Enhancement of central norepinephrinergic neurotransmission contributes to inhibition of seizure-induced respiratory arrest by targeting the beta-1 adrenergic receptor (β1-AR) locating in the cardiomyocytes in the DBA/1 mouse SUDEP model

Sudden unexpected death of epilepsy (SUDEP) is the key cause of of death in patients with epilepsy. Due to the complicated pathogenesis of SUDEP, however, the exact mechanism of SUDEP remains elusive. Currently, although it is recognized that the seizure-induced respiratory arrest (S-IRA) may be a main cause for SUDEP, other factors resulting in SUDEP can not be excluded e.g arrhythmias. Our previous findings indicated that the incidence of seizure-induced respiratory arrest S-IRA and SUDEP evoked by acoustic stimulation or pentetrazol (PTZ) injection was significantly reduced by atomoxetine, a norepinephrine reuptake inhibitor (NRI), suggesting that noradrenergic neurotransmission modulates S-IRA and SUDEP. Given that norepinephrine acts on the central and peripheral target to modulate respiratory and circulation function by targeting adrenergic receptor α and beta (a-AR and β-AR) and the arrhythmias can be contributed to SUDEP. Meanwhile, to further test whether cardiac factors are implicated in S-IRA and SUDEP, we choose esmolol hydrochloride, a selective antagonist of beta-1 adrenergic receptor (β1-AR) to test it in our models. Our findings demonstrated that the lower incidence of S-IRA and SUDEP evoked by acoustic stimulation or PTZ in DBA/1 mice by administration with atomoxetine was significantly reversed by intraperitoneal (IP) of esmolol hydrochloride. Importantly, the data of electrocardiogram (ECG) showed that the cardiac arrhythmia evoked by acoustic stimulation including the ventricular tachycardia, ventricular premature beat and atrioventricular block and administration of atomoxetine significantly reduced theses arrhythmias and the incidence of S-IRA and SUDEP in our models. Thus, the dysfunction of respiratory and circulation may be implicated in the pathogenesis of S-IRA and SUDEP hand in hand and enhancing central norepinephrinergic neurotransmission contributes to inhibition of seizure-induced respiratory arrest by targeting β1-AR locating in the cardiomyocytes. Our findings will show a new light on decoding the pathogenesis of SUDEP. Keywords: sudden unexpected death in epilepsy (SUDEP); seizure-induced respiratory arrest S-IRA); esmolol hydrochloride (Esmolol); Electrocardiogram (ECG); locus coeruleus (LC); cardiac arrhythmia; pentetrazol (PTZ)

The Effect of Serotonin-Norepinephrine Reuptake Inhibitor Milnacipran on Anxiety-like Behaviors in Diabetic Mice

Background: Diabetes mellitus is a chronic disease that causes neuronal plasticity and increased hypothalamic pituitary adrenal (HPA) axis of stress disorders. The change in metabolism is reportedly associated with inadequate response to antianxiety and antidepressant agents. Objective: This study aimed to determine the effect of milnacipran antidepressants on anxiety-like behavior in mice with diabetes mellitus. Methods: Male ICR mice were divided into naive, stress, diabetes mellitus (DM), DM + stress groups to measure anxiety-like behavior. Diabetes mellitus was induced using alloxan, and electric footshock stress was used as a stressor for 14 consecutive days. Anxiety-like behavior was measured using the light-dark box (LDB) and elevated plus maze (EPM) test at days 0, 7 and 14. The antidepressant milnacipran (MIL) was given for 7 days, on days 8 to 14. On day 14, evaluation of anxiety-like behavior after administration of MIL was carried out in all groups using LDB and EPM tests. Results: The results showed that administration of milnacipran effectively ameliorated anxiety-like behavior in the non-DM, but not in the DM group, using the LDB test. A similar result was demonstrated in the EPM test showing the non-DM group's attenuation after milnacipran administration. Conclusion: The present results indicate that there is an inadequate attenuation of the anxiety-like behavior after treatment with milnacipran in diabetes conditions.

