Three ATP-binding cassette (ABC)-superfamily multidrug efflux pumps are known to be responsible for chemoresistance; P-glycoprotein (ABCB1), MRP1 (ABCC1) and ABCG2 (BCRP). These transporters play an important role in normal physiology by protecting tissues from toxic xenobiotics and endogenous metabolites. Hydrophobic amphipathic compounds, including many clinically used drugs, interact with the substrate-binding pocket of these proteins via flexible hydrophobic and H-bonding interactions. These efflux pumps are expressed in many human tumors, where they likely contribute to resistance to chemotherapy treatment. However, the use of efflux-pump modulators in clinical cancer treatment has proved disappointing. Single nucleotide polymorphisms in ABC drug-efflux pumps may play a role in responses to drug therapy and disease susceptibility. The effect of various genotypes and haplotypes on the expression and function of these proteins is not yet clear, and their true impact remains controversial.

ABC multidrug transporters: structure, function and role in chemoresistance

Nearly a quarter of patients with seizures have drug-resistant epilepsy. This review examines how this diagnosis should be established and how to recognize pseudoresistance. It explains possible mechanisms of drug-resistant epilepsy and presents treatment strategies.

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Drug-Resistant Epilepsy

Importance A study published in 2000 showed that more than one-third of adults with epilepsy have inadequate control of seizures with antiepileptic drugs (AEDs). This study evaluates overall treatment outcomes in light of the introduction of more than 1 dozen new AEDs in the past 2 decades. Objective To assess long-term treatment outcome in patients with newly diagnosed and treated epilepsy. Design, Setting, and Participants This longitudinal observational cohort study was conducted at the Epilepsy Unit of the Western Infirmary in Glasgow, Scotland. A total of 1795 individuals who were newly treated for epilepsy with AEDs between July 1, 1982, and October 31, 2012, were included in this analysis. All patients were followed up for a minimum of 2 years (until October 31, 2014) or until death, whichever came sooner. Data analysis was completed between March 2015 and May 2016. Exposures Treatment with antiepileptic drugs for patients newly diagnosed with epilepsy. Main Outcomes and Measures Seizure control was assessed at the end of the study period. Probability of achieving 1-year seizure freedom was estimated for each AED regimen prescribed. Multivariable models assessed the associations between risk factors and AED treatment outcome after adjustments were made for demographic and clinical characteristics. Results Of the 1795 included patients, 964 (53.7%) were male; the median age was 33 years (range, 9-93 years). At the end of the study period, 1144 patients (63.7%) had been seizure free for the previous year or longer. Among those achieving 1-year seizure freedom, 993 (86.8%) were taking monotherapy and 1028 (89.9%) had achieved seizure control with the first or second AED regimens. Of the total patient pool, 906 (50.5%) remained seizure free for 1 year or longer with the initial AED. If this AED failed, the second and third regimens provided an additional 11.6% and 4.4% likelihoods of seizure freedom, respectively. Only 2.12% of patients attained optimal seizure control with subsequent AEDs. Epilepsy that was not successfully controlled with the first AED had 1.73 times greater odds of not responding to treatment for each subsequent medication regimen (odds ratio, 1.73; 95% CI, 1.56-1.91;P  Conclusions and Relevance Despite the availability of many new AEDs with differing mechanisms of action, overall outcomes in newly diagnosed epilepsy have not improved. Most patients who attain control do so with the first or second AED. The probability of achieving seizure freedom diminishes substantially with each subsequent AED regimen tried. More than one-third of patients experience epilepsy that remains uncontrolled.

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Treatment Outcomes in Patients With Newly Diagnosed Epilepsy Treated With Established and New Antiepileptic Drugs: A 30-Year Longitudinal Cohort Study.

Background and aims Alcohol use is a major contributor to injuries, mortality and the burden of disease. This review updates knowledge on risk relations between dimensions of alcohol use and health ...

https://onlinelibrary.wiley.com/doi/pdf/10.1111/add.13757

The relationship between different dimensions of alcohol use and the burden of disease-an update.

Although largely neglected in earlier literature, sudden unexpected death in epilepsy (SUDEP) is the most important epilepsy-related mode of death, and is the leading cause of death in people with chronic uncontrolled epilepsy. Research during the past two to three decades has shown that incidence varies substantially depending on the epilepsy population studied, ranging from 0.09 per 1000 patient-years in newly diagnosed patients to 9 per 1000 patient-years in candidates for epilepsy surgery. Risk profiles have been delineated in case-control studies. These and other studies indicate that SUDEP mainly occurs in the context of a generalised tonic-clonic seizure. However, it remains unclear why a seizure becomes fatal in a person that might have had many similar seizures in the past. Here, we review SUDEP rates, risk factors, triggers, and proposed mechanisms, and critically assess potential preventive strategies. Gaps in knowledge are discussed and ways forward are suggested.

/pdf/sudden-unexpected-death-in-epilepsy-current-knowledge-and-2o1f79qbu2.pdf

Sudden unexpected death in epilepsy: current knowledge and future directions.

