WO2021211867A1

WO2021211867A1 - Kv7 modulators for treating sleep or anxiety disorders

Info

Publication number: WO2021211867A1
Application number: PCT/US2021/027518
Authority: WO
Inventors: Pablo Villoslada; Rajiv MAHADEVAN
Original assignee: Attune Neurosciences, Inc.
Priority date: 2020-04-16
Filing date: 2021-04-15
Publication date: 2021-10-21

Abstract

The present specification discloses methods and uses for treating a sleep or anxiety disorder by administering a Kv7 modulator alone or in combination with another at least one other therapeutic sleep agent.

Description

Kv7 MODULATORS FOR TREATING SLEEP OR ANXIETY DISORDERS INTRODUCTION [001] This application claims the benefit of priority and is entitled to the filing date pursuant to 35 U.S.C. § 119(e) of U.S. Provisional Patent Application 63/011,198, filed April 16, 2020, the content of which is hereby incorporated by reference in its entirety. [002] More than one-quarter of people in the U.S. report occasionally not getting enough sleep, according to the Centers for Disease Control and Prevention. However, the clinical definition of insomnia, as explained in the psychiatric textbook the Diagnostic and Statistical Manual of Mental Disorders (DSM), includes feeling impaired during the daytime or stressed by having a sleep disorder. According to the DSM, in a person suffering from true insomnia, symptoms persist for at least a month, and do not occur along with another sleep disorder, mental disorder, medical condition or substance use. By this definition, about 6 percent of people have insomnia, according to the National Institutes of Health. It is well known that losing sleep has negative effects on health, and people who persistently get less sleep are more likely to be in traffic accidents, have higher rates of missed workdays, are less satisfied with their jobs and are more likely to get easily irritated. [003] Studies show that the rate of sleeping pills use in the U.S. continue to rise. One in four Americans take some type of medication every year to help them sleep, according to the National Sleep Foundation. But these pills may not be leading to better sleep. Many compounds that are prescribed and utilized to treat sleep have undesirable side effects, which can include headache, next day drowsiness, dizziness, abnormal dreams, diarrhea, dry mouth, cough, upper respiratory tract infection, blurred vision, constipation, trouble urinating, urinary retention problems, nausea, vomiting, upset stomach. symptoms of anxiety, panic attacks, thoughts about suicide or dying, feelings of restlessness, feelings of agitation, irritability and weight gain, for example. [004] Insomnia can be caused by psychiatric and medical conditions, unhealthy sleep habits, specific substances, and/or certain biological factors. The brain has a sleep cycle and a wake cycle, when one is turned on the other is turned off; insomnia can be a problem with either part of this cycle: too much wake drive or too little sleep drive. [005] Two main models exist as to the mechanism of insomnia, (1) cognitive and (2) physiological. The cognitive model suggests rumination and hyperarousal contribute to preventing a person from falling asleep and might lead to an episode of insomnia. The physiological model is based upon three major findings in people with insomnia; firstly, increased urinary cortisol and catecholamines have been found suggesting increased activity of the HPA axis and arousal; second increased global cerebral glucose utilization during wakefulness and non-rapid eye movement (NREM) sleep in people with insomnia; and lastly increased full body metabolism and heart rate in those with insomnia. All these findings taken together suggest a dysregulation of the arousal system, cognitive system, and HPA axis all contributing to insomnia. However, it Is unknown if the hyperarousal is a result of, or cause of insomnia. Altered levels of the inhibitory neurotransmitter GABA have been found, but the results have been inconsistent, and the implications of altered levels of such a ubiquitous neurotransmilter are unknown. Around half of post-menopausa! women experience sleep disturbances, and generally sleep disturbance is about twice as common in women as men; this appears to be due in part, but not completely, to changes in hormone levels, especially in and post-menopause. Changes in sex hormones in both men and women as they age may account in part for increased prevalence of sleep disorders in older people.

[006] In medicine, insomnia is widely measured using the Athens insomnia scale (Table 1). it is measured using eight different parameters related to sleep, finally represented as an overall scale which assesses an individual's sleep pattern. This was first introduced In the year 2000 by a group of researchers from Athens, Greece to assess the insomnia symptoms in patients with sleep disorders, it is measured by assessing eight factors (as tabulated below) amongst which first five factors are related to nocturnal sleep and last three factors are related to daytime dysfunction. These are rated on a 0-3 scale and the sleep is finally evaluated from the cumulative score of all factors and reported as an Individual’s sleep outcome. AIS is considered to be an effective tool in sleep analysis, and it is validaled in various countries by testing it on local patients. A cut-off score of >6 on the AlS is used to establish the diagnosis of insomnia.

[007] While it is well known that sleep destabilizes during aging, the underlying mechanisms have been poorly understood. As mentioned above, millions of people currently are administered various types of medications, for example, antidepressant and/or antianxiety medications, every year to help them sleep. However, use of these current compounds for treating sleep disorders ail too often are associated with undesirable side effects. [008] Accordingly, there is a need for compounds, compositions, and regimens for treating a sleep disorder. In one aspect, compounds, compositions, methods and regimens provided in accordance with the teachings of the present disclosure reduce the intensity and/or frequency of undesired side effects associated with the use of compositions currently utilized to treat a neurological condition or disorder, including sleep disorders.

SUMMARY

[009] Aspects of the present specification disclose methods for treating a sleep or anxiety disorder in an individual in need thereof. Aspects of the disclosed methods comprises administering to the individual a therapeutically effective amount of a potassium channel modulator thereby treating the sleep or anxiety disorder of the individual. A disclosed potassium channel modulator modulates one or more Kv7 members of voltage-gated potassium channels and includes a neuronal Kv7 activator. Non-limiting examples of a neuronal Kv7 activator include a Triaminopyridine or one of its derivatives, an Acrylamide, a Benzamide, a Fenamate, a Dimethoxypyrimidine or one of its derivatives, Oxindole, Celecoxib, zinc pyrithione, ML213, QO58, QO58 lysine, NS1643, Benzbromarone, ZG1732 and ZG2083. An individual disclosed herein ban be at least 50 years of age and/or can suffer from a form of age-related cognitive impairment, neurological disease or psychiatric disease. An individual disclosed herein can suffer from post-traumatic stress syndrome, traumatic brain injury, or an autism spectrum disorder.

