Potiga (retigabine) News

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|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (XEN496) / Xenon, Seizalam (midazolam intramuscular) / Pfizer
Development and Clinical Modeling of Kv7 Channel Opener Prodrug for Treatment of Focal Onset Seizures and Status Epilepticus (MCP Hall A) - Aug 22, 2024 - Abstract #Neuroscience2024Neuroscience_615;
Its efficacy after IM dosing in maximal-electroshock was determined in rat and potential for DDI with IM midazolam was assessed...Allometrically scaled to human, a 200 mg dose is > 2uM at 100 minutes and is sustained for 20 h. The half-life of ezogabine from the administration of the prodrug is simulated to be 31 h by the IM route from the Kv7 prodrug compared to 6-8 h by the oral route from the tablet for Potiga

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Journal: Pharmacological Activation of Neuronal Voltage-Gated Kv7/KCNQ/M-Channels for Potential Therapy of Epilepsy and Pain. (Pubmed Central) - Oct 1, 2021
Fortunately, these side effects are compound-structures related and can be avoided. Thus, further identification and development of novel potent and selective Kv7 channel openers may lead to an effective therapy with improved safety window for anti-epilepsy and anti-nociception.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Journal: Molecular Mechanisms and Structural Basis of Retigabine Analogues in Regulating KCNQ2 Channel. (Pubmed Central) - May 4, 2021
Our finding provides insight into the molecular mechanism by which KCNQ2 channels are regulated by RTG analogues. It also provides direct theoretical support for optimizing design of the KCNQ2 channel openers in the future, which will help treat refractory epilepsy caused by nerve excitability.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Preclinical, Journal: KCNQ Current Contributes to Inspiratory Burst Termination in the Pre-Bötzinger Complex of Neonatal Rats in vitro. (Pubmed Central) - May 1, 2021
By contrast, activation of KCNQ with retigabine decreased inspiratory burst duration by ~35%. These data from reduced preparations suggest that the KCNQ current in preBötC neurons contributes to inspiratory burst termination.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Clinical, Journal: Effects of the KCNQ channel opener ezogabine on functional connectivity of the ventral striatum and clinical symptoms in patients with major depressive disorder. (Pubmed Central) - Mar 10, 2021
In addition, a subgroup of patients tested with a probabilistic reward task (n = 9) showed increased reward learning following treatment. These findings highlight the KCNQ-type potassium channel as a promising target for future drug discovery efforts in mood disorders.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
[VIRTUAL] QRA-244 a Potent, Selective KCNQ2/3 Opener and a Potential Therapy for ALS patients () - Mar 4, 2021 - Abstract #CNSS2021CNSS_71;
Overall, QurAlis is developing QRA-244, a more potent and selective Kv7.2/7.3 activator aimed at normalizing excitability of the ALS motor system, with a significant reduction in off-target driven adverse events. We believe that this compound offers a promising therapeutic approach to counteract disease progression induced by hyperexcitability in ALS patients.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Clinical: Groundbreaking from @IcahnDAC's @JMurrough: "I think it's fair to say that most of us on the study team were quite surprised at the large size of the beneficial effect of ezogabine on clinical symptoms across multiple measures related to depression." https://t.co/I1svEbo84B 👏 (Twitter) - Mar 3, 2021

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Clinical: From @JMurrough in @APAPubJournals: The first #RCT showing that ezogabine, a drug that opens KCNQ2/3 type of potassium channels in the brain, is associated with significant improvements in depressive symptoms and #anhedonia in patients with #depression. https://t.co/WnkUg67Z6j (Twitter) - Mar 3, 2021