A Novel Analytical Method for the Estimation of Solriamfetol in Plasma Samples by Lc-Ms/Ms

Solriamfetol is a selective dopamine and norepinephrine reuptake inhibitor with wake‐promoting effects. The aim of the present study is to develop a rapid, sensitive and reliable method for the estimation of Solriamfetol in plasma samples using LC-MS. In the present investigation, a rapid, specific, selective and novel method has been optimized for evaluation of solriamfetol in in plasma using modafinil as an internal standard and identification of degradants by LC-MS/MS. The solriamfetol and internal standard were extracted from plasma in a single step using acetonitrile. The principle analytes were eluted with the conditions of mobile phase having the 5mM ammonium format in methanol: 50% Methanol in acetonitrile (90:10%, v/v). The Chromatographic column used is Xterra MS C18, 3.5µ.m, 1mmX150mm analytical column with the 0.5 ml/min flow rate. The detector is CEM array detector. The retention times of solriamfetol and modafinil were 1.50min-1.51min with a total run time of 3 min. The curve indicates correlation coefficient (r2) for modafinil was superior by having the value 1.000 with linear range of 5ng/ml to 500ng/ml. The correlation coefficient (r2) for solriamfetol was found to be 0.999. The LOQ and LOD for the solriamfetol was 33.70pg/ml and 11.12pg/ml respectively The developed method was validated by evaluating system suitability, selectivity, sensitivity, linearity, precision, accuracy, ruggedness and stability in conformity with the guidelines of the United States Food and Drug Administration (US-FDA). The results of validation parameters were found to be within the acceptance limits. Hence, the developed and validated method can be utilized for the routine determination of solriamfetol in plasma samples.

P148 Solriamfetol Titration & AdministRaTion (START): Dosing and titration strategies in patients with narcolepsy starting solriamfetol

Introduction Solriamfetol (Sunosi) is a dopamine/norepinephrine reuptake inhibitor approved (EU/US) to treat excessive daytime sleepiness (EDS) in adults with narcolepsy (75–150 mg/day) or obstructive sleep apnoea (OSA) (37.5–150 mg/day). This study characterised real-world dosing and titration with solriamfetol in patients with narcolepsy. Methods A retrospective patient chart review was conducted among US-based physicians prescribing solriamfetol. Initiation strategies were de novo (no prior EDS medication), transition (switched/switching from existing EDS medications to solriamfetol), or add-on (adding solriamfetol to current EDS medication). Results Twenty-three physicians entered data from 70 patients with narcolepsy (type 1, 24/70; type 2, 46/70; mean+/-SD age, 40+/-11 years; 57% female; 6 also had OSA). EDS was mainly moderate (59%) or severe (36%). Nineteen patients (27%) initiated de novo, 31 (44%) transitioned, and 20 (29%) were add-on. Most patients started solriamfetol at 75 mg (86%) and were stable at 150 mg (76%). Most (67%) had 1 dose adjustment; median (range) time to a stable dose was 14 (1–60) days. EDS severity (44% of patients) was frequently considered when titrating. Fourteen of 22 (64%) transitioning from wake-promoting agents (WPAs) stopped them abruptly; 5/9 (56%) using stimulants tapered off. Discussion In a real-world study, most physicians prescribing solriamfetol to patients with narcolepsy started at 75 mg, tapered stimulants, abruptly discontinued WPAs, and made 1 dose adjustment. Support Jazz Pharmaceuticals

P147 Solriamfetol Titration & AdministRaTion (START): Characteristics of patients with obstructive sleep apnoea (OSA) and prescriber rationale for starting treatment with solriamfetol

Introduction Solriamfetol (Sunosi) is a dopamine/norepinephrine reuptake inhibitor approved (EU/US) to treat excessive daytime sleepiness (EDS) in adults with OSA (37.5–150 mg/day) or narcolepsy (75–150 mg/day). This study examined characteristics of patients with OSA initiating solriamfetol and prescribers’ rationales. Methods This descriptive study included a retrospective patient chart review among US-based physicians prescribing solriamfetol for patients with OSA/narcolepsy. Solriamfetol initiation strategies were classified as de novo (no prior EDS medication), transition (switched/switching from existing EDS medications), or add-on (adding to current EDS medication). Results Physicians (n=24) entered data from 50 patients with OSA (mean+/-SD age, 52+/-9.1 years; 62% male). EDS was primarily moderate (56%) or severe (36%). Mean+/-SD Apnea-Hypopnoea Index at OSA diagnosis was 33.1+/-19.7 (n=37). The most common nonpharmacologic treatment was positive airway pressure (n=39, 78%); 36/39 (92%) were considered adherent. Common comorbidities included obesity (BMI>/=30) (n=25, 50%), cardiovascular disorders (n=16, 32%), and type 2 diabetes (n=14, 28%). Twenty-two (44%) patients were de novo, 26 (52%) transitioned (primarily from wake-promoting agents [18/26, 69%]), and 2 (4%) added solriamfetol (to stimulants). The efficacy of solriamfetol prompted most discussions to prescribe de novo (18/22, 82%); a desire for improved efficacy and/or augmentation of other medications prompted most transitioning (15/26, 58%) and add-on (2/2, 100%) therapy. At data collection, 48 (96%) patients were stable on solriamfetol; one each discontinued due to lack of efficacy and side effects. Discussion Efficacy was a key consideration for physicians prescribing solriamfetol for EDS in a real-world sample of patients with OSA. Support Jazz Pharmaceuticals