[010] Aspects of the present specification disclose combinatorial methods for treating a sleep or anxiety disorder in an individual in need thereof. Aspects of the disclosed methods comprises administering to the individual a therapeutically effective amount of a potassium channel modulator in combination with an amount of at least one other therapeutic sleep agent utilized to treat the sleep or anxiety disorder, thereby treating the sleep or anxiety disorder of the individual. A disclosed potassium channel modulator modulates one or more Kv7 members of voltage-gated potassium channels and includes a neuronal Kv7 activator. Non-limiting examples of a neuronal Kv7 activator include a Triaminopyridine or one of its derivatives, an Acrylamide, a Benzamide, a Fenamate, a Dimethoxypyrimidine or one of its derivatives, Oxindole, Celecoxib, zinc pyrithione, ML213, QO58, QO58 lysine, NS1643, Benzbromarone, ZG1732 and ZG2083. A therapeutic sleep agent includes, without limitation, an antidepressant, an antianxiety medication or any combination thereof. Non-limiting examples of a disclosed therapeutic sleep agent include doxepln, estazolarn, eszopicione, mirtazapine and its enantiomers, ramelieon, suvorexant, temazepam, trazodone, triazolam, zalep!on, and zolpidem. Aspects of the disclosed combinatorial methods for treating a sleep or anxiety disorder use an amount of the least one other therapeutic sleep agent that is an amount that is a therapeutically ineffective amount of the at least one other therapeutic sleep agent if the at least one other therapeutic sleep agent was being administered to the individual without the potassium channel modulator. For example, the amount of the least one other therapeutic sleep agent is an amount that is about half of a regulatory agency-approved dosage of the least one other therapeutic sleep agent. Administration of a potassium channel modulator disclosed herein results in a decrease in a frequency and/or an intensity of an undesired side effect brought on by administration of the at least one other therapeutic sleep agent. Non-limiting examples, of an undesired side include at least one of headache, next day drowsiness, dizziness, abnormal dreams, diarrhea, dry mouth, cough, upper respiratory tract infection, blurred vision, constipation, trouble urinating, urinary retention problems, nausea, vomiting, upset stomach, symptoms of anxiety, panic attacks, thoughts about suicide or dying, feelings of restlessness, feelings of agitation, irritability or weight gain. An individual disclosed herein can suffer from a form of age-related cognitive impairment and/or be at least 50 years of age.

[011] Other aspects disclose a potassium channel modulator disclosed herein for use in treating a sleep or anxiety disorder. Other aspects disclose use of a potassium channel modulator disclosed herein in treating a sleep or anxiety disorder. Other aspects disclose use of a potassium channel modulator disclosed herein in the manufacture of a medicament for treating a sleep or anxiety disorder.

[012] Other aspects disclose a potassium channel modulator disclosed herein in combination at least one other therapeutic sleep agent disclosed herein for use in treating a sleep or anxiety disorder. Other aspects disclose use of a potassium channel modulator disclosed herein in combination at least one other therapeutic sleep agent disclosed herein in treating a sleep or anxiety disorder. Other aspects disclose use of a potassium channel modulator disclosed herein in combination at least one other therapeutic sleep agent disclosed herein in the manufacture of a medicament for treating a sleep or anxiety disorder.

[013] Other aspects of the present specification disclose a kit. A disclosed kit can comprise a potassium channel modulator disclosed herein and at least one other therapeutic sleep agent disclosed herein.

DETAILED DESORPTION

[014] Sleep quality declining and is one of the most prevalent senile epidemics during aging in humans and sleep quality is strongly correlated with cognitive ability. Aging is associated with alteration in sleep architecture, and fragmentation, which usually causes non-restorative sleep. It has also been reported the ability of sustaining sleep/wake states is reduced in mice during aging. Underlying mechanisms that are responsible for sleep destabilization experienced during aging have been poorly understood.

[015] In one aspect of the disclosure, it has been found that altered excitability of hypocretin/orexin neurons contribute to sleep destabilization. For example, population activity of hypocretin neurons are weaker in aged mice than in young mice. In another aspect, optogenetic activation of hypocretin neurons elicits significantly longer wake bouts in aged mice than in young mice. We have conducted In vitro electrophysiology that demonstrates genetically-defined aged hypocretin neurons have higher excitability including less polarized resting membrane potential, reduced difference between resting membrane potential and firing threshold, and elevated sensitivity to current injection and light stimulation, than young hypocretin neurons. Blockade of Kv7 voltage-gated potassium channels was found to make the hypocretin neurons more excitable, whereas activation of Kv7 renders hypocretin neurons to be less active. In yet another aspect, systemic administration compounds that are Kv7 blockers or openers are sufficient to increase/decrease wakefulness through controlling the activity of hypocretin neurons. [016] The Kv7, or voltage-dependent K+ channel-KQT-like (KCNQ), subfamily of voltage-gated potassium channels comprise five members (Kv7.1-Kv7.5), each encoded by a distinct mammalian gene (KCNQ1-5) and showing a characteristic tissue distribution and physiological roles. Kv7 subunits form functional channels assembling as homo- or hetero-tetramers within the same family, Currents carried by all Kv7 channels are characterized by a rather negative activation threshold (around -60/-50 millivolts), slow activation and deactivation kinetics (current time constants are in the range of around 50-100 milliseconds at physiologically-relevant voltages), and absence of inactivation. Further functional heterogeneity is achieved upon incorporation of b-subunits belonging to the KCNE family. Given their functional heterogeneity, Kv7 channels represent important pharmacological targets for the development of new drugs for neuronal, cardiovascular and metabolic diseases.

[017] A review of the transmembrane topology of Kv7 channels and their regulatory factors and a myriad of functions where they play significant roles is provided in Miceli, et al., ‘‘Pharmacological Targeting of Neuronal Kv7.2/3 Channels: A Focus on Chemotypes and Receptor Sites, Current Medicinal Chemistry 25: 2637-2660 (2018), the content of which is hereby incorporated by reference in its entirety. In this review article, the pharmacological relevance and the potential therapeutic applications of drugs acting on Kv7 channels are explored, placing particular emphasis on the pharmacology of neuronally-expressed Kv7.2/3 channels; an in-depth description of the different chemotypes of Kv7.2/3 channels modulators, highlighting their pharmacodynamic and, whenever possible, pharmacokinetic peculiarities is also provided. A discussion regarding the topological architecture of Kv7 potassium channels including overall structure and regulatory sites and the distribution pattern and pathophysiological roles of Kv7 subunits is also detailed therein.

[018] Interestingly and in contrast to Kv7.1 channels, whose pathophysiological and pharmacological role has been mostly investigated in the cardiovascular system, all other four Kv7 members are mainly expressed in the nervous system and in sensory organs. KCNQ2 and KCNQ3 genes encode for Kv7.2 and Kv7.3 subunits, respectively. When expressed heterologously, Kv7.2 homomers exhibit robust K⁺ currents activated by depolarization at around -50 mV, while Kv7.3 homomers generate smaller-size K⁺ currents activated at more negative potentials (~-60 mV); channels formed by heteromeric assembly of Kv7.2 and Kv7.3 subunits carry 3-10 fold greater currents when compared to those expected by the simple summation of the currents produced by Kv7.2 and Kv7.3 individually.