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Clinical, Journal: Antinociceptive Efficacy of Retigabine and Flupirtine for Gout Arthritis Pain. (Pubmed Central) - Feb 7, 2021
We believe that this compound offers a promising therapeutic approach to counteract disease progression induced by hyperexcitability in ALS patients. Retigabine and flupirtine showed antinociceptive effects for MSU-induced gout pain at different times during pain development.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Journal: Structural Basis for the Modulation of Human KCNQ4 by Small-Molecule Drugs. (Pubmed Central) - Jan 28, 2021
Electrophysiological analyses of various mutants corroborated the structural observations. Our studies reveal the molecular basis for the modulatory mechanism of neuronal KCNQ channels and provide a framework for structure-facilitated drug discovery targeting these important channels.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Journal: Functional and behavioral signatures of Kv7 activator drug subtypes. (Pubmed Central) - Jan 23, 2021
We also establish the use of in vivo CaMPARI as a tool for screening effects of anticonvulsant drugs on neuronal excitability in zebrafish. In summary, despite a shared ability to suppress neuronal excitability, our findings illustrate how mechanistic differences between Kv7 activator subtypes influence their effects on heteromeric channels and lead to vastly different in vivo outcomes.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Journal: Prevention of brain damage after traumatic brain injury by pharmacological enhancement of KCNQ (Kv7, "M-type") K currents in neurons. (Pubmed Central) - Jan 6, 2021
Using the mouse controlled closed-cortical impact blunt TBI model, we found that systemic administration of the prototype M-channel "opener", retigabine (RTG), 30 min after TBI, reduces the post-TBI cascade of events, including spontaneous seizures, enhanced susceptibility to chemo-convulsants, metabolic stress, inflammatory responses, blood-brain barrier breakdown, and cell death. This work suggests that acutely reducing neuronal excitability and energy demand via M-current enhancement may be a novel model of therapeutic intervention against post-TBI brain damage and dysfunction.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Journal: Depolarization-dependent C-Raf signaling promotes hyperexcitability and reduces opioid sensitivity of isolated nociceptors after spinal cord injury. (Pubmed Central) - Jan 5, 2021
This study shows that SCI and one consequence of SCI -- chronic depolarization of resting membrane potential -- decrease sensitivity to opioid-mediated inhibition of cAMP and promote hyperactivity of nociceptors by enhancing C-Raf activity. ERK activation downstream of C-Raf is necessary for maintaining ongoing depolarization and hyperactivity, demonstrating an unexpected positive feedback loop to persistently promote pain.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Journal: The Functional Availability of Arterial Kv7 Channels Is Suppressed Considerably by Large-Conductance Calcium-Activated Potassium Channels in 2- to 3-Month Old but Not in 10- to 15-Day Old Rats. (Pubmed Central) - Jan 3, 2021
Importantly, BK channels govern the extent of functional impact of Kv7 channels. This effect depends on the relationship between the functional activities of BK and Kv7 channels.

|||||||||| carbamazepine / Generic mfg.
Preclinical, Journal: Evaluation of subchronic administration of antiseizure drugs in spontaneously seizing rats. (Pubmed Central) - Dec 2, 2020
This effect depends on the relationship between the functional activities of BK and Kv7 channels. Despite reductions in seizure burden, the lack of full seizure freedom for any ASD tested suggests that this screening paradigm may be useful for testing novel compounds with potential utility in pharmacoresistant epilepsy.

|||||||||| pregabalin / Generic mfg.
[VIRTUAL] Efficacy of 250 antiseizure drug combinations in a zebrafish model of Dravet Syndrome () - Nov 28, 2020 - Abstract #AES2020AES_1135;
Alternative combinations of ASD therapies might be efficacious for monogenic intractable epilepsies. Funding: None

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
[VIRTUAL] Pharmacokinetic (PK) and Food Effect Assessment of XEN496, a Pediatric Formulation of Ezogabine, in Healthy Adults and Retrospective PK and Safety Comparison with Potiga® () - Nov 28, 2020 - Abstract #AES2020AES_1133;
For NAMR, the fed and fasted states were BE for both of these PK parameters. When compared to historical Potiga® data, XEN496 exhibited comparable biopharmaceutical and safety performance, suggesting that no formulation-related dose adjustments are indicated for future clinical studies.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
[VIRTUAL] Limited Effect of Inhibiting Parvalbumin-Expressing Interneurons in a Mouse Model of Dravet Syndrome () - Nov 28, 2020 - Abstract #AES2020AES_1123;
Further work with pharmacological and chemogenetic studies are warranted to test whether specifically targeting somatostatin-expressing interneurons (SOM-INs) may have therapeutic potential in Dravet Syndrome. Funding: NINDS K08 NS096029

|||||||||| carbamazepine / Generic mfg.
[VIRTUAL] Administration of Selected Sodium Channel- Blocking Antiseizure Drugs Alters the Development of Pharmacoresistant Kindled Seizures () - Nov 28, 2020 - Abstract #AES2020AES_939;
This study suggests that early, chronic administration of fast-inactivation state preferring ASDs, such as lamotrigine, versus slow-inactivation state preferring ASDs, like LCM, early in the kindling process may significantly alter the development of pharmacoresistance in the corneal kindled mouse model of chronic neuronal hyperexcitability. Funding: NCATS KL2 TR002317 to MBH

