Effect of Memantine on QT/QTc Interval in a Healthy Korean Population.

Studies on the effects of memantine on QT prolongation have yielded conflicting results. For a long time, memantine was reported to be a safe drug without QT prolongation; however, several case studies have reported memantine-induced QT prolongation in Alzheimer's patients. This study evaluated the relationship between memantine blood levels, and QT interval changes. Over a 2-week period, we orally administered 20 mg of memantine daily to achieve a steady state in 57 healthy Korean subjects. We measured and analyzed the QT interval and blood memantine concentrations simultaneously before and after treatment, as well as 2 weeks after the last dosing. Correlation analysis was done between blood memantine level and QT interval. No serious adverse events occurred during the study period. Repeated dosing of memantine did not show clinically significant QT interval changes after treatment. Regression analysis was performed based on the results; there was no statistical association between memantine blood level and QT prolongation. In conclusion, the results of the present study demonstrated no clinically significant changes in the QT interval with therapeutic blood levels of memantine.

A randomized, placebo-controlled, phase 1 study to evaluate the effects of TAK-063 on ketamine-induced changes in fMRI BOLD signal in healthy subjects.

RATIONALE: Phosphodiesterase 10A inhibitor TAK-063 has shown effects that suggest efficacy in schizophrenia treatment. OBJECTIVE: This randomized, double-blind, placebo-controlled, incomplete-crossover study investigated effects of single oral administration of TAK-063 on ketamine-induced changes in blood oxygen level-dependent (BOLD) signal in healthy males. METHODS: Healthy men aged 18 to 45 years with normal magnetic resonance imaging (MRI) scans and electroencephalogram measurements at screening were eligible. Each subject was randomized to one of nine treatment schedules: all subjects received placebo and two of three doses of TAK-063 followed by ketamine. The primary endpoint was ketamine-induced brain activity in select regions of the brain during resting state. Secondary endpoints included pharmacokinetic parameters of TAK-063, proportion of subjects with treatment-emergent adverse events (AEs), and percentage of subjects meeting criteria for abnormal safety laboratory tests and vital sign measurements. RESULTS: The study comprised 27 subjects. Prior to ketamine infusion, TAK-063 exerted region-specific effects on resting state functional MRI (fMRI) BOLD signal. After ketamine administration, TAK-063 reduced the Cohen's effect size for resting-state fMRI BOLD signal in key brain regions examined, and exerted similar effects on BOLD signal during the working memory task across all doses. TAK-063 was safe and well tolerated. CONCLUSIONS: Our results are consistent with non-clinical studies of ketamine and TAK-063 and clinical studies of ketamine and risperidone. It is unknown whether these data are predictive of potential antipsychotic efficacy, and further analyses are required.

A pharmaceutical answer to nonadherence: Once weekly oral memantine for Alzheimer's disease.

Adherence to medication regimens is a major barrier to effective treatment in many disease areas, notably in dementia which causes cognitive impairment that reduces patients' awareness of non-adherence and their ability to manage medication. The development of oral dosage forms that can be infrequently dosed, and therefore improve adherence rate and facilitate direct observed therapy, has been a goal for decades. We describe the first demonstration of an oral formulation that achieves >7-day gastric retention and sustained pharmacokinetics in the challenging dog model. Gastric retention requires physical resistance of the dosage form to gastric emptying forces, which are known to be stronger in dogs than in humans, making successful gastric retention in dogs a stringent test for predicting human translatability. This formulation of memantine hydrochloride is the first oral dosage form that achieves multi-day drug release with near zero-order kinetics and efficient delivery. In the dog model, relative memantine bioavailability approaches 100% with sustained plasma levels of memantine over seven days and profiles that can be tuned by varying components of the formulation. A single gastric resident dosage form achieves an AUC equivalent to 7 daily treatments with the marketed daily capsule, with a Cmax that is no higher than the daily product. PK modeling predicts that the gastroretentive formulation will maintain therapeutic blood levels in humans when administered once weekly. The formulation methodology presented here is applicable to many water soluble drugs and may enable the development of long-acting oral therapies for a wide variety of conditions.