[019] Kv7.2/3 heteromers underlie the M-current (I_KM), a subthreshold K⁺ current widely expressed in central and peripheral neurons. IKM is a slowly activating, deactivating, and non-inactivating current, which stabilizes the resting membrane potential, and reduces the intrinsic bursting and repetitive action potential firing triggered by excitatory stimuli. Moreover, IKM is also involved in network oscillation and synchronization control. IKM can be inhibited by the activation of G_q/11-coupled neurotransmitters receptors (like mAChR, hence its name, which, by increasing phospholipase-Cβ activity, trigger the depletion of phosphatidylinositol- 4,5-bisphosphate (PIP2), a lipid mediator required for channel opening. In neurons, expression of Kv7.2 and Kv7.3 subunits occurs in a highly-polarized fashion; their highest density occurs at the level of the axon initial segment (AIS) and nodes of Ranvier, where they co-localize with the Na⁺ channels through the binding of ankyrin-G. In Ranvier nodes, Kv7.2 subunits mediate slow potassium conductance (known as first described in frog myelinated nerve fibres, but then also found in mammalian nerve fibers. Depending on neuronal subcellular localization, Kv7 channels may play different functional roles. Indeed, while perisomatic Kv7 channels counteract the persistent Nav current and restrain repetitive firing, Kv7 channels in nodes ofRanvierofneocortical and hippocampal neurons prevent aberrant spontaneous firing and can also increase Nav channel availability and action potential amplitude by hyperpolarizing the resting membrane potential and removing Nav inactivation.

[020] Mutations in KCNQ2 and KCNQ3 are responsible for neonatal-onset epileptic diseases with widely diverging clinical manifestations, ranging from mostly benign to very severe phenotypes. Indeed, mutations in these two genes have been identified in patient affected with Benign Familial Neonatal Seizures (BFNS), a rare autosomal-dominant subset of epilepsy, characterized by a wide range of seizure types, which start in newborns between the second and the eighth day of life and disappear within the first year of life, with normal subsequent neuropsychological development. More recently, de novo missense KCNQ2 mutations have been identified in neonates affected with pharmacoresistant seizures, distinct EEG and neuroradiological features, and various degrees of developmental delay, defining a “Kv7.2 encephalopathy”. Notably, KCNQ2 variants have also been described in patients affected by myokymia, a peripheral nerve hyperexcitability disease.

[021] Functional studies for several Kv7.2 or Kv7.3 mutations have been carried out, with consequences ranging from slight changes in channel behavior to a complete ablation of channel function. A slight (about 25%) decrease of I is believed to be sufficient to cause BFNS, and haploinsufficiency seems to be the primary pathogenetic mechanism for BFNS. On the other hand, a more marked degree of current suppression (dominant negative effects) appears to be caused by Kv7.2 encephalopathy mutations, suggesting that disease severity may be related to the extent of mutation-induced functional K⁺ channel impairment. More recently, few disease-associated mutations in Kv7.2 and Kv7.3 increase I amplitude, suggesting that a gain-of-function mechanism may also cause epileptic encephalopathy. The role of KCNQ2 or KCNQ3 in epilepsy has also been assessed in genetically-modified animals. While targeted disruption of both KCNQ2 alleles (KCNQ2-/-) in mice led to pups death within a few hours after birth, heterozygous KCNQ2+/- mice showed a reduced threshold for epileptic manifestations upon exposure to the proconvulsant drug pentylenetetrazole. More recently, transgenic mice conditionally expressing a Kv7.2 subunit incorporating a non-natural mutation prompting dominant-negative effects were developed; these mice showed deficits in hippocampus-dependent spatial memory and increased excitability in hippocampal CA1 region, spontaneous seizures, behavioral hyperactivity and morphological hippocampal alterations during the first postnatal weeks. The conditional deletion of KCNQ2 gene expression in murine pyramidal neurons prompted abnormal electrocorticogram activity, early death and increased spontaneous excitability, whereas similar deletion of KCNQ3 did not. In addition, knock-in mice carrying missense mutations (KCNQ2 Y284C; KCNQ2 A306T; KCNQ3 G311V) found in families with autosomal dominantly inherited BFNS have been generated; also in these cases, while early-onset spontaneous generalized tonicclonic seizures and premature death occurred in homozygous KCNQ2^mut/mut mice, heterozygous KCNQ2^wt/mut mice exhibited a decreased I_KM density in CA1 pyramidal neurons, and a reduced seizures threshold when exposed to pro-convulsant. [022] The KCNQ5 gene encodes for Kv7.5 subunits having a brain distribution similar to that of Kv7.2 and Kv7.3, showing the highest expression levels in the neocortex, and lower levels in hippocampus and putamen. These subunits are believed to contribute to the functional heterogeneity of I_KM in different neuronal populations: as an example, Kv7.5 channels are highly expressed in the CA3 area of hippocampus, where they contribute to the after-hyperpolarization current. Recently, these channels have been found postsynaptically in inhibitory synapses on hippocampal pyramidal cells and in interneurons, with a role in dampening synaptic inhibition and shaping network synchronization. Kv7.5 has been recently shown to play a role in auditory pathways: in fact, Kv7.5 channels are localized in excitatory endings of auditory brainstem nuclei in the adult rat.

[023] Kv7 channels play pathophysiological roles and Kv7 channel modulators have the potential to influence the function of several organs and systems, thus being exploitable for therapeutic use in several disease states. Compounds/drugs which affect the function of neuronal Kv7 channels, in particular embodiments Kv7.2 and/or Kv7.3 channels, are particularly useful in accordance with the teachings of the instant disclosure, that is, for administration to a patient in need thereof to treat a neurological disorder, such as a sleep or anxiety disorder, for example. A review of exemplary neuronal Kv7 channel inhibitors and activators are described in Miceli, et al., “Pharmacological Targeting of Neuronal Kv7.2/3 Channels: A Focus on Chemotypes and Receptor Sites, Current Medicinal Chemistry 25: 2637-2660 (2018), the content of which is hereby incorporated by reference in its entirety. This reference discloses structural formula for exemplary Kv7 channel inhibitors in Table 1 and structural formula for exemplary Kv7 channel activators are shown in Table 2, particularly flupirtine, retigabine and their derivatives.

[024] Activation of voltage-gated potassium channels (for example, Kv7 channels) render particular, specific subsets of central neurons to be less active. The suppression/decrease in activation in these neurons have been shown to decrease a wake drive in mammals and to result in an increase in the amount of sleep. Hypocretin(Hcrt)/Orexin (Orx) neurons are of particular interest. These neurons are located in the lateral hypothalamus, mainly in the perifornical area of the posterolateral hypothalamus. Hypocretins or orexins (Hcrt/Orx) are hypothalamic neuropeptides synthesized by these neurons. Hcrt/Orx neuropeptides control of the sleep-wakefulness cycle, including sleep-to-wake transitions and wake maintenance. For example, Hcrt/Orx neuropeptides activate two subtypes of G protein-coupled receptors (Hcrt/Orx1R and Hcrt/Orx2R) that show a partly segregated and prominent distribution in neural structures involved in sleep- wakefulness regulation. Thus, Hcrt/Orx neurons appear to be involved in Kv7 ligand-mediated modulation of sleep and thus compounds that effect these neurons may be utilized in accordance with the teachings herein disclosed.

