Adjunctive therapy for the treatment of primary generalized tonic-clonic seizures: focus on oncedaily lamotrigine

Idiopathic generalized epilepsies are frequently encountered by neurologists, and providing an accurate diagnosis and effective treatment(s) are the necessary components of successful patient care. With the introduction of new antiepileptic medications, physicians are better equipped for this goal. The immediate-release formulation of lamotrigine (LTG-IR) has been approved for primary generalized tonic-clonic seizures since 2006. The extended-release formulation of lamotrigine (LTG-XR) was approved for adjunctive therapy in patients with primary generalized tonic-clonic seizures in 2010. Although its exact mechanism of action is not yet fully elucidated, studies have demonstrated multiple possible pathways. Although both the LTG-IR and LTG-XR formulations have similar side effects and are generally well tolerated, LTG-XR may be preferable for its ease of use, which may increase patient compliance and decrease fluctuations in serum drug levels. The ease of conversion between the formulations also makes lamotrigine an attractive treatment option for patients with primary generalized tonic-clonic seizures. LTG-IR has demonstrated efficacy in treatment-resistant idiopathic generalized epilepsies in both adults and children. Although there are still some questions regarding all possible applications of LTG-XR, as further research is being done, it is clear that LTG-XR may hold some advantages when compared with other anticonvulsants

Monensin Improves the Effectiveness of meso-Dimercaptosuccinate when Used to Treat Lead Intoxication in Rats

Among divalent cations, the ionophore monensin shows high activity and selectivity for the transport of lead ions (Pb(2+)) across phospholipid membranes. When coadministered to rats that were receiving meso-dimercaptosuccinate for treatment of Pb intoxication, monensin significantly increased the amount of Pb removed from femur, brain, and heart. It showed a tendency to increase Pb removal from liver and kidney but had no effect of this type in skeletal muscle. Tissue levels of several physiologic (calcium, cobalt, copper, iron, magnesium, manganese, molybdenum, zinc) and nonphysiologic (arsenic, cadmium, chromium, nickel, strontium) elements were also determined after the application of these compounds. Among the physiologic elements, a number of significant changes were seen, including both rising and falling values. The size of these changes was typically around 20% compared with control values, with the largest examples seen in femur. These changes often tended to reverse those of similar size that had occurred during Pb administration. Among the nonphysiologic elements, which were present in trace amounts, the changes were smaller in number but larger in size. None of these changes appears likely to be significant in terms of toxicity, and there were no signs of overt toxicity under any of the conditions employed. Monensin may act by cotransporting Pb(2+) and OH(–) ions out of cells, in exchange for external sodium ions. The net effect would be to shuttle intracellular Pb(2+) to extracellular dimercaptosuccinic acid thereby enhancing its effectiveness. Thus, monensin may be useful for the treatment of Pb intoxication when applied in combination with hydrophilic Pb(2+) chelators

Metastable Atrial State Underlies the Primary Genetic Substrate for MYL4 Mutation-Associated Atrial Fibrillation

Background:Atrial fibrillation (AF) is the most common clinical arrhythmia and is associated with heart failure, stroke, and increased mortality. The myocardial substrate for AF is poorly understood because of limited access to primary human tissue and mechanistic questions around existing in vitro or in vivo models.Methods:Using an MYH6:mCherry knock-in reporter line, we developed a protocol to generate and highly purify human pluripotent stem cell–derived cardiomyocytes displaying physiological and molecular characteristics of atrial cells. We modeled human MYL4 mutants, one of the few definitive genetic causes of AF. To explore non–cell-autonomous components of AF substrate, we also created a zebrafish Myl4 knockout model, which exhibited molecular, cellular, and physiologic abnormalities that parallel those in humans bearing the cognate mutations.Results:There was evidence of increased retinoic acid signaling in both human embryonic stem cells and zebrafish mutant models, as well as abnormal expression and localization of cytoskeletal proteins, and loss of intracellular nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide + hydrogen. To identify potentially druggable proximate mechanisms, we performed a chemical suppressor screen integrating multiple human cellular and zebrafish in vivo endpoints. This screen identified Cx43 (connexin 43) hemichannel blockade as a robust suppressor of the abnormal phenotypes in both models of MYL4 (myosin light chain 4)–related atrial cardiomyopathy. Immunofluorescence and coimmunoprecipitation studies revealed an interaction between MYL4 and Cx43 with altered localization of Cx43 hemichannels to the lateral membrane in MYL4 mutants, as well as in atrial biopsies from unselected forms of human AF. The membrane fraction from MYL4-/- human embryonic stem cell derived atrial cells demonstrated increased phospho-Cx43, which was further accentuated by retinoic acid treatment and by the presence of risk alleles at the Pitx2 locus. PKC (protein kinase C) was induced by retinoic acid, and PKC inhibition also rescued the abnormal phenotypes in the atrial cardiomyopathy models.Conclusions:These data establish a mechanistic link between the transcriptional, metabolic and electrical pathways previously implicated in AF substrate and suggest novel avenues for the prevention or therapy of this common arrhythmia.</p

Xenobiotic-Metabolizing Enzymes Elevated in Multiple Mouse Models of Slow Aging.

Single gene mutations, dietary manipulations, and pharmacological agents can increase lifespan and delay aging in multiple species, including mice. Mutations that impair growth hormone (GH) and/or insulin-like growth factor 1 (IGF 1) production, as well as caloric restriction (CR), have been shown to enhance both longevity and resistance to multiple forms of cytotoxic stress. The mechanism that enables slow-aging mice to become more resistant to stress is not known. In this study, we discovered that the ERK mitogen-activated protein kinase (MAPK) signal cascade and xenobiotic-metabolizing enzymes (XME) are differentially regulated in multiple long-lived mouse models. Activation of the ERK pathway in response to cytotoxic stress (e.g. CdCl2, H2O2, paraquat, and UV-C light) was attenuated in cultured primary skin-derived fibroblasts from GH/IGF 1-deficient Snell dwarf mice and growth hormone receptor knockout (GHRKO) mice. Similar attenuation of ERK phosphorylation was also observed in liver tissue from Snell dwarf mice exposed to the oxidative toxin diquat. Xenobiotic metabolism plays a central role in detoxification of cytotoxic stressors and has been proposed to influence the rate of aging. XMEs are similarly upregulated in multiple GH/IGF 1-deficient dwarf mice and also in CR mice. In this study, we show that XME genes are similarly elevated in “crowded litter” (CL) mice, whose lifespan has been increased by food restriction limited to the first 3 weeks of life, and also in mice treated with rapamycin. Cytochrome P450s, flavin monooxygenases, hydroxyacid oxidase, and metallothioneins were found to be significantly elevated in similar proportions in each of the models of delayed aging tested, whether these are based on mutation, diet, drug treatment, or transient early intervention. The same pattern of mRNA elevation can be induced by 2 weeks of treatment with tert-butylhydroquinone (tBHQ), an oxidative stressor known to activate Nrf2-dependent target genes. These results suggest that upregulation of xenobiotic metabolism is a hallmark of long-lived mice and may facilitate screens for agents worth testing in intervention-based lifespan studies.PHDCellular and Molecular BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/94063/1/msteinba_1.pd

stephenturner/annotables: Ensembl 90

Updated annotations to Ensembl version 90 http://www.ensembl.info/blog/2017/08/22/ensembl-90-has-been-released