Temporally dissociable effects of ketamine on neuronal discharge and gamma oscillations in rat thalamo-cortical networks.

BACKGROUND: Sub-anesthetic doses of the non-competitive N-methyl-d-aspartate receptor (NMDA-R) antagonist ketamine evoke transient psychotomimetic effects, followed by persistent antidepressant effects in treatment-resistant depressed patients and rodents through still poorly understood mechanisms. Since phencyclidine (PCP) disinhibits thalamo-cortical networks by blocking NMDA-Rs on GABAergic neurons of the reticular thalamic nucleus (RtN), we examined ketamine's actions in the same areas. METHODS: Single units and local field potentials were recorded in chloral hydrate anesthetized male Wistar rats. The effects of cumulative ketamine doses (0.25-5 mg/kg, i.v.) on neuronal discharge and oscillatory activity were examined in RtN, mediodorsal and centromedial (MD/CM) thalamic nuclei, and layer VI of the medial prefrontal cortex (mPFC). RESULTS: Ketamine (1, 2 and 5 mg/kg, i.v.) significantly decreased the discharge of MD/CM, RtN and layer VI mPFC pyramidal neurons. Simultaneously, ketamine decreased the power of low frequency oscillations in all areas examined and increased gamma oscillations in mPFC and MD/CM. Lower ketamine doses (0.25 and 0.5 mg/kg, i.v.) were ineffective. CONCLUSIONS: As observed for PCP, ketamine markedly inhibited the activity of RtN neurons. However, unlike PCP, this effect did not translate into a disinhibition of MD/CM and mPFC excitatory neurons, possibly due to a more potent and simultaneous blockade of NMDA-Rs by ketamine in MD/CM and mPFC neurons. Hence, the present in vivo results show that ketamine evokes an early transient inhibition of neuronal discharge in thalamo-cortical networks, following its rapid pharmacokinetics, which is likely associated to its psychotomimetic effects. The prolonged increase in gamma oscillations may underlie its antidepressant action.

The Safety and Tolerability of Topically Delivered Kynurenic Acid in Humans. A Phase 1 Randomized Double-Blind Clinical Trial.

Scarring is a consequence of biological tissue repair following trauma. Currently, there are no generally agreed ways to prevent scarring. Recently, kynurenic acid has shown to be a potent modulator of extracellular matrix deposition and remodeling. Kynurenic acid can reduce matrix deposition and other fundamental characteristics of fibrosis in vitro and in vivo. Specifically, kynurenic acid has shown to increase matrix metalloproteinase-1 activity and subsequently reduce collagen deposition in a rabbit ear scar model. In the present study kynurenic acid cream in different concentrations was topically applied on healthy skin on volunteers to assess skin reactions and skin sensitivity in both acute and chronic application settings. Skin reactions were assessed, and concentrations for kynurenic acid were assessed both form serum and urine. Results showed to acute or delayed skin reactions. Kynurenic acid was not detectable in blood at any time point, and only trace elements of kynurenic acid were found in urine. This study supports safety and tolerability of topically administered FS2 when using a liposomal, compounding base carrier.

Riluzole Serum Concentration in Pediatric Patients Treated for Obsessive-Compulsive Disorder.