[025] Furthermore, given the prominent inhibitory role of I_KM in neuronal excitability control in both central and peripheral neurons, neuronal Kv7 activators are believed to relieve disease states in which neuronal hyperexcitability is a relevant pathogenetic mechanism. Thus, potential therapeutic applications of neuronal Kv7 activators range from anti-nociceptive and anticonvulsant to the treatment of migraine, anxiety mania, ADHD, addiction to psychostimulants and depression. Non-limiting examples of Kv7 activators include Triaminopyridines and their derivatives, Acrylamides, Benzamides, Fenamates, and Dimethoxypyrimidines and their derivatives, as well as orphan compounds such as Oxindole, Celecoxib, zinc pyrithione, ML213, QO58, QO58 lysine, NS1643, Benzbromarone, ZG1732 and ZG2083.

[026] Among neuronal Kv7 activators, the first compound described was flupirtine (2-amino-6-(4-fluoro- benzylamino)-pyridin-3-yl)-carbamic acid ethyl ester), which belongs to the class of triaminopyridines; this compound was developed by Chemiewerk Homburg, in Frankfurt am Main, Germany in search for novel nonopioid centrally-acting analgesics. In addition to being effective in several animal models of nociception, flupirtine was also shown to exert anticonvulsant effects against pentylenetetrazol (PTZ)-induced seizures. Nowadays, flupirtine is clinically used as a centrally acting non-opioid analgesic with muscle relaxing properties in several countries. The most common side effects of flupirtine include insomnia, drowsiness, dizziness, dry mouth, vomiting, gastric and abdominal discomfort. More recently, flupirtine has been associated to serious liver injury and its use is now limited to short-term pain management as recommended from European Medicines Agency. Although earlier studies suggested that the analgesic actions of flupirtine could in part be ascribed to its ability to block N-methyl-D-aspartate (NMDA) receptors or to potentiate y-amino-butyric acid (GABAA) receptors, more recent evidence suggest that flupirtine enhances the activity of I_KM formed by Kv7.2 channels at concentrations close to those achieved during standard therapy with this drug (2-6 μM). In addition to analgesia, flupirtine also exerts neuroprotective properties in in vitro and in vivo models of acute energy deprivation or exposure to neurotoxic stimuli and in in vivo models of myelin oligodendrocyte glycoprotein (MOG)-induced optic neuritis. In patients with Creutzfeldt- Jakob disease, flupirtine delayed cognitive deterioration in the dementia tests. Early uncontrolled, small- scale clinical studies in 1983 and 1986 also suggested that flupirtine was effective in reducing seizure frequency in ten patients resistant to conventional therapy with antiepileptic drugs (AEDs). However, anticonvulsant effects occurred at doses ten-times higher than those producing analgesia.

[027] In order to separate the analgesic from the anticonvulsant activity, molecular modeling studies of flupirtine and its analogues were performed. The results obtained suggested that the pharmacophore for central analgesic activity was a phenyl ring and the basic nitrogen atom in the pyridine at a specified distance from this ring and that the absence of this basic nitrogen atom enhances the antiepileptic activity, at the same time reducing analgesic activity. Thus, a series of desazaflupirtine derivatives were synthesized and evaluated for their anticonvulsant activity. Among these, the most potent was retigabine (N-[2-amino- 4-(4-fluorobenzylamino)-phenyl] carbamic acid ethyl ester). Indeed, this compound exhibits anticonvulsant activity in a broad spectrum of seizure models, including PTZ-induced seizures, maximal electric shock, audiogenic seizures in DBA/2J mice as well as seizures produced by amygdala kindling. Retigabine is also effective in reducing seizure burden in genetic models of I_KM deficit. The main effect of retigabine on macroscopic Kv7 currents is a hyperpolarizing shift of the channel activation process, along with a slowing of current deactivation and acceleration of current activation. The effect on the voltage-sensitivity of Kv7 currents appears to be of variable amplitude in channels formed by different Kv7 subtypes: indeed, the shift is maximal for Kv7.3 (-43 mV), intermediate for Kv7.2 (-24 mV), and even smaller for Kv7.4 (-14 mV) homomeric channels. Importantly, retigabine does not affect cardiac Kv7.1 channels (see below). In homomeric Kv7.5 channels, retigabine does not affect current voltage sensitivity, but markedly increases amplitude, irrespectively of the membrane potential. In Kv7.4 channels retigabine causes both the shift in the voltage dependent activation and the increase in the maximal conductance. Single channel recordings revealed that retigabine increases single channel open probability of heteromeric Kv7.2/3 channels, without changing their single channel conductance. The effects observed in both macroscopic and single-channel recordings suggest that the primary molecular consequence of the interaction of retigabine with the channel protein is a stabilization of the open conformation of the channel. The potency for flupirtine- and retigabine- induced activation of Kv7.2/3 channels (EC50 ~ 1-3 μM) is compatible with the free drug concentration range achieved in the plasma during standard treatment; at similar concentrations (3 μM), flupirtine failed to affect currents through benzodiazepinesensitive a1 b2g2 GABAA receptors expressed in the hippocampus, whereas it potentiated those carried by neurosteroid-sensitive, and benzodiazepine-insensitivea1β2δ and a4b3d extrasynaptic GABAA receptors preferentially expressed in dorsal root ganglion and spinal dorsal horn neurons. These results suggest that, in addition to those on Kv7.2/3 channels, GABAmimetic effects might participate in the pharmacological actions of flupirtine and, possibly, retigabine. In fact, similarly to flupirtine, retigabine also potentiates GABA-activated currents at concentrations ≥ 10μM, and it was speculated that this could contribute to the anticonvulsive effects of retigabin. Based on its unique anticonvulsant profile and mechanism of action, the antiepileptic efficacy of retigabine has been further evaluated in numerous human studies, leading to its approval for clinical use (trade name Trobalt in Europe or Potiga in USA) as adjunctive treatment of partial-onset seizures in patients who respond inadequately to alternative treatments. Off-label treatment in children affected with KCNQ2-related epilepsies has shown that retigabine use was associated with improvement in seizures and/or development, particularly when treatment was started early in life, providing a proof-of-principle for its usefulness in personalized treatment in this severe form of genetic epilepsy. Unfortunately, over the last five years, the use of this drug in the adult population has been limited because of its unfavorable risk/benefit ratio; therefore, the manufacturing Company GlaxoSmithKline has decided to discontinue the commercialization of retigabine after June 2017. Table 2 lists exemplary flupirtine and its analogues.

