory Epilepsy ◽  
Functional Decline ◽  
Clinical Signs ◽  
Epileptic Seizures ◽  
Alpha Activity ◽  
Drug Resistant ◽  
Scalp Eeg ◽  
Russian Scientific Research Institute ◽  
Drug Resistant Epilepsy

As a result of pathomorphosis affecting the mechanisms of electrical activity generation interictal EEG may show reduced epileptiform changes whereas clinically apparent epileptic seizures may be present. In these cases patterns of dominant alpha activity are sometimes recorded on the scalp. In this study variations of alpha activity in patients with refractory epilepsy are classified. A group of 50 refractory epilepsy patients aged between 20 and 55 years who were submitted to Polenov Russian Scientific Research Institute of Neurosurgery in 2014-2017 was included in this study. They underwent scalp EEG as a part of their presurgical assessment. In 12 cases patterns of potentially pathological alpha activity were observed. Three variations of alpha-patterns were described: 1) alpha-rhythm with decreased regional diversity and a marked synchronization in temporal areas; 2) alpha-rhythm with reduced epileptiform complexes integrated into the spindles, 3) decelerated non-rhythmic alpha activity distorted by the higher frequency components. Distinguished varieties of potentially pathological alpha-activity according to their order here represent gradual functional decline of normal thalamo-cortical interaction. Considering clinical manifestation of drug-resistant epilepsy with frequent seizures in these patients, reported varieties of alpha activity can not be interpreted as Landolt’s syndrome (forced normalization of EEG). Invasive electrocorticographic monitoring demonstrated that bursts of sharpened polyphasic waves coinciding with alpha-rhythm on scalp EEG are consistent with epileptic discharges on the brain cortex surface. This allows to think of these components as correlates of epileptic activity. Therefore, on a number of occasions in patients with epilepsy a dissonance between clinical signs and electroencephalographic patterns recorded during restful wakefulness may be observed, when epileptiform components are absent or reduced to nonspecific complexes.

scholarly journals Two Lytic Bacteriophages That Depend on theEscherichia coliMulti-Drug Efflux GenetolCand Differentially Affect Bacterial Growth and Selection

2018 ◽  
Author(s):  
Alita R. Burmeister ◽  
Rose G. Bender ◽  
Abigail Fortier ◽  
Adam J. Lessing ◽  
Benjamin K. Chan ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Antibiotic Resistance ◽  
Resistance Gene ◽  
Bacterial Growth ◽  
Bacterial Pathogens ◽  
Antibiotic Resistance Gene ◽  
Resistant Bacteria ◽  
Drug Efflux ◽  
Drug Resistant ◽  
Resistant Mutants

AbstractBacterial pathogens are increasingly evolving drug resistance under natural selection from antibiotics in medicine, agriculture, and nature. Meanwhile, bacteria ubiquitously encounter bacteriophages and can rapidly evolve phage resistance. However, the role of phages in interacting with drug-resistant and drug-sensitive bacteria remains unclear. To gain insight into such relationships, we screened for and characterized phages that rely on the multi-drug efflux pump genetolC. First, we screened a collection of 33 environmental and commercialEscherichia coliphages for their ability to infect cells that lackedtolC. Our screen revealed two phages that had reduced efficiency of plating (EOP) on thetolCknockout compared to wild type. We further characterized these phages with bacterial growth curves, transmission electron microscopy, and analysis of phage-resistant mutants. Phage U136B is a curly-tailed virus in familySiphoviridaewith no ability to infect atolCknockout, suggesting TolC is the U136B receptor. Phage 132 is a contractile-tailed virus in familyMyoviridaewith reduced EOP on cells lackingompFand its positive regulatorstolCandompR. U136B and 132 differentially effect bacterial growth and lysis, and U136B-resistant mutants contain mutations of thetolCgene. Together, these results show that thetolCgene involved in drug resistance can modify bacteria-phage interactions in multiple ways, altering bacterial lysis and selection. These new phages offer utility for studying evolution, tradeoffs, and infection mechanisms.ImportanceBacteria face strong selection by antibiotics in medicine and agriculture, resulting in increasing levels of drug resistance among bacterial pathogens. Slowing this process will require an understanding of the environmental contexts in which drug resistance evolutionarily increases or decreases. In this study, we investigate two newly-isolated bacteriophages that rely on a bacterial antibiotic resistance gene. These bacteriophages vary in their interactions with drug-resistant bacteria, with one of the phages selecting for phage-resistant mutants that have mutations in the antibiotic resistance gene. Further study of these new phages will be useful to understanding evolutionary tradeoffs and how phages might be applied in natural settings to reverse the problem of drug resistance.

scholarly journals “Ictal” Bradyarrhythmias in Patients with Drug-Resistant Epilepsy: Results of Long-Term Heart Rhythm Monitoring

Kardiologiia ◽  
2021 ◽  
Vol 60 (12) ◽  
pp. 90-96
Author(s):  
S. E. Serdyuk ◽  
K. V. Davtyan ◽  
S. G. Burd ◽  
E. S. Mishina ◽  
O. M. Drapkina ◽  
...  
Keyword(s):  
Heart Rhythm ◽  
Epileptic Seizures ◽  
Channel Blockers ◽  
Drug Resistant ◽  
Disorder Of Consciousness ◽  
Functional Changes ◽  
Long Duration ◽  
Drug Resistant Epilepsy ◽  
Patients With Epilepsy

Aim      To determine the type and incidence of ictal bradyarrhythmias in patients with drug-resistant types of epilepsy by long-term electrocardiogram (ECG) monitoring.Material and methods  Subcutaneous ECG monitors programed for recording pauses >3 sec and episodes of bradycardia ≤45 bpm were implanted in 193 patients with persistent epileptic seizures without organic pathology of the myocardium. Recording was activated by the patient/family at the onset of epileptic seizure. The follow-up period was 36 months with visits to the clinic every three months.Results For 36 months of monitoring, 6494 ECG fragments were recorded. Ictal bradycardia was observed in 6.7 % of patients, including ictal asystole in 2.6 % of patients. Episodes of bradycardia and asystole during epileptic seizures were transient and developed significantly more frequently in men, patients with long duration of the disease, bilateral tonic-clonic or focal seizures with disorder of consciousness, during sleep, on the background of treatment with several antiepileptic agents, mostly from the group of potassium channel blockers.Conclusion      Bradyarrhythmias accompanying epileptic seizures are transient and reproducible from seizure to seizure. They reflect functional changes in the myocardium and do not determine the life prediction for patients with epilepsy without organic pathology of the heart.

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