|||||||||| Potiga (retigabine) / Bausch Health, GSK, XEN1101 / Xenon, ezogabine (pediatric formulation of potiga) / Xenon
[VIRTUAL] Preclinical In Vitro and In Vivo Comparison of the Kv7 Activator XEN1101 with Ezogabine. () - Nov 28, 2020 - Abstract #AES2020AES_406;
XEN1101 provides a mechanism of action not currently available for the treatment of epilepsy and top line data in a large adult focal seizure trial should be available in H1, 2021. Funding: N/A

|||||||||| ezogabine (pediatric formulation of potiga) / Xenon
Clinical, Journal: Safety of retigabine in adults with partial-onset seizures after long-term exposure: focus on unexpected ophthalmological and dermatological events. (Pubmed Central) - Oct 24, 2020
P3
Discoloration of various tissues occurred in a proportion of patients treated with retigabine and resolved completely in a small number of these patients following treatment discontinuation. In addition, comprehensive eye examination identified a new adverse reaction of acquired vitelliform maculopathy in a limited number of patients.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Journal: Design and evaluation of pyrazolopyrimidines as KCNQ channel modulators. (Pubmed Central) - Sep 23, 2020
In this paper, we describe the discovery and evaluation of a series of novel pyrazolopyrimidines and their affinity for potassium channels KCNQ2/3. These pyrazolopyrimidines have also shown good efficacy in the capsaicin-induced acute and secondary mechanical allodynia model and excellent pharmacokinetic properties, which may be superior to Retigabine.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Journal: Enhancing KCNQ channel activity improves neurobehavioral recovery after spinal cord injury. (Pubmed Central) - Sep 9, 2020
Necrotic neuronal death and chronic pain often are the cost of pathological neural excitation after SCI. We show that early brief application of retigabine could aid locomotor and sensory neurobehavioral recovery following SCI, supporting the use of this drug in the clinic to promote motor and sensory function in SCI patients.

|||||||||| pregabalin / Generic mfg.
Preclinical, Journal: Polygonogram and isobolographic analysis of interactions between various novel antiepileptic drugs in the 6-Hz corneal stimulation-induced seizure model in mice. (Pubmed Central) - Aug 27, 2020
The most beneficial combination, offering the highest level of synergistic suppression of seizures in mice was that of LEV+RTG, whereas the most additive combination that protected the animals from seizures was that reporting additivity for RTG+LCM. The strength of interaction for two-drug combinations can be arranged from the synergistic to the additive, as follows: LEV+RTG > LEV+LCM > GBP+RTG > PGB+LEV > GBP+LEV > PGB+RTG > PGB+LCM > GBP+LCM > GBP+PGB > RTG+LCM.

|||||||||| paclitaxel / Generic mfg.
Journal: Activation of KCNQ channels prevents paclitaxel-induced peripheral neuropathy and associated neuropathic pain. (Pubmed Central) - Aug 20, 2020
Perspective: Paclitaxel-induced peripheral neuropathy and associated neuropathic pain are severe and resistant to intervention. The results of our study demonstrated that retigabine (a clinically available medicine) can be used to attenuate the development of paclitaxel-induced peripheral neuropathy.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Preclinical, Journal: Activation of K7 channels with the anticonvulsant retigabine alleviates neuropathic pain behaviour in the streptozotocin rat model of diabetic neuropathy. (Pubmed Central) - Aug 19, 2020
This analgesic effect of retigabine was completely reversed by the K7/M channel blocker XE991 (3 mg/kg, i.p.) indicating that the anti-allodynic effects of retigabine were mediated by K7 channels. In conclusion, the findings suggest that Kv7 channels are involved in DPNP pathogenesis, and that strategies that target their activation may prove to be effective in treating DPNP.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Preclinical, Journal: Efficacy of retigabine in ameliorating the brain insult following sarin exposure in the rat. (Pubmed Central) - Aug 18, 2020
In conclusion, the findings suggest that Kv7 channels are involved in DPNP pathogenesis, and that strategies that target their activation may prove to be effective in treating DPNP. The M current modulator retigabine has been shown to be an effective adjunct therapy following OP induced convulsion, minimizing epileptiform seizure activity and attenuating the ensuing brain damage.