[028] Retigabine analogues with distinct physico-chemical, pharmacokinetic or pharmacodynamic properties has also been developed (Table 2). Introduction of a fluorine atom at the 3-position of the aniline ring of retigabine has led to the synthesis of SF0034. This novel compound is more potent than retigabine in activating Kv7.2 channels, being also significantly less active on Kv7.4 channels. These pharmacodynamic characteristics may be predictive of a lower tendency to trigger side effects associated with activation of Kv7.4 channels. Finally, SF0034 seems to be more chemically stable. Preclinical studies also revealed that SF0034 exhibits a more potent anticonvulsant activity and less toxicity when compared to retigabine. Even more recently, another analogue of retigabine, named RL648_81 , has been reported. This compound was obtained by introducing a CF3-group at the 4-position of the benzylamine moiety, combined with a fluorine atom at the 3-position of the aniline ring of retigabine. In vitro electrophysiological studies show that RL648_81 is 3-times more potent than SF0034 and 15 times more potent than retigabine in activating Kv7.2 channels; also this compound appears to preferentially target Kv7.2 channels over other Kv7 channels. Although no study has yet demonstrated its anticonvulsant activity in vivo, RL648_81 appears a promising clinical candidate for treating or preventing disorders associated with neuronal hyperexcitability.

[029] Notably, to improve blood-brain barrier penetration, a propargyl group was introduced at the N position of retigabine; this propargyled-retigabine (P-retigabine) shows an increased brain-to-plasma ratio (2.30 versus 0.16 for retigabine) and an improved antiepileptic activity in the maximal electroshock (MES)- induced mouse seizure model. Another flupirtine/retigabine chemical analogue is NS15370, which acts as a potent anticonvulsant in animal models, and was shown to potently (EC₅₀s between 40 and 150 nM) enhance Kv7.2-Kv7.5 channels, without any detectable effect on the GABAA receptors combinations most abundantly expressed in the brain (α 1β2y2; a3b2g2; α 3β2y2) in concentrations up to 30μM, suggesting that the activation of Kv7 channels in itself is sufficient to elicit antiepileptic activity in rodents. In particular aspects, the instant specification discloses the use of these retigabine, flupirtine and related analogues/derivatives for use in methods of use herein disclosed to treat a disorder, such as a sleep disorder, for example and not limited to, insomnia and other sleep-related disorders, or an anxiety disorder.

[030] In addition to the described retigabine derivatives, IKM openers/activators with different chemical scaffolds have been synthesized (see Miceli, et al. for review).

[031] Aspects of the present specification disclose, in part, a pharmaceutical composition. A pharmaceutical composition refers to a therapeutically effective concentration of an active ingredient, such as, e.g., any of the potassium channel modulators disclosed herein. Preferably, the pharmaceutical composition does not produce an adverse, allergic, or other untoward or unwanted reaction when administered to an individual. A pharmaceutical composition as disclosed herein is useful for medical and veterinary applications. A pharmaceutical composition disclosed herein may be formulated as a liquid or solid pharmaceutical composition and can be an immediate or a controlled-released formulation. A pharmaceutical composition may be administered to an individual alone, or in combination with other supplementary active compounds, agents, drugs or hormones.

[032] In an aspect, the instant disclosure provides a method for treating a sleep disorder in a patient in need thereof, comprising the step of administering a therapeutically effective amount of a potassium channel modulator to the patient to thereby treat the sleep disorder of the patient in need thereof. In particular embodiments, the potassium channel modulator modulates a Kv7 member of voltage-gated potassium channels, more particularly the potassium channel modulator is a neuronal Kv7 activator. In aspects of this embodiment, a neuronal Kv7 activator is a Triaminopyridine or one of its derivatives, an Acrylamide, a Benzamide, a Fenamate, a Dimethoxypyrimidine or one of its derivatives, Oxindole, Celecoxib, zinc pyrithione, ML213, QO58, QO58 lysine, NS1643, Benzbromarone, ZG1732 and ZG2083. In another aspect the neuronal Kv7 activator is a Triaminopyridine. In yet another aspect, the neuronal Kv7 activator is a flupirtine or retigabine or a derivative thereof, or any combination thereof. Exemplary derivatives include, but are not limited to NS15370, P-Retigabine, SF0034 or RL648_81 or any combination thereof, and the like.

[033] In one embodiment, a method for treating a sleep disorder in a patient in need thereof, comprising the step of administering a therapeutically effective amount of a potassium channel modulator to the patient to control the excitability of Hcrt/Orx neurons. In particular embodiments, the potassium channel modulator modulates a Kv7 member of voltage-gated potassium channels present in Hcrt/Orx neurons, more particularly the potassium channel modulator is a neuronal Kv7 activator. In aspects of this embodiment, a neuronal Kv7 activator is a Triaminopyridine or one of its derivatives, an Acrylamide, a Benzamide, a Fenamate, a Dimethoxypyrimidine or one of its derivatives, Oxindole, Celecoxib, zinc pyrithione, ML213, QO58, QO58 lysine, NS1643, Benzbromarone, ZG1732 and ZG2083. In another aspect the neuronal Kv7 activator is a Triaminopyridine. In yet another aspect, the neuronal Kv7 activator is a flupirtine or retigabine or a derivative thereof, or any combination thereof. Exemplary derivatives include, but are not limited to NS15370, P-Retigabine, SF0034 or RL648_81 or any combination thereof, and the like.

[034] In one embodiment, a method for treating an anxiety disorder in a patient in need thereof, comprising the step of administering a therapeutically effective amount of a potassium channel modulator to the patient to manage one or mroe symptoms of an anxiety disorder. In particular embodiments, the potassium channel modulator modulates a Kv7 member of voltage-gated potassium channels, more particularly the potassium channel modulator is a neuronal Kv7 activator. In aspects of this embodiment, a neuronal Kv7 activator is a Triaminopyridine or one of its derivatives, an Acrylamide, a Benzamide, a Fenamate, a Dimethoxypyrimidine or one of its derivatives, Oxindole, Celecoxib, zinc pyrithione, ML213, QO58, QO58 lysine, NS1643, Benzbromarone, ZG1732 and ZG2083. In another aspect the neuronal Kv7 activator is a Triaminopyridine. In yet another aspect, the neuronal Kv7 activator is a flupirtine or retigabine or a derivative thereof, or any combination thereof. Exemplary derivatives include, but are not limited to NS15370, P-Retigabine, SF0034 or RL648_81 or any combination thereof, and the like.

