Nd anhedonia, both of that are somewhat widespread comorbidities of epilepsy.
Nd anhedonia, each of that are reasonably common comorbidities of epilepsy. An assessment of XEN1101 in acute rodent models of depression and anhedonia was undertaken. The forced swim test (FST) is usually a model of behavioral despair, and is sensitive to many classes of antidepressant drugs. Mice received a single dose of 1 mg/kg or three mg/kg XEN1101, 30 mg/kg imipramine, or vehicle. Thirty minutes post-dose, animals were placed into glass cylinders filled with water. Right after a period of vigorous activity, mice cease swimming and adopt an immobile posture. Over a 6-min test session, the 1 mg/kg and 3 mg/kg XEN1101 dose groups showed a dose-dependent trend towards elevated latency to immobility too as a dose-dependent reduction in time spent immobile (154 49.9 s and 142 42.eight s for 1 and three mg/ kg doses, respectively, in comparison to 201 42.9 s for car (p 0.05)); each indicative of an anti-depressant impact. The progressive ratio test (PRT) is often a model of anhedonia. The effect of XEN1101 around the motivation of educated rats to respond with a lever press for any meals reward was assessed. The rats followed a progressive schedule of reinforcement in which the number of lever presses expected to obtain a food reward increased for successive reinforcers. The break point was defined as the point at which a rat failed to earn a meals pellet in 20 min. The amount of meals pellets earned was the major measure of efficacy, with increases indicating improvements in anhedonia. Within a crossover design and style, rats received a single dose of 1, 3, or 8 mg/kg XEN1101, 0.6 mg/kg amphetamine (as a positive manage), or automobile. XEN1101 substantially elevated the number of food pellets earned at the break point for both the 3 mg/kg (n = 12.5 0.four) and eight mg/kg doses (n = 12.8 0.five), respectively, in comparison with n = 11.5 0.five for car (p 0.05 and p 0.01, respectively). The results from these two research support a prospective advantage of XEN1101 in mood problems.ASENT2021 Annual Meeting AbstractsAbstract 21 Anticonvulsant Effects of your Differentiated Kv7 Channel Potentiator XEN1101 in Combination with Commonly Employed Anti-seizure Drugs J.P. Johnson, Jr., Girish Bankar, Celine Dube, Parisa Tari, Karen Leukotriene Receptor Storage & Stability Nelkenbrecher, Matthew Waldbrook, Nina Weishaupt, Gregory Beatch, Jeff Bechard, Rostam Namdari, Robin Sherrington, Alison Cutts, Charles Cohen, James Empfield; Xenon Pharmaceuticals, Inc. XEN1101 is actually a constructive allosteric modulator of Kv7 channels being created for the therapy of epilepsy. Combination of anti-seizure drugs (ASDs) is prevalent in clinical practice. Hence we examined the potential for mixture therapy with XEN1101 as well as other ASDs. The MNK custom synthesis efficacy of XEN1101 was evaluated in mixture with valproic acid, phenytoin, or levetiracetam in the direct current maximum electroshock seizure assay (DC-MES). The combined efficacy of XEN1101 and levetiracetam was also evaluated within the 6-Hz psychomotor seizure assay (six Hz). We tested the efficacy of XEN1101 in combination with phenytoin within the DC-MES assay. A weakly efficacious dose of phenytoin (two mg/kg protected 25 of mice) was combined with XEN1101 at 0.75, 1, 1.five, and two.5 mg/kg within the DC-MES assay. XEN1101 was successful, having a total plasma EC50 of 0.154 when dosed alone and 0.04 when dosed in mixture with phenytoin, a three.85-fold increase in apparent potency. We next tested XEN1101 inside the DC-MES assay in combination with valproic acid. A weakly efficacious dose of XEN1101 (1 mg/kg protected 30 of mice) was combined w.

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