|||||||||| chloroquine phosphate / Generic mfg.
Preclinical, Journal: Inhibition of M/K7 Currents Contributes to Chloroquine-Induced Itch in Mice. (Pubmed Central) - Jul 24, 2020
Systemic application of RTG or TA also significantly inhibits the itch behavior induced by a variety of pruritogens. Taken together, our findings provide novel insight into the molecular basis of CQ-induced itch sensation in mammals that can be applied to the development of strategies to mitigate itch behavior.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Journal: Modulation of K7 Channel Deactivation by PI(4,5)P. (Pubmed Central) - Jul 9, 2020
Furthermore, it was observed that the action of either Ci-VS-TPIP or Wortmannin reduced the effect of Retigabine on the kinetics of deactivation, having a higher impact when activation was prolonged. These combined observations led to the conclusion that the deactivation kinetic of K7.2/K7.3 channels was sensitive to PI(4,5)P depletion in an activation-dependent manner, displaying a stronger effect on deactivation following prolonged activation.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Preclinical, Journal: Modelling monogenic autism spectrum disorder using mouse cortical organoids. (Pubmed Central) - Jul 7, 2020
Our findings suggest that, in the early fetal cortical development, the cell adhesion molecule Cntnap2 plays a crucial role in the regulation of the differentiation of GABAergic neurons in the organoid platform. The reduced number of GABAergic neurons was efficiently restored in KO mCOs by treatment with the antiepileptic drug retigabine, showing the effectiveness of Cntnap2 KO mCOs in the therapeutic targeting of ASD.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Journal: Synthesis and pharmacological characterization of conformationally restricted retigabine analogues as novel neuronal Kv7 channels activators. (Pubmed Central) - Jul 2, 2020
Stability studies evidenced improved chemical stability of 23a and 24a in comparison with retigabine. Overall, the present results highlight that the N5-alkylamidoindole moiety provides a suitable pharmacophoric scaffold for the design of chemically-stable, highly-potent and selective Kv7 agonists.

|||||||||| nitroprusside / Generic mfg., Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Clinical, Journal: Effect of increased potassium intake on the renin-angiotensin-aldosterone system and subcutaneous resistance arteries: a randomized crossover study. (Pubmed Central) - Jul 1, 2020
Overall, the present results highlight that the N5-alkylamidoindole moiety provides a suitable pharmacophoric scaffold for the design of chemically-stable, highly-potent and selective Kv7 agonists. Four weeks of increased potassium intake activates the RAAS in normotensive men without changing BP and this is not explained by improved vasodilatory responses ex vivo.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Preclinical, Journal: Cutaneous Aβ-Non-nociceptive, but Not C-Nociceptive, Dorsal Root Ganglion Neurons Exhibit Spontaneous Activity in the Streptozotocin Rat Model of Painful Diabetic Neuropathy in vivo. (Pubmed Central) - Jun 13, 2020
Compared with control, we found in STZ-rats with established pain hypersensitivity (5 weeks post-STZ) several significant changes including: (a) A 23% increase in the incidence of spontaneous activity (SA) in Aβ-LTMs (but not C-mechanosensitive nociceptors) that may cause dysesthesias/paresthesia suffered by DPNP patients, (b) membrane hyperpolarization and a ∼85% reduction in SA rate in Aβ-LTMs by K7 channel activation with retigabine (6 mg/kg, i.v.) suggesting that K7/M channels may be involved in mechanisms of SA generation in Aβ-LTMs, (c) decreases in AP duration and in duration and amplitude of afterhyperpolarization (AHP) in C-and/or Aβ-nociceptors. These faster AP and AHP kinetics may lead to repetitive firing and an increase in afferent input to the CNS and thereby contribute to DPNP development, and (d) a decrease in the electrical thresholds of Aβ-nociceptors that may contribute to their sensitization, and thus to the resulting hypersensitivity associated with DPNP.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Preclinical, Journal: KCNQ/M-channels regulate mouse vagal bronchopulmonary C-fiber excitability and cough sensitivity. (Pubmed Central) - Jun 5, 2020
In conclusion, KCNQ/M-channels play a role in regulating the excitability of vagal airway C-fibers at both the cell soma and nerve terminals. Drugs that open M-channels in airway sensory afferents may relieve the sufferings associated with pulmonary inflammatory diseases such as chronic coughing.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Journal: Electrophysiological and pharmacological characterization of a novel and potent neuronal Kv7 channel opener SCR2682 for antiepilepsy. (Pubmed Central) - Jun 5, 2020
Taken together, our findings demonstrate that a novel small molecule, SCR2682, selectively and potently activates neuronal Kv7 channels and reverses epileptic seizures in rodents. Thus, SCR2682 may warrant further evaluation for clinical development of antiepileptic therapy.-Zhang, F., Liu, Y., Tang, F., Liang, B., Chen, H., Zhang, H., Wang, K. Electrophysiological and pharmacological characterization of a novel and potent neuronal Kv7 channel opener SCR2682 for antiepilepsy.

