- Glutamatergic Modulators in Depression. [Journal Article]
- HRHarv Rev Psychiatry 2018 Feb 20
- Both preclinical and clinical studies have implicated glutamatergic system dysfunction in the pathophysiology of mood disorders such as bipolar depression and major depressive disorder. In particular...
Both preclinical and clinical studies have implicated glutamatergic system dysfunction in the pathophysiology of mood disorders such as bipolar depression and major depressive disorder. In particular, rapid reductions in depressive symptoms have been noted in response to subanesthetic doses of the glutamatergic modulator ketamine in subjects with major depressive disorder or bipolar depression. These results have prompted the repurposing or development of other glutamatergic modulators, both as monotherapy or adjunctive to other therapies. Here, we highlight the evidence supporting the antidepressant effects of various glutamatergic modulators, including (1) broad glutamatergic modulators (ketamine, esketamine, dextromethorphan, dextromethorphan-quinidine [Nuedexta], AVP-786, nitrous oxide [N2O], AZD6765), (2) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (CP-101,606/traxoprodil, MK-0657 [CERC-301]), (3) glycine-site partial agonists (D-cycloserine, GLYX-13, sarcosine, AV-101), and (4) metabotropic glutamate receptor modulators (AZD2066, RO4917523/basimglurant, JNJ40411813/ADX71149, R04995819 [RG1578]).
- Targeted gene panel and genotype-phenotype correlation in children with developmental and epileptic encephalopathy. [Journal Article]
- EREpilepsy Res 2018 Feb 12; 141:48-55
- CONCLUSIONS: Targeted gene-panel sequencing is a useful diagnostic tool for DEE in children, and genotype-phenotype correlations are helpful in anticipating the clinical progression and treatment efficacy among these patients.
- Molecular Features Underlying Selectivity in Chicken Bitter Taste Receptors. [Journal Article]
- FMFront Mol Biosci 2018; 5:6
- Chickens sense the bitter taste of structurally different molecules with merely three bitter taste receptors (Gallus gallustaste 2 receptors, ggTas2rs), representing a minimal case of bitter percepti...
Chickens sense the bitter taste of structurally different molecules with merely three bitter taste receptors (Gallus gallustaste 2 receptors, ggTas2rs), representing a minimal case of bitter perception. Some bitter compounds like quinine, diphenidol and chlorpheniramine, activate all three ggTas2rs, while others selectively activate one or two of the receptors. We focus on bitter compounds with different selectivity profiles toward the three receptors, to shed light on the molecular recognition complexity in bitter taste. Using homology modeling and induced-fit docking simulations, we investigated the binding modes of ggTas2r agonists. Interestingly, promiscuous compounds are predicted to establish polar interactions with position 6.51 and hydrophobic interactions with positions 3.32 and 5.42 in all ggTas2rs; whereas certain residues are responsible for receptor selectivity. Lys3.29and Asn3.36are suggested as ggTas2r1-specificity-conferring residues; Gln6.55as ggTas2r2-specificity-conferring residue; Ser5.38and Gln7.42as ggTas2r7-specificity conferring residues. The selectivity profile of quinine analogs, quinidine, epiquinidine and ethylhydrocupreine, was then characterized by combining calcium-imaging experiments andin silicoapproaches. ggTas2r models were used to virtually screen BitterDB compounds. ~50% of compounds known to be bitter to human are likely to be bitter to chicken, with 25, 20, 37% predicted to be ggTas2r1, ggTas2r2, ggTas2r7 agonists, respectively. Predicted ggTas2rs agonists can be tested within vitroandin vivoexperiments, contributing to our understanding of bitter taste in chicken and, consequently, to the improvement of chicken feed.
- Significance of Coronary Artery Spasm Diagnosis in Patients With Early Repolarization Syndrome. [Journal Article]
- JAJ Am Heart Assoc 2018 Feb 07; 7(4)
- CONCLUSIONS: Approximately 40% of patients with CAS with documented VF and inferolateral J wave did not experience chest symptoms at the first VF, and could have been misdiagnosed as having ERS. The use of the spasm provocation test is considered essential to differentiate patients for optimal medical treatment.
- Predicting drug-induced arrhythmias by multiscale modeling. [Journal Article]
- IJInt J Numer Method Biomed Eng 2018 Feb 09
- Drugs often have undesired side effects. In the heart, they can induce lethal arrhythmias such as torsades de pointes. The risk evaluation of a new compound is costly and can take a long time, which ...