[035] In one aspect the present disclosure provides for a combinatorial method for treating a sleep disorder in a patient in need thereof, comprising the step above administering a therapeutically effective amount of a potassium channel modulator to the patient in combination with at least one other composition utilized to treat the sleep disorder in the patient in need thereof. As an example, the at least one composition utilized to treat the sleep disorder is an antidepressant or an antianxiety medication. In particular embodiments, a potassium channel modulator modulates a Kv7 member of voltage-gated potassium channels and as one example, the potassium channel modulator is a neuronal Kv7 activator. In aspects of this embodiment, a neuronal Kv7 activator is a Triaminopyridine or one of its derivatives, an Acrylamide, a Benzamide, a Fenamate, a Dimethoxypyrimidine or one of its derivatives, Oxindole, Celecoxib, zinc pyrithione, ML213, QO58, QO58 lysine, NS1643, Benzbromarone, ZG1732 and ZG2083. In another aspect the neuronal Kv7 activator is a Triaminopyridine. Exemplary useful neuronal Kv7 activators for use in method according to the teaching provided herein include a flupirtine or a retigabine or a derivative thereof or any combination thereof, for example. Exemplary derivatives include, but are not limited to, NS15370, P-Retigabine, SF0034 or RL648_81 or any combination thereof. In some aspects, the at least one other composition utilized to treat the sleep disorder is at least one of doxepin, estazolam, eszopiclone, mirtazapine and its enantiomers, ramelteon, suvorexant, temazepam, trazodone, triazolam, zaiep!on, or zoipidem. Particularly desired effects of administration of the therapeutically effective amount of a potassium channel modulator to a patient results in a decrease in the amount of the least one other composition administered to treat the sleep disorder in the patient in need thereof.

[036] In one aspect the present disclosure provides for a combinatorial method for treating a sleep disorder in a patient in need thereof, comprising the step above administering a therapeutically effective amount of a potassium channel modulator to the patient to control the excitability of Hcrt/Orx neurons in combination with at least one other composition utilized to treat the sleep disorder in the patient in need thereof. As an example, the at least one composition utilized to treat the sleep disorder is an antidepressant or an antianxiety medication. In particular embodiments, a potassium channel modulator modulates a Kv7 member of voltage-gated potassium channels present in Hcrt/Orx neurons and as one example, the potassium channel modulator is a neuronal Kv7 activator. In aspects of this embodiment, a neuronal Kv7 activator is a Triaminopyridine or one of its derivatives, an Acrylamide, a Benzamide, a Fenamate, a Dimethoxypyrimidine or one of its derivatives, Oxindole, Celecoxib, zinc pyrithione, ML213, QO58, QO58 lysine, NS1643, Benzbromarone, ZG1732 and ZG2083. In another aspect the neuronal Kv7 activator is a Triaminopyridine. Exemplary useful neuronal Kv7 activators for use in method according to the teaching provided herein include a flupirtine or a retigabine or a derivative thereof or any combination thereof, for example. Exemplary derivatives include, but are not limited to, NS15370, P-Retigabine, SF0034 or RL648_81 or any combination thereof. In some aspects, the at least one other composition utilized to treat said sleep disorder is at least one of doxepin, estazolam, eszopiclone, mirtazapine and its enantiomers, ramelteon, suvorexant, temazepam, trazodone, triazolam, zalep!on, or zoipidem. Particularly desired effects of administration of the therapeutically effective amount of a potassium channel modulator to a patient results in a decrease in the amount of the least one other composition administered to treat the sleep disorder in the patient in need thereof.

[037] In one aspect the present disclosure provides for a combinatorial method for treating an anxiety disorder in a patient in need thereof, comprising the step above administering a therapeutically effective amount of a potassium channel modulator to the patient to manage one or more symptoms of an anxiety disorder in combination with at least one other composition utilized to treat the sleep disorder in the patient in need thereof. As an example, the at least one composition utilized to treat the sleep disorder is an antidepressant or an antianxiety medication. In particular embodiments, a potassium channel modulator modulates a Kv7 member of voltage-gated potassium channels and as one example, the potassium channel modulator is a neuronal Kv7 activator. In aspects of this embodiment, a neuronal Kv7 activator is a Triaminopyridine or one of its derivatives, an Acrylamide, a Benzamide, a Fenamate, a Dimethoxypyrimidine or one of its derivatives, Oxindole, Celecoxib, zinc pyrithione, ML213, QO58, QO58 lysine, NS1643, Benzbromarone, ZG1732 and ZG2083. In another aspect the neuronal Kv7 activator is a Triaminopyridine. Exemplary useful neuronal Kv7 activators for use in method according to the teaching provided herein include a flupirtine or a retigabine or a derivative thereof or any combination thereof, for example. Exemplary derivatives include, but are not limited to, NS15370, P-Retigabine, SF0034 or RL648_81 or any combination thereof. In some aspects, the at least one other composition utilized to treat the sleep disorder is at least one of doxepin, estazolam, eszopicione, mirtazapine and its enantiomers, rameiteon, suvorexant, temazepam, trazodone, triazolam, zaleplon, or zoipidem. Particularly desired effects of administration of the therapeutically effective amount of a potassium channel modulator to a patient results in a decrease in the amount of the least one other composition administered to treat the sleep disorder in the patient in need thereof. [038] In aspects of the disclosure, administration of the therapeutically effective amount of a potassium channel modulator is delivered to the patient in need thereof via an enteral, a parenteral or a topical route of administration. Non-limiting examples of such routes of administration include oral, nasal, sublingual, rectal, dermal, or by injection, including intravenous, intramuscular, intradermal implant, subcutaneous, transdermal. In aspects of the disclosure, administration of the therapeutically effective amount of a potassium channel modulator is delivered to the patient in need thereof locally or systemically. In yet other aspects of the disclosure, administration of the therapeutically effective amount of a potassium channel modulator is delivered to the patient in need thereof as an immediate or a controlled-release formulation.

[039] In particular embodiments of method herein provided, the combinatorial methods result in a decrease by about half of a regulatory agency-approved dosage of the least one other composition utilized to treat the sleep disorder in the patient in need thereof. In yet another aspect, methods in accordance with the teachings of the instant disclosure, for example the administration of the therapeutically effective amount of a potassium channel modulator, results in a decrease in the frequency and/or intensity of an undesired side effect brought on by/typically associated with administration of the at least one other composition utilized to treat the sleep disorder in the patient in need thereof. Such undesirable side-effects are typically listed in information sheets of regulatory-agency approved compounds, these are prescribed by a medical professional to treat a sleep disorder (including off-label uses), examples of regulatory-agency approved compounds; exemplary regulatory-agency approved compounds include doxepin, estazolam, eszopiclone, mirtazapine and its enantiomers, ramelteon, suvorexant, temazepam, trazodone, triazolam, zaiepion, or zolpidem, for example. Exemplary undesired side effect that may be lessened in frequency or intensity in as a result of the administration of a potassium channel modulator (such as a neuronal Kv7 activators, for example) is, for example, at least one of headache, next day drowsiness, dizziness, abnormal dreams, diarrhea, dry mouth, cough, upper respiratory tract infection, blurred vision, constipation, trouble urinating, urinary retention problems, nausea, vomiting, upset stomach, symptoms of anxiety, panic attacks, thoughts about suicide or dying, feelings of restlessness, feelings of agitation, irritability and weight gain. In further aspect, the teachings of the instant disclosure provide for a method or combinatorial method of treating a sleep disorder by administration of a potassium channel modulator, such as a modulator that modulates a Kv7 member of voltage-gated potassium channels (e.g. an opener/activator), wherein the patient in need thereof suffers from a form of age-related cognitive impairment or age-related neurodegenerative disease and the like. In particular aspects, the patient in need thereof is at least 50 years of age.