|||||||||| Potiga (retigabine) / Bausch Health, GSK
Journal: Neuropathic pain and Kv7 voltage-gated potassium channels: The potential role of Kv7 activators in the treatment of neuropathic pain. (Pubmed Central) - Jun 4, 2020
Thus, SCR2682 may warrant further evaluation for clinical development of antiepileptic therapy.-Zhang, F., Liu, Y., Tang, F., Liang, B., Chen, H., Zhang, H., Wang, K. Electrophysiological and pharmacological characterization of a novel and potent neuronal Kv7 channel opener SCR2682 for antiepilepsy. No abstract available

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Preclinical, Journal: The K 7 channel activator retigabine suppresses mouse urinary bladder afferent nerve activity without affecting detrusor smooth muscle K channel currents. (Pubmed Central) - May 15, 2020
These results indicate that retigabine primarily affects urinary bladder function by inhibiting TC generation and afferent nerve activity, which are key to sensing bladder fullness. Any direct inhibition of UBSM contractility is likely non-specific effects on VDCCs and K 2 channels.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Preclinical, Journal: The dual role of KCNQ/M channels upon OGD or OGD/R insults in cultured cortical neurons of mice: Timing is crucial in targeting M-channels against ischemic injur ies. (Pubmed Central) - May 13, 2020
Our present study indicates the dual role of KCNQ/M-channels in OGD and OGD/R, which will decide the fate of neurons. Provided that activation of KCNQ/M-channels has differential effects on neuronal injuries during OGD or OGD/R, we propose that therapy targeting KCNQ/M-channels may be effective for ischemic injuries but the proper timing is so crucial for the corresponding treatment.

|||||||||| Afinitor (everolimus) / Novartis
Journal: New anti-epileptic drugs in Paediatrics (Pubmed Central) - Apr 23, 2020
These new molecules have been developed in order to provide a pharmaceutical profile and tolerance superior to the previously available drugs, and it is forecast that as their use increases, their true potential and profile will widen. Furthermore, for the first time in Paediatric Epileptology, the extrapolation of the efficacy data in adults have been used (together with specific safety and pharmacokinetic studies in the paediatric population), in order to speed up their approval for use in the child population.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Preclinical, Journal: Treatment of myotonia congenita with retigabine in mice. (Pubmed Central) - Feb 25, 2020
There are a number of potential explanations for the lack of motor improvement in vivo including central nervous system side effects. Nonetheless, the striking effectiveness of retigabine on muscle itself suggests that activating potassium currents is an effective method to treat disorders of muscle hyperexcitability.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Journal: Sulfide Analogues of Flupirtine and Retigabine with Nanomolar KV7.2/KV7.3 Channel Opening Activity. (Pubmed Central) - Feb 20, 2020
Sulfide analogs were identified that are devoid of the risk of quinone formation but possess potent KV7.2/3 opening activity. For example, flupirtine analog 3-(3,5-difluorophenyl)-N-(6-(isobutylthio)-2-(pyrrolidin-1-yl)pyridin-3-yl)propanamide (48) has a 100-fold enhanced activity (EC50 = 1.4 nM), vastly improved toxicity/activity ratio and the same efficacy as retigabine in vitro.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, NBI-921352 / Neurocrine, ezogabine (pediatric formulation of potiga) / Xenon
Development of Pediatric Formulations of the Potassium Channel Opener Ezogabine and the NaV1.6-Selective Sodium Channel Blocker XEN901 for the Treatment of Developmental and Epileptic Encephalopathies () - Feb 3, 2020 - Abstract #AAN2020AAN_5204;
For example, flupirtine analog 3-(3,5-difluorophenyl)-N-(6-(isobutylthio)-2-(pyrrolidin-1-yl)pyridin-3-yl)propanamide (48) has a 100-fold enhanced activity (EC50 = 1.4 nM), vastly improved toxicity/activity ratio and the same efficacy as retigabine in vitro. Pediatric formulations of ezogabine (XEN496) and of XEN901 were developed as granules suitable for dispersal in breast milk, infant formula or soft foods, packaged in single-use sachets or sprinkle capsules of varying fill weights and progressed into Phase 1 PK studies in healthy adult subjects.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Pharmacokinetic and Food Effect Assessment of XEN496 (Pediatric Formulation of Ezogabine) in Healthy Adults and Relative Bioavailability Assessment with Potiga® (Adult Formulation of Ezogabine) () - Feb 3, 2020 - Abstract #AAN2020AAN_5203;
Pediatric formulations of ezogabine (XEN496) and of XEN901 were developed as granules suitable for dispersal in breast milk, infant formula or soft foods, packaged in single-use sachets or sprinkle capsules of varying fill weights and progressed into Phase 1 PK studies in healthy adult subjects. The results from this study are expected to provide guidance and facilitate dose selection for a planned XEN496 pediatric study in KCNQ2-DEE.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Pharmacokinetic and Food Effect Assessment of XEN496 (Pediatric Formulation of Ezogabine) in Healthy Adults and Relative Bioavailability Assessment with Potiga® (Adult Formulation of Ezogabine) () - Jan 21, 2020 - Abstract #AAN2020AAN_3268;