Drugs often have undesired side effects. In the heart, they can induce lethal arrhythmias such as torsades de pointes. The risk evaluation of a new compound is costly and can take a long time, which often hinders the development of new drugs. Here we establish a high resolution, multiscale computational model to quickly assess the cardiac toxicity of new and existing drugs. The input of the model is the drug-specific current block from single cell electrophysiology; the output is the spatio-temporal activation profile and the associated electrocardiogram. We demonstrate the potential of our model for a low risk drug, ranolazine, and a high risk drug, quinidine: For ranolazine, our model predicts a prolonged QT interval of 19.4% compared to baseline and a regular sinus rhythm at 60.15 beats per minute. For quinidine, our model predicts a prolonged QT interval of 78.4% and a spontaneous development of torsades de pointes both in the activation profile and in the electrocardiogram. Our model reveals the mechanisms by which electrophysiological abnormalities propagate across the spatio-temporal scales, from specific channel blockage, via altered single cell action potentials and prolonged QT intervals, to the spontaneous emergence of ventricular tachycardia in the form of torsades de pointes. Our model could have important implications for researchers, regulatory agencies, and pharmaceutical companies on rationalizing safe drug development and reducing the time-to-market of new drugs. This article is protected by copyright. All rights reserved.
- Case Report: A Case of Severe Cerebral Malaria Managed with Therapeutic Hypothermia and Other Modalities for Brain Edema. [Journal Article]
- AJAm J Trop Med Hyg 2018 Feb 05
- Malarial infections are uncommon in the United States and almost all reported cases stem from recent travelers coming from endemic countries. Cerebral malaria (CM) is a severe form of the disease usu...
Malarial infections are uncommon in the United States and almost all reported cases stem from recent travelers coming from endemic countries. Cerebral malaria (CM) is a severe form of the disease usually affecting children and individuals with limited immunity. Despite proper management, mortality from CM can reach up to 25%, especially when it is associated with brain edema. Inefficient management of the edema may result in brain herniation and death. Uniform guidelines for management of CM-associated brain edema are lacking. In this report, we present a case of CM with associated severe brain edema that was successfully managed using a unique combination of therapeutic hypothermia, hypertonic saline, mannitol, and hyperventilation along with the antimalarial drugs quinidine and doxycycline. Our use of hypothermia was based on its proven benefit for improving neurological outcomes in post-cardiac arrest patients and previous in vitro research, suggesting its potential inhibitory role on malaria growth.
- Therapeutic strategies for congenital myasthenic syndromes. [Review]
- ANAnn N Y Acad Sci 2018; 1412(1):129-136
- To date, more than 25 genes have been implicated in the etiology of the congenital myasthenic syndromes (CMS), and an ever-growing phenotypic landscape is now encountered in the CMS clinic. Unlike th...
To date, more than 25 genes have been implicated in the etiology of the congenital myasthenic syndromes (CMS), and an ever-growing phenotypic landscape is now encountered in the CMS clinic. Unlike the autoimmune form of myasthenia, there is no role for immunomodulatory agents in the treatment of CMS. The present-day drug repertoire comprises acetylcholinesterase inhibitors (mainly pyridostigmine), 3,4-diaminopyridine (3,4-DAP), ephedrine, salbutamol/albuterol, open-channel blockers (fluoxetine, quinidine), or a combination of these. These are prescribed by the specialist in an off-label manner, as there is no drug currently licensed for the treatment of these rare diseases. The effective pharmacological agent varies according to the genetic form of CMS, and it is important to realize that an agent that provides benefit in one CMS subtype can be harmful in another. In addition, the time to treatment response is variable and tends to be commensurate with the drug used. Here, we summarize for the clinician the therapeutic strategies employed in this ever-evolving disease spectrum. We also address the barriers to treatment and discuss the treatment of CMS in pregnancy.
- P2Y receptor regulation of K2P channels that facilitate K+secretion by human mammary epithelial cells. [Journal Article]
- AJAm J Physiol Cell Physiol 2018 Jan 24
- The objective of this study was to determine the molecular identity of ion channels involved in K+secretion by the mammary epithelium and to examine their regulation by purinoceptor agonists. Apical ...