Predictors of pharmacoresistant epilepsy.

Summary Background People with epilepsy are at increased risk of premature death compared with the general population. Many clinicians are unsure whether and when this issue should be broached with their patients. We analysed mortality in patients with newly diagnosed and chronic epilepsy over a 20-year period. Methods Patients who attended the epilepsy service at the Western Infirmary in Glasgow, UK between 1981 and 2001, with newly diagnosed epilepsy (n=890) or referred after receiving unsuccessful treatment elsewhere (n=2689) were included in the study. Mortality data were obtained from the General Registrar Office for Scotland. Causes of death were ascertained from death certificates and primary care and health authority records. The two patient cohorts were compared with age-matched and sex-matched Scottish comparison groups. Standardised mortality ratios (SMR) were calculated for each epilepsy type, 10-year age band, and cause of death category. Findings Newly diagnosed patients had a 42% increase in mortality (SMR 1·42, 95% CI 1·16–1·72) compared with the comparison group. Increased mortality was recorded in those who had not responded to treatment, with no increase in risk observed in patients who were seizure free. In the chronic epilepsy cohort, there was more than double the expected number of deaths (2·05, 1·83–2·26). The incidence of sudden unexpected death in epilepsy was 1·08 and 2·46 per 1000 patient-years in patients with newly diagnosed and chronic epilepsy, respectively. The greatest excess in mortality was reported in patients younger than 30 years. Interpretation Mortality risks and preventive strategies should be discussed with patients with epilepsy when treatment fails or is refused despite recurrent seizures.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(06)70448-3.pdf

Mortality in adults with newly diagnosed and chronic epilepsy: a retrospective comparative study

To the Editor: We read with great interest the manuscript by Sills and colleagues (1), who investigated association between the C3435T polymorphism in the human multidrug resistance ABCB1 (previously MDR1) gene and response to antiepileptic drug (AED) treatment. However, several significant items from this article should be discussed. In their study, the authors investigated clinical response to AED therapy in 400 patients, irrespective of individual drug exposure. This is the major restricting factor in this work, which can jeopardize all possible conclusions. Valproate (VPA) is not a substrate of P-glycoprotein (PGP), and therefore an association between the polymorphism of ABCB1 (MDR1) gene and a response to VPA therapy cannot be investigated (2). As no data were in this work were about the kinds of AEDs the patients were taking, it is highly possible that some of them were taking VPA, which compromises the results of this work. Furthermore, the authors did not mention anything about possible combinations of the AEDs that the patients were using. Some suggestions are found in the literature that different AEDs can have inhibitory or stimulatory effects on the function and expression of PGP (3). The possible effect of PGP polymorphism on a clinical response to pharmacotherapy is a very important issue in the contemporary approach to treating epilepsy. Therefore before establishing the effect of PGP on the AED polytherapy, its precise effect on each AED monotherapy must be established. Even more important, the authors did not pay attention to some concomitant medications in their group of patients. It is well known that some of the widely consumed drugs (verapamil, nifedipine, diltiazem, nicardipine, amiodarone, propranol, trifluoperazine, chlorpromazine, erythromycin, ceftriaxone, steroids, reserpine, etc.) are inhibitors of PGP (2,4). Coadministration of these drugs with AEDs can significantly influence the results of the study. Furthermore, only the patients with a history of alcoholrelated seizures were excluded from the study, which leaves the possibility that the patients with symptomatic epilepsy (underlying tumors, cortical dysgenesis, cerebrovascular stroke, hippocampal sclerosis, etc.) were included (5). Such symptomatic epilepsies are difficult to

Lack of association between the C3435T polymorphism in the human multidrug resistance (MDR1) gene and response to antiepileptic drug treatment

Mortality in epilepsy.

Longitudinal studies of newly diagnosed epilepsy in children and adults have identified prognostic factors that allow early identification of patients whose seizures are likely to remain uncontrolled with antiepileptic medication. Results from outcome studies may be subject to bias, depending on the setting (community versus clinic), design (retrospective versus prospective) and characteristics of the patient cohort studied (age, types of epilepsy, specific comorbidities). Nevertheless, factors such as early response to medication, underlying aetiology, and number of seizures prior to initiation of treatment have consistently been found to be predictive of seizure outcomes. Other variables such as age, electroencephalographic findings and the presence or absence of psychiatric co-morbidities have been correlated with outcomes in some analyses. This review has examined studies of seizure outcomes in adults and children with newly diagnosed epilepsy identifying the risk factors that are associated with subsequent refractory epilepsy.

Rajiv Mohanraj

Papers

Predictors of pharmacoresistant epilepsy.

Mortality in adults with newly diagnosed and chronic epilepsy: a retrospective comparative study

Lack of association between the C3435T polymorphism in the human multidrug resistance (MDR1) gene and response to antiepileptic drug treatment

Mortality in epilepsy.

Early predictors of outcome in newly diagnosed epilepsy