PURPOSE/BACKGROUND: The goals of this study were to determine whether pediatric serum concentration of riluzole is similar to that observed in adults and to determine whether riluzole serum concentration is associated with adverse effects or efficacy in children and adolescents with treatment-refractory obsessive-compulsive disorder. METHODS/PROCEDURES: Data were drawn from previously published studies: 1 open-label trial and 1 randomized controlled trial with an open-label extension phase. Serum was drawn at 24, 36, and 52 weeks in 37 patients who were taking approximately 100 mg riluzole daily (mean dose at 24 weeks, 99 ± 28 mg). FINDINGS/RESULTS: Across all samples, serum riluzole concentration ranged from 7 to 963 ng/mL. At week 24 (n = 37), the median concentration was 76 ng/mL (interquartile range, 53-172 ng/mL). Within-patient concentration was relatively stable. One subject who had the highest serum concentration levels during the study developed pancreatitis after exiting the study. The patient had recently added fluvoxamine to the riluzole regimen. Controlling for concomitant fluvoxamine (in 6 participants) and time of draw, serum riluzole concentration was not associated with obsessive-compulsive disorder symptom severity, nor was it associated with adverse effect profile. IMPLICATIONS/CONCLUSIONS: The dose of riluzole used in these pediatric subjects seems to have achieved serum concentration levels similar to those observed in adults. However, as previously reported in adults, the serum concentration had no discernable relationship to efficacy or adverse effects.

Transdermal therapeutic systems for memantine delivery. Comparison of passive and iontophoretic transport.

Memantine is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist used in the treatment of moderate to severe dementia including the symptoms of Alzheimer's disease (AD). It is administered orally but compliance, swallowing problems and the routine use of multiple medications in elderly AD patients means that an alternative route of administration would be of interest. The aim of the present study was to develop memantine hydrochloride occlusive transdermal therapeutic systems (TTS) for passive and iontophoretic delivery across the skin. Polyvinyl pyrrolidone (PVP) and a mixture with polyvinyl alcohol (PVA) were employed as polymeric matrices. The study involved the TTS characterization in addition to quantification of the memantine transport across porcine skin in vitro. The evaluation of the TTS physical properties suggested that systems were made more mechanically resistant by including PVA (6%) or high concentrations of PVP (24%). Moreover, a linear correlation was observed between the concentration of PVP and the bioadhesion of the systems. Drug delivery experiments showed that the highest transdermal flux provided by a passive TTS (PVP 24% w/w limonene) was 8.89±0.81µgcm-2h-1 whereas the highest iontophoretic transport was 46.4±3.6µgcm-2h-1. These innovative TTS would enable two dosage regimens that could lead to therapeutic plasma concentrations.

Pharmacokinetics of dextromethorphan and its metabolites in horses following a single oral administration.

Dextromethorphan is an N-methyl-D-aspartate (NMDA) non-competitive antagonist commonly used in human medicine as an antitussive. Dextromethorphan is metabolized in humans by cytochrome P450 2D6 into dextrorphan, which is reported to be more potent than the parent compound. The goal of this study is to describe the metabolism of and determine the pharmacokinetics of dextromethorphan and its major metabolites following oral administration to horses. A total of 23 horses received a single oral dose of 2 mg/kg. Blood samples were collected at time 0 and at various times up to 96 h post drug administration. Urine samples were collected from 12 horses up to 120 h post administration. Plasma and urine samples were analyzed using liquid chromatography-mass spectrometry, and the resulting data analyzed using non-compartmental analysis. The Cmax , Tmax , and the t1/2 of dextromethorphan were 519.4 ng/mL, 0.55 h, and 12.4 h respectively. The area under the curve of dextromethorphan, free dextrorphan, and conjugated dextrorphan were 563.8, 2.19, and 6,691 h*ng/mL respectively. In addition to free and glucuronidated dextrorphan, several additional glucuronide metabolites were identified in plasma, including hydroxyl-desmethyl dextrorphan, desmethyl dextrorphan, and three forms of hydroxylated dextrorphan. Dextromethorphan was found to be eliminated from the urine predominately as the O-demethylated metabolite, dextrorphan. Several additional metabolites including several novel hydroxy-dextrorphan metabolites were also detected in the urine in both free and glucuronidated forms. No significant undesirable behavioural effects were noted throughout the duration of the study. Copyright © 2016 John Wiley & Sons, Ltd.

Effects of ketamine on brain function during smooth pursuit eye movements.