[040] The present specification discloses, in part, a therapeutically effective amount. An effective amount of can be 1) an amount sufficient to cause a desired effect (e.g. reduction in intensity and/or frequency of an undesired side effect associated with at least one other composition utilized to treat a sleep or anxiety disorder in the patient and/or increase in sleep time, increase in the quality of sleep, and/or increased length of time in a particular sleep state and/or a decrease in worry, fear or specific phobia). A therapeutically effective amount of a potassium channel modulator disclosed herein alone or in combination with at least one other therapeutic sleep agent disclosed herein is an amount sufficient to reduce or eliminate a sleep or anxiety disorder. In aspects of this embodiment, a therapeutically effective amount of a potassium channel modulator disclosed herein alone or in combination with at least one other therapeutic sleep agent disclosed herein is an amount sufficient to reduce one or more physiological conditions or symptoms associated with a sleep or anxiety disorder or an amount sufficient to protect the individual against one or more physiological conditions or symptoms associated with a sleep or anxiety disorder. As used herein, the term “therapeutically effective amount” includes the terms “amount sufficient”, “therapeutically sufficient amount”, “effective amount”, “effective dose”, or “therapeutically effective dose” and refers to the minimum amount of a potassium channel modulator disclosed herein alone or in combination with at least one other therapeutic sleep agent disclosed herein necessary to achieve the desired therapeutic effect and includes an amount sufficient to reduce or inhibit one or more physiological conditions or symptoms associated with a sleep or anxiety disorder.

[041] In aspects of this embodiment, a therapeutically effective amount of a potassium channel modulator disclosed herein reduces or inhibits one or more physiological conditions or symptoms associated with a sleep or anxiety disorder by, e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100%. In other aspects of this embodiment, an effective amount of a potassium channel modulator disclosed herein reduces or inhibits one or more physiological conditions or symptoms associated with a sleep or anxiety disorder by, e.g., at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90% or at most 100%. In yet other aspects of this embodiment, an effective amount of a potassium channel modulator disclosed herein reduces or inhibits one or more physiological conditions or symptoms associated with a sleep or anxiety disorder by, e.g., about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 20% to about 30%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, about 30% to about 50%, about 30% to about 40%, about 40% to about 100%, about 40% to about 90%, about 40% to about 80%, about 40% to about 70%, about 40% to about 60%, about 40% to about 50%, about 50% to about 100%, about 50% to about 90%, about 50% to about 80%, about 50% to about 70%, about 50% to about 60%, about 60% to about 100%, about 60% to about 90%, about 60% to about 80%, about 60% to about 70%, about 70% to about 100%, about 70% to about 90%, about 70% to about 80%, about 80% to about 100%, about 80% to about 90%, or about 90% to about 100%. In still other aspects of this embodiment, an effective amount of a potassium channel modulator disclosed herein reduces or inhibits one or more physiological conditions or symptoms associated with a sleep or anxiety disorder for, e.g., at least one hour, at least two hours, at least three hours, at least four hours, at least five hours, at least six hours, at least seven hours, at least eight hours, or at least nine hours.

[042] In aspects of this embodiment, a therapeutically effective amount of a potassium channel modulator disclosed herein in combination with at least one other therapeutic sleep agent disclosed herein reduces or inhibits one or more physiological conditions or symptoms associated with a sleep or anxiety disorder by, e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100%. In other aspects of this embodiment, an effective amount of a potassium channel modulator disclosed herein in combination with at least one other therapeutic sleep agent disclosed herein reduces or inhibits one or more physiological conditions or symptoms associated with a sleep or anxiety disorder by, e.g., at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90% or at most 100%. In yet other aspects of this embodiment, an effective amount of a potassium channel modulator disclosed herein in combination with at least one other therapeutic sleep agent disclosed herein reduces or inhibits one or more physiological conditions or symptoms associated with a sleep or anxiety disorder by, e.g., about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 20% to about 30%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, about 30% to about 50%, about 30% to about 40%, about 40% to about 100%, about 40% to about 90%, about 40% to about 80%, about 40% to about 70%, about 40% to about 60%, about 40% to about 50%, about 50% to about 100%, about 50% to about 90%, about 50% to about 80%, about 50% to about 70%, about 50% to about 60%, about 60% to about 100%, about 60% to about 90%, about 60% to about 80%, about 60% to about 70%, about 70% to about 100%, about 70% to about 90%, about 70% to about 80%, about 80% to about 100%, about 80% to about 90%, or about 90% to about 100%. In still other aspects of this embodiment, an effective amount of a potassium channel modulator disclosed herein in combination with at least one other therapeutic sleep agent disclosed herein reduces or inhibits one or more physiological conditions or symptoms associated with a sleep or anxiety disorder for, e.g., at least one hour, at least two hours, at least three hours, at least four hours, at least five hours, at least six hours, at least seven hours, at least eight hours, or at least nine hours.