|||||||||| Potiga (retigabine) / Bausch Health, GSK, XEN901 / Neurocrine, ezogabine (pediatric formulation of potiga) / Xenon
Development of Pediatric Formulations of the Potassium Channel Opener Ezogabine and the NaV1.6-Selective Sodium Channel Blocker XEN901 for the Treatment of Developmental and Epileptic Encephalopathies () - Jan 21, 2020 - Abstract #AAN2020AAN_3267;

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon, Trileptal (oxcarbazepine) / Novartis
PK/PD data, Journal: Study of gender-related pharmacokinetics of ezogabine in Egyptian volunteers by a validated LC-MS/MS bioanalytical method. (Pubmed Central) - Jan 21, 2020
These findings highlight the difference of ezogabine pharmacokinetics among populations. Further, gender-based ezogabine dose adjustment may be considered.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Journal: Activation of Kv7 Potassium Channels Inhibits Intracellular Ca Increases Triggered By TRPV1-Mediated Pain-Inducing Stimuli in F11 Immortalized Sensory Neurons. (Pubmed Central) - Jan 16, 2020
Moreover, all tested Kv7 openers inhibited BK- and CAP-induced responses by a similar extent (~60%); at least for BK-induced Ca responses, the potency of retigabine (IC~1 µM) was higher than that of ICA-27243 (IC~5 µM) and (S)-1 (IC~7 µM). Altogether, these results suggest that I activation effectively counteracts the cellular processes triggered by TRPV1-mediated pain-inducing stimuli, and highlight a possible critical contribution of Kv7.4 subunits.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon, fluoxetine / Generic mfg.
Journal: Reversal of a Treatment-Resistant, Depression-Related Brain State with the Kv7 Channel Opener Retigabine. (Pubmed Central) - Dec 26, 2019
By contrast, retigabine (also known as ezogabine) normalized neural excitability and I currents recorded from slices of HFD-treated animals and significantly ameliorated most of the behavioral impairments, without effects in control diet exposed animals. Thus, treatment resistant depressive-like brain states that are associated with chronic neuroinflammation may involve hyperexcitability of pyramidal neurons and may be effectively treated by retigabine.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Clinical, Journal: Whole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss. (Pubmed Central) - Dec 23, 2019
However, channels assembled from WT-p.Val87_Asn89del concatemers showed impaired conductance, suggesting that p.Val87_Asn89del caused complete loss-of-function with a strong dominant-negative effect on functional WT channels. Therefore, the main pathological mechanism may be related to loss of K channel activity, not defects in trafficking.

|||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (pediatric formulation of potiga) / Xenon
Preclinical, Journal: An Investigation into Retigabine (Ezogabine) Associated Dyspigmentation in Rat Eye by MALDI Imaging Mass Spectrometry (IMS). (Pubmed Central) - Dec 23, 2019
High lateral resolution images illustrate that the blood-retinal barrier effectively restricts retinal access to RTG-related compounds. The spatial information provided by MALDI IMS was critical in contextualizing the homogenate concentrations of key RTG-related compounds and helped provide a basis for the mechanism of dimer formation.



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