The uncompetitive NMDA receptor antagonist ketamine has been proposed to model symptoms of psychosis. Smooth pursuit eye movements (SPEM) are an established biomarker of schizophrenia. SPEM performance has been shown to be impaired in the schizophrenia spectrum and during ketamine administration in healthy volunteers. However, the neural mechanisms mediating SPEM impairments during ketamine administration are unknown. In a counter-balanced, placebo-controlled, double-blind, within-subjects design, 27 healthy participants received intravenous racemic ketamine (100 ng/mL target plasma concentration) on one of two assessment days and placebo (intravenous saline) on the other. Participants performed a block-design SPEM task during functional magnetic resonance imaging (fMRI) at 3 Tesla field strength. Self-ratings of psychosis-like experiences were obtained using the Psychotomimetic States Inventory (PSI). Ketamine administration induced psychosis-like symptoms, during ketamine infusion, participants showed increased ratings on the PSI dimensions cognitive disorganization, delusional thinking, perceptual distortion and mania. Ketamine led to robust deficits in SPEM performance, which were accompanied by reduced blood oxygen level dependent (BOLD) signal in the SPEM network including primary visual cortex, area V5 and the right frontal eye field (FEF), compared to placebo. A measure of connectivity with V5 and FEF as seed regions, however, was not significantly affected by ketamine. These results are similar to the deviations found in schizophrenia patients. Our findings support the role of glutamate dysfunction in impaired smooth pursuit performance and the use of ketamine as a pharmacological model of psychosis, especially when combined with oculomotor biomarkers. Hum Brain Mapp 37:4047-4060, 2016. © 2016 Wiley Periodicals, Inc.

A Predictive Model of Plasma Lamotrigine Levels.

Introduction: Lamotrigine is one of several mood stabilizers and its effects for the treatment and prevention of depressive episodes, particularly in bipolar disorder, are generally accepted. Although the findings about a therapeutic window of lamotrigine are yet to be determined, it seems important to obtain information on individual pharmacokinetic peculiarities. This study was conducted to formulate the predictive model of plasma lamotrigine levels. Methods: Using the data of 47 patients whose lamotrigine levels, liver function, and renal function were measured, predictive models of lamotrigine levels were formulated by stepwise multiple regression analyses. The predictive power of the models was compared using another dataset of 25 patients. Results: Two models were created using stepwise multiple regression. The first model was: plasma lamotrigine level (µg/mL)=2.308+0.019×lamotrigine dose (mg/day). The second model was: plasma lamotrigine level (µg/mL)=0.08+0.024×lamotrigine dose (mg/day)+4.088×valproate combination (no=0, yes=1). The predictive power of the second model was better than that of the first model. Discussion: The present study proposes a prompt and relatively accurate equation to predict lamotrigine levels.

The Psychostimulant Khat (Catha edulis) Inhibits CYP2D6 Enzyme Activity in Humans.

The use of khat (Catha edulis) while on medication may alter treatment outcome. In particular, the influence of khat on the metabolic activities of drug-metabolizing enzymes is not known. We performed a comparative 1-way crossover study to evaluate the effect of khat on cytochrome P450 (CYP)2D6 and CYP3A4 enzyme activity. After 1 week of khat abstinence, baseline CYP2D6 and CYP3A4 metabolic activities were determined in 40 Ethiopian male volunteers using 30 mg dextromethorphan (DM) as a probe drug and then repeated after 1 week of daily use of 400 g fresh khat leaves. Urinary concentrations of cathinone and cathine were determined to monitor the subjects' compliance to the study protocol. Genotyping for CYP2D6*3 and CYP2D6*4 was done. Plasma DM, dextrorphan and 3-methoxymorphinan concentrations were quantified. CYP2D6 and CYP3A4 enzyme activities were assessed by comparing plasma log DM/dextrorphan and log DM/methoxymorphinan metabolic ratio (MR) respectively in the presence and absence of khat. Cytochrome 2D6 MR was significantly increased from baseline by concurrent khat use (paired t test, P = 0.003; geometric mean ratio, 1.38; 95% confidence interval [95% CI], 1.12-1.53). Moreover, the inhibition of CYP2D6 activity by khat was more pronounced in CYP2D6*1/*1 compared with CYP2D6*1/*4 genotypes (P = 0.01). A marginal inhibition of CYP3A4 activity in the presence of khat was observed (P = 0.24). The mean percentage increase of CYP2D6 and CYP3A4 MR from baseline by khat use was 46% (95% CI, 20-72) and 31% (95% CI, 8-54), respectively. This is the first report linking khat use with significant inhibition of CYP2D6 metabolic activity in humans.