The objective of this study was to determine the molecular identity of ion channels involved in K+secretion by the mammary epithelium and to examine their regulation by purinoceptor agonists. Apical membrane voltage clamp experiments were performed on human mammary epithelial cells where the basolateral membrane was exposed to the pore-forming antibiotic amphotericin B dissolved in a solution with intracellular-like ionic composition. Addition of the Na+channel inhibitor benzamil reduced the basal current, consistent with inhibition of Na+uptake across the apical membrane whereas the KCa3.1 channel blocker TRAM-34 produced an increase in current resulting from inhibition of basal K+efflux. Treatment with K2P channel blockers quinidine, bupivacaine and a selective TASK1/TASK3 inhibitor (PK-THPP) all produced concentration-dependent inhibition of apical K+efflux. qRT-PCR experiments detected mRNA expression for nine K2P channel subtypes. Western blot analysis of biotinylated apical membranes and confocal immunocytochemistry revealed that at least five K2P subtypes (TWIK1, TREK1, TREK2, TASK1 and TASK3) are expressed in the apical membrane. Apical UTP also increased the current, but pretreatment with the PKC inhibitor GF109203X blocked the response. Similarly, direct activation of PKC with phorbol 12-myristate 13-acetate produced a similar increase in current as observed with UTP. These results support the conclusion that the basal level of K+secretion involves constitutive activity of apical KCa3.1 channels and multiple K2P channel subtypes. Apical UTP evoked a transient increase in KCa3.1 channel activity, but over time caused persistent inhibition of K2P channel function leading to an overall decrease in K+secretion.
- Carrier-mediated uptake of clonidine in cultured human lung cells. [Journal Article]
- NSNaunyn Schmiedebergs Arch Pharmacol 2018 Jan 19
- The lung is a preferential organ site for accumulation of lipophilic basic amine drugs, so-called pneumophilic drugs and belonging to various pharmacological classes, which can result in lung toxicit...
The lung is a preferential organ site for accumulation of lipophilic basic amine drugs, so-called pneumophilic drugs and belonging to various pharmacological classes, which can result in lung toxicity. In order to investigate the mechanism involved in such pulmonary accumulation of drugs, uptake of clonidine, used here as a prototypical basic amine drug, was characterized in cultured human lung cells. Clonidine accumulation in lung alveolar A549 cells was found to be temperature- and pH-dependent; it was saturable, with a Michaelis-Menten affinity constant (Km) value of 569.4 μM. Various pneumophilic drugs, including amitriptyline, verapamil, propranolol, chlorpromazine, imipramine, and quinidine, markedly cis-inhibited clonidine uptake in A549 cells, in a dose-dependent manner for at least some of them. They additionally trans-stimulated clonidine efflux from A549 cells, thus suggesting that they are substrates for the putative clonidine transporter. In addition to alveolar A549 cells, bronchial epithelial BEAS-2B cells as well as lung endothelial HULEC-5a cells were found to exhibit clonidine accumulation abrogated by amitriptyline, verapamil, and chlorpromazine. Taken together, these data likely provided evidence for carrier-mediated uptake of clonidine in human lung cells. This carrier, which remains to be molecularly identified, interacts with various pneumophilic drugs, suggesting that it may contribute to lung accumulation of these drugs in a notable way.
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- Arrhythmogenic drugs can amplify spatial heterogeneities in the electrical restitution in perfused guinea-pig heart: An evidence from assessments of monophasic action potential durations and JT intervals. [Journal Article]
- PlosPLoS One 2018; 13(1):e0191514
- Non-uniform shortening of the action potential duration (APD90) in different myocardial regions upon heart rate acceleration can set abnormal repolarization gradients and promote arrhythmia. This stu...
Non-uniform shortening of the action potential duration (APD90) in different myocardial regions upon heart rate acceleration can set abnormal repolarization gradients and promote arrhythmia. This study examined whether spatial heterogeneities in APD90 restitution can be amplified by drugs with clinically proved proarrhythmic potential (dofetilide, quinidine, procainamide, and flecainide) and, if so, whether these effects can translate to the appropriate changes of the ECG metrics of ventricular repolarization, such as JT intervals. In isolated, perfused guinea-pig heart preparations, monophasic action potentials and volume-conducted ECG were recorded at progressively increased pacing rates. The APD90 measured at distinct ventricular sites, as well as the JTpeak and JTend values were plotted as a function of preceding diastolic interval, and the maximum slopes of the restitution curves were determined at baseline and upon drug administration. Dofetilide, quinidine, and procainamide reverse rate-dependently prolonged APD90 and steepened the restitution curve, with effects being greater at the endocardium than epicardium, and in the right ventricular (RV) vs. the left ventricular (LV) chamber. The restitution slope was increased to a greater extent for the JTend vs. the JTpeak interval. In contrast, flecainide reduced the APD90 restitution slope at LV epicardium without producing effect at LV endocardium and RV epicardium, and reduced the JTpeak restitution slope without changing the JTend restitution. Nevertheless, with all agents, these effects translated to the amplified epicardial-to-endocardial and the LV-to-RV non-uniformities in APD90 restitution, paralleled by the increased JTend vs. JTpeak difference in the restitution slope. In summary, these findings suggest that arrhythmic drug profiles are partly attributable to the accentuated regional heterogeneities in APD90 restitution, which can be indirectly determined through ECG assessments of the JTend vs. JTpeak dynamics at variable pacing rates.