Kleptomania Induced by Venlafaxine

Introduction. Kleptomania is an impulse-control disorder that results in an irresistible urge to steal. It is often observed as a comorbidity in patients undergoing pharmacological treatment for Parkinson’s disease. Recurrent shopliftings are also observed in the clinical course of frontotemporal dementia. Case Presentation. After successful treatment of severe depression with venlafaxine at a dose of 225 mg/day, a 54-year-old euthymic female patient exhibited recurrent stealing behavior. After the diagnostic exclusion of frontotemporal dementia, kleptomania induced by venlafaxine administration was suspected. The symptoms of kleptomania disappeared with the gradual decrease in the venlafaxine dosage to 37.5 mg/day. Discussion. Venlafaxine is a dual serotonin-norepinephrine reuptake inhibitor. We considered two possible mechanisms to explain the pathophysiology of kleptomania in the present case: (1) increased dopaminergic neural transmission due to the inhibited dopamine reuptake by the norepinephrine transporter with a high dose of venlafaxine or (2) enhanced serotonergic neural transmission by the inhibition of serotonin reuptake by venlafaxine. In past studies, five cases of impulse-control disorder induced by selective serotonin reuptake inhibitors have been reported. This is the fourth report of venlafaxine-induced kleptomania and highlights the importance of considering the possibility of a rare side effect of kleptomania induced by antidepressant.

A Review on Analytical Method for Determination of Venlafaxine HCl in Bulk and Pharmaceutical dosage form

Venlafaxine HCl is one of the antidepressant agent which comes under the category of serotonin-norepinephrine reuptake inhibitor i.e SNRI. This medication is usually used to treat major depressive disorder in adult. It may help to improve the mood and energy level and also to regain the interest in daily activities in the depressed person. The present review focus on various approaches for the analysis on Venlafaxine in bulk and pharmaceutical dosage forms. The review represents the various analytical method like the RP-HPLC, HPTLC, UV Spectroscopy and Stability Indicating Methods which were used for the investigation of Venlafaxine in bulk and different dosage formulations.

Antidepressant Drugs Effects on Blood Pressure

Individuals suffering from depressive disorders display a greater incidence of hypertension compared with the general population, despite reports of the association between depression and hypotension. This phenomenon may depend, at least in part, on the use of antidepressant drugs, which may influence blood pressure through different effects on adrenergic and serotoninergic pathways, as well as on histaminergic, dopaminergic, and cholinergic systems. This review summarizes extant literature on the effect of antidepressant drugs on blood pressure. Selective serotonin reuptake inhibitors are characterized by limited effects on autonomic system activity and a lower impact on blood pressure. Thus, they represent the safest class—particularly among elderly and cardiovascular patients. Serotonin–norepinephrine reuptake inhibitors, particularly venlafaxine, carry a greater risk of hypertension, possibly related to greater effects on the sympathetic nervous system. The norepinephrine reuptake inhibitor reboxetine is considered a safe option because of its neutral effects on blood pressure in long-term studies, even if both hypotensive and hypertensive effects are reported. The dopamine–norepinephrine reuptake inhibitor bupropion can lead to blood pressure increases, usually at high doses, but may also cause orthostatic hypotension, especially in patients with cardiovascular diseases. The norepinephrine–serotonin modulators, mirtazapine and mianserin, have minimal effects on blood pressure but may rarely lead to orthostatic hypotension and falls. These adverse effects are also observed with the serotonin-reuptake modulators, nefazodone and trazodone, but seldomly with vortioxetine and vilazodone. Agomelatine, the only melatonergic antidepressant drug, may also have limited effects on blood pressure. Tricyclic antidepressants have been associated with increases in blood pressure, as well as orthostatic hypotension, particularly imipramine. Oral monoamine–oxidase inhibitors, less frequently skin patch formulations, have been associated with orthostatic hypotension or, conversely, with hypertensive crisis due to ingestion of tyramine-containing food (i.e., cheese reaction). Lastly, a hypertensive crisis may complicate antidepressant treatment as a part of the serotonin syndrome, also including neuromuscular, cognitive, and autonomic dysfunctions. Clinicians treating depressive patients should carefully consider their blood pressure status and cardiovascular comorbidities because of the effects of antidepressant drugs on blood pressure profiles and potential interactions with antihypertensive treatments.