Inhibition of in vivo [(3)H]MK-801 binding by NMDA receptor open channel blockers and GluN2B antagonists in rats and mice.

N-methyl-D-aspartate (NMDA) receptor antagonists, including open channel blockers and GluN2B receptor subtype selective antagonists, have been developed for the treatment of depression. The current study investigated effects of systemically administered NMDA channel blockers and GluN2B receptor antagonists on NMDA receptor activity in rodents using in vivo [(3)H]MK-801 binding. The receptor occupancy of GluN2B antagonists was measured using ex vivo [(3)H]Ro 25-6981 binding. Ketamine, a NMDA receptor channel blocker, produced a dose/exposure- and time-dependent inhibition of in vivo [(3)H]MK-801 binding that was maximal at ~100%. The complete inhibition of in vivo [(3)H]MK-801 binding was also observed with NMDA receptor channel blockers, AZD6765 (Lanicemine) and MK-801 (Dizocilpine). CP-101,606 (Traxoprodil), a GluN2B antagonist, produced a dose/exposure- and time-dependent inhibition of in vivo [(3)H]MK-801 binding that was maximal at ~60%. Partial inhibition was also observed with other GluN2B antagonists including MK-0657 (CERC-301), EVT-101, Ro 25-6981 and radiprodil. For all GluN2B antagonists tested, partial [(3)H]MK-801 binding inhibition was achieved at doses saturating GluN2B receptor occupancy. Combined treatment with ketamine (10mg/kg, i.p.) and Ro 25-6981(10mg/kg, i.p.) produced a level of inhibition of in vivo [(3)H]MK-801 binding that was similar to treatment with either agent alone. In conclusion, this in vivo [(3)H]MK-801 binding study shows that NMDA receptor activity in the rodent forebrain can be inhibited completely by channel blockers, but only partially (~60%) by GluN2B receptor antagonists. At doses effective in preclinical models of depression, ketamine may preferentially inhibit the same population of NMDA receptors as Ro 25-6981, namely those containing the GluN2B subunit.

Application of a Bayesian approach to physiological modelling of mavoglurant population pharmacokinetics.

Mavoglurant (MVG) is an antagonist at the metabotropic glutamate receptor-5 currently under clinical development at Novartis Pharma AG for the treatment of central nervous system diseases. The aim of this study was to develop and optimise a population whole-body physiologically-based pharmacokinetic (WBPBPK) model for MVG, to predict the impact of drug-drug interaction (DDI) and age on its pharmacokinetics. In a first step, the model was fitted to intravenous (IV) data from a clinical study in adults using a Bayesian approach. In a second step, the optimised model was used together with a mechanistic absorption model for exploratory Monte Carlo simulations. The ability of the model to predict MVG pharmacokinetics when orally co-administered with ketoconazole in adults or administered alone in 3-11 year-old children was evaluated using data from three other clinical studies. The population model provided a good description of both the median trend and variability in MVG plasma pharmacokinetics following IV administration in adults. The Bayesian approach offered a continuous flow of information from pre-clinical to clinical studies. Prediction of the DDI with ketoconazole was consistent with the results of a non-compartmental analysis of the clinical data (threefold increase in systemic exposure). Scaling of the WBPBPK model allowed reasonable extrapolation of MVG pharmacokinetics from adults to children. The model can be used to predict plasma and brain (target site) concentration-time profiles following oral administration of various immediate-release formulations of MVG alone or when co-administered with other drugs, in adults as well as in children.

In vivo ketamine-induced changes in [¹¹C]ABP688 binding to metabotropic glutamate receptor subtype 5.

BACKGROUND: At subanesthetic doses, ketamine, an N-methyl-D-aspartate glutamate receptor antagonist, increases glutamate release. We imaged the acute effect of ketamine on brain metabotropic glutamatergic receptor subtype 5 with a high-affinity positron emission tomography (PET) ligand [(11)C]ABP688 (E)-3-[2-(6-methyl-2-pyridinyl)ethynyl]-2-cyclohexen-1-one-O-(methyl-11C)oxime, a negative allosteric modulator of the metabotropic glutamatergic receptor subtype 5. METHODS: Two [(11)C]ABP688 PET scans were performed in 10 healthy nonsmoking human volunteers (34 ± 13 years old); the two PET scans were performed on the same day-before (scan 1) and during intravenous ketamine administration (.23 mg/kg over 1 min, then .58 mg/kg over 1 hour; scan 2). The PET data were acquired for 90 min immediately after [(11)C]ABP688 bolus injection. Input functions were obtained through arterial blood sampling with metabolite analysis. RESULTS: A significant reduction in [(11)C]ABP688 volume of distribution was observed in scan 2 relative to scan 1 of 21.3% ± 21.4%, on average, in the anterior cingulate, medial prefrontal cortex, orbital prefrontal cortex, ventral striatum, parietal lobe, dorsal putamen, dorsal caudate, amygdala, and hippocampus. There was a significant increase in measurements of dissociative state after ketamine initiation (p < .05), which resolved after completion of the scan. CONCLUSIONS: This study provides first evidence that ketamine administration decreases [(11)C]ABP688 binding in vivo in human subjects. The results suggest that [(11)C]ABP688 binding is sensitive to ketamine-induced effects, although the high individual variation in ketamine response requires further examination.

Therapeutic window of lamotrigine for mood disorders: a naturalistic retrospective study.

INTRODUCTION: Lamotrigine is widely used for mood disorders including bipolar disorder and major depression, but its therapeutic levels have yet to be determined. This study was conducted to investigate the hypothesis that lamotrigine may have a therapeutic window for mood disorders. METHODS: 25 patients with mood disorders received lamotrigine for more than one year during which time plasma lamotrigine levels were measured at least once. Their mental state was retrospectively and regularly but blindly assessed using the Clinical Global Impression-Severity (CGI-S) scale. In order to investigate our hypothesis, we depicted the relationship between the last lamotrigine levels and the last CGI scores in 25 patients. If any, the potential therapeutic window was further investigated. RESULTS: The relationship between the last lamotrigine levels and the last CGI scores in the 25 patients indicated the presence of a therapeutic window of lamotrigine from 5 to 11 µg/mL. The repeated measures of ANOVA reached a significant tendency of the effects of lamotrigine levels within 5-11 µg/mL on better CGI-S scores, and the CGI-S scores at the last observation of the 15 patients whose lamotrigine levels were within 5-11 µg/mL were significantly better than those of 10 patients whose lamotrigine levels were not within 5-11 µg/mL. CONCLUSION: These findings suggest that lamotrigine may have a therapeutic window for patients with mood disorder from 5 to 11 µg/mL.

The mGluR5 negative allosteric modulator dipraglurant reduces dyskinesia in the MPTP macaque model.

BACKGROUND: Blocking metabotropic glutamate receptor type 5 (mGluR5) has been proposed as a target for levodopa-induced dyskinesias (LID) in Parkinson's disease (PD). We assessed the effect on LID of dipraglurant, a potent selective mGluR5 receptor negative allosteric modulator in the gold-standard LID macaque model. METHODS: Dipraglurant (3, 10, and 30 mg/kg, by mouth) was tested in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaque model of LID in a four-way crossover, single-dose, controlled study (n = 8). RESULTS: Dipraglurant inhibited dyskinesias in the LID macaque model, with best effect reached at 30 mg/kg dose with no alteration of levodopa efficacy. CONCLUSION: Acute challenges of dipraglurant were efficacious on choreic and dystonic LID in the MPTP-macaque model. Dipraglurant pharmacokinetic variables were similar to those of levodopa, suggesting that both drugs can be co-administered simultaneously in further studies.

A case series of patients with lamotrigine toxicity at one center from 2003 to 2012.

INTRODUCTION: Lamotrigine is a phenyltriazine compound that inhibits voltage-gated sodium channels, decreasing release of glutamate and aspartate, and inhibits serotonin, norepinephrine and dopamine reuptake. Reports of toxicity in the literature are limited to case reports and primarily involve coingestants. This case series is intended to report the clinical manifestations of lamotrigine toxicity. METHODS: This retrospective case series from 2003 to 2012 studies the effects of lamotrigine toxicity when not confounded by coingestants. Admission records at an inpatient toxicology center were reviewed for lamotrigine-only exposure based on history with supporting laboratory data when available. After identification, these charts were reviewed again to characterize vital signs, neurological examination findings, specific laboratory and electrocardiography parameters, and complications. RESULTS: Fifty-seven patients were identified with possible lamotrigine toxicity. Nine patients, including three toddlers, had lamotrigine-only ingestions. Three of these patients had seizures, four were hypertensive, five were tachycardic, and four experienced tachypnea. Mental status was altered in all nine (depressed (n = 4), agitated (n = 5) or both (n = 3)). Five patients were hyperreflexic and experienced intermittent myoclonus, and two had inducible clonus. On electrocardiogram, two patients experienced QRS prolongation (114-116 ms), and four had QTc prolongation (463-586 ms). No patient had life-threatening symptoms or signs. Serum levels of lamotrigine were available in seven patients, and averaged 35.4 mg/L (17-90 mg/L). The therapeutic range for sLTG is 3-14 mg/L. CONCLUSIONS: Lamotrigine toxicity manifested with minor-moderate neurologic and/or electrocardiographic effects. Toxicity reflects the known pharmacologic actions of lamotrigine: serotonin, norepinephrine and dopamine reuptake inhibition, and sodium channel blockade.

Neurophysiological signals as potential translatable biomarkers for modulation of metabotropic glutamate 5 receptors.

The Group I metabotropic glutamate receptor subtype 5 (mGluR5) is widely distributed in the brain with dense expression in the cerebral cortex, hippocampus, and basal ganglia. These receptors have been implicated in psychiatric and neurological disorders such as schizophrenia, Fragile X syndrome, addiction, anxiety/depression, Parkinson's disease and neuropathic pain. The present study evaluated the effects of the mGluR5 negative allosteric modulators (NAMs) 4-difluoromethoxy-3-(pyridine-2-ylethynyl)phenyl)5H-pyrrolo[3,4-b]pyridine-6(7H)-yl methanone (GRN-529) and methyl (3aR,4S,7aR)-4-hydroxy-4-[(3-methylphenyl)ethynyl]octahydro-1H-indole-1-carboxylate (AFQ056) on polysomnographic (PSG) and quantitative electroencephalographic (qEEG) measures in freely moving rats. Furthermore, the anxiolytic profile of GRN-529 was characterized in anesthetized rats by measuring stimulation-induced hippocampal theta oscillation. The present findings demonstrate that inhibition of mGluR5 via its allosteric site profoundly modulates high-level neuronal network activities as indicated by changes in sleep-wake activity and power distribution of qEEG. Both GRN-529 and AFQ056 reduced the total time spent in rapid-eye movement with AFQ056 producing a significant increase in wakefulness at the highest dose tested. Additionally, qEEG revealed significant compound-induced increases in delta power concomitant with more subtle decreases in theta and alpha band power. Receptor occupancy (RO) studies revealed that GRN-529 and AFQ056 at all doses resulted in over 45% mGluR5 occupancy. Furthermore, GRN-529 dose-dependently decreased elicited hippocampal theta frequency, consistent with previous findings using clinically active anxiolytic compounds. The described changes in neurophysiological signals identified in freely moving rats may be considered suitable translational biomarkers for the clinical evaluation of mGluR5 NAMs.