[043] In some embodiments, a therapeutically effective amount of a potassium channel modulator disclosed herein about 25 mg/day, about 50 mg/day, about 75 mg/day, about 100 mg/day, about 125 mg/day, about 150 mg/day, about 175 mg/day, about 200 mg/day, about 225 mg/day, about 250 mg/day, about 275 mg/day, about 300 mg/day, about 325 mg/day, about 350 mg/day, about 375 mg/day, about 400 mg/day, about 425 mg/day, about 450 mg/day, about 475 mg/day, about 500 mg/day, about 525 mg/day, about 550 mg/day, about 575 mg/day, about 600 mg/day, about 625 mg/day, about 650 mg/day, about 675 mg/day, about 700 mg/day, about 750 mg/day, about 800 mg/day, about 850 mg/day, about 900 mg/day, about 950 mg/day, or about 1 ,000 mg/day. In some embodiments, a therapeutically effective amount of a potassium channel modulator disclosed herein at least 25 mg/day, at least 50 mg/day, at least 75 mg/day, at least 100 mg/day, at least 125 mg/day, at least 150 mg/day, at least 175 mg/day, at least 200 mg/day, at least 225 mg/day, at least 250 mg/day, at least 275 mg/day, at least 300 mg/day, at least 325 mg/day, at least 350 mg/day, at least 375 mg/day, at least 400 mg/day, at least 425 mg/day, at least 450 mg/day, at least 475 mg/day, at least 500 mg/day, at least 525 mg/day, at least 550 mg/day, at least 575 mg/day, at least 600 mg/day, at least 625 mg/day, at least 650 mg/day, at least 675 mg/day, at least 700 mg/day, at least 750 mg/day, at least 800 mg/day, at least 850 mg/day, at least 900 mg/day, at least 950 mg/day, or at least 1 ,000 mg/day. In some embodiments, a therapeutically effective amount of a potassium channel modulator disclosed herein at most 25 mg/day, at most 50 mg/day, at most 75 mg/day, at most 100 mg/day, at most 125 mg/day, at most 150 mg/day, at most 175 mg/day, at most 200 mg/day, at most 225 mg/day, at most 250 mg/day, at most 275 mg/day, at most 300 mg/day, at most 325 mg/day, at most 350 mg/day, at most 375 mg/day, at most 400 mg/day, at most 425 mg/day, at most 450 mg/day, at most 475 mg/day, at most 500 mg/day, at most 525 mg/day, at most 550 mg/day, at most 575 mg/day, at most 600 mg/day, at most 625 mg/day, at most 650 mg/day, at most 675 mg/day, at most 700 mg/day, at most 750 mg/day, at most 800 mg/day, at most 850 mg/day, at most 900 mg/day, at most 950 mg/day, or at most 1 ,000 mg/day.

[044] In some embodiments, a therapeutically effective amount of a potassium channel modulator disclosed herein about 25 mg/day to about 50 mg/day, about 25 mg/day to about 100 mg/day, about 25 mg/day to about 150 mg/day, about 25 mg/day to about 200 mg/day, about 25 mg/day to about 250 mg/day, about 25 mg/day to about 300 mg/day, about 25 mg/day to about 350 mg/day, about 25 mg/day to about 400 mg/day, about 25 mg/day to about 450 mg/day, about 25 mg/day to about 500 mg/day, about 50 mg/day to about 100 mg/day, about 50 mg/day to about 150 mg/day, about 50 mg/day to about 200 mg/day, about 50 mg/day to about 250 mg/day, about 50 mg/day to about 300 mg/day, about 50 mg/day to about 350 mg/day, about 50 mg/day to about 400 mg/day, about 50 mg/day to about 450 mg/day, about 50 mg/day to about 500 mg/day, about 100 mg/day to about 200 mg/day, about 100 mg/day to about 300 mg/day, about 100 mg/day to about 400 mg/day, about 100 mg/day to about 500 mg/day, about 100 mg/day to about 600 mg/day, about 100 mg/day to about 700 mg/day, about 100 mg/day to about 800 mg/day, about 100 mg/day to about 900 mg/day, about 100 mg/day to about 1 ,000 mg/day, about 200 mg/day to about 300 mg/day, about 200 mg/day to about 400 mg/day, about 200 mg/day to about 500 mg/day, about 200 mg/day to about 600 mg/day, about 200 mg/day to about 700 mg/day, about 200 mg/day to about 800 mg/day, about 200 mg/day to about 900 mg/day, about 200 mg/day to about 1 ,000 mg/day, about 300 mg/day to about 400 mg/day, about 300 mg/day to about 500 mg/day, about 300 mg/day to about 600 mg/day, about 300 mg/day to about 700 mg/day, about 300 mg/day to about 800 mg/day, about 300 mg/day to about 900 mg/day, about 300 mg/day to about 1 ,000 mg/day, about 400 mg/day to about 500 mg/day, about 400 mg/day to about 600 mg/day, about 400 mg/day to about 700 mg/day, about 400 mg/day to about 800 mg/day, about 400 mg/day to about 900 mg/day, about 400 mg/day to about 1 ,000 mg/day, about 500 mg/day to about 600 mg/day, about 500 mg/day to about 700 mg/day, about 500 mg/day to about 800 mg/day, about 500 mg/day to about 900 mg/day, about 500 mg/day to about 1 ,000 mg/day, about 600 mg/day to about 700 mg/day, about 600 mg/day to about 800 mg/day, about 600 mg/day to about 900 mg/day, about 600 mg/day to about 1 ,000 mg/day, about 700 mg/day to about 800 mg/day, about 700 mg/day to about 900 mg/day, about 700 mg/day to about 1 ,000 mg/day, about 800 mg/day to about 900 mg/day, about 800 mg/day to about 1 ,000 mg/day, or about 800 mg/day to about 1 ,000 mg/day.

[045] In some embodiments, a therapeutically effective amount of a therapeutic sleep agent disclosed herein is, e.g., about 1 mg/day, about 5 mg/day, about 10 mg/day, about 15 mg/day, about 20 mg/day, about 25 mg/day, about 30 mg/day, about 40 mg/day, about 50 mg/day, about 75 mg/day, about 100 mg/day, about 125 mg/day, about 150 mg/day, about 175 mg/day, about 200 mg/day, about 225 mg/day, about 250 mg/day, about 275 mg/day, about 300 mg/day, about 325 mg/day, about 350 mg/day, about 375 mg/day, about 400 mg/day, about 425 mg/day, about 450 mg/day, about 475 mg/day, about 500 mg/day, about 525 mg/day, about 550 mg/day, about 575 mg/day, about 600 mg/day, about 625 mg/day, about 650 mg/day, about 675 mg/day, about 700 mg/day, about 750 mg/day, about 800 mg/day, about 850 mg/day, about 900 mg/day, about 950 mg/day, or about 1 ,000 mg/day. In some embodiments, a therapeutically effective amount of a therapeutic sleep agent disclosed herein is, e.g., at least 1 mg/day, at least 5 mg/day, at least 10 mg/day, at least 15 mg/day, at least 20 mg/day, at least 25 mg/day, at least 30 mg/day, at least 40 mg/day, at least 50 mg/day, at least 75 mg/day, at least 100 mg/day, at least 125 mg/day, at least 150 mg/day, at least 175 mg/day, at least 200 mg/day, at least 225 mg/day, at least 250 mg/day, at least 275 mg/day, at least 300 mg/day, at least 325 mg/day, at least 350 mg/day, at least 375 mg/day, at least 400 mg/day, at least 425 mg/day, at least 450 mg/day, at least 475 mg/day, at least 500 mg/day, at least 525 mg/day, at least 550 mg/day, at least 575 mg/day, at least 600 mg/day, at least 625 mg/day, at least 650 mg/day, at least 675 mg/day, at least 700 mg/day, at least 750 mg/day, at least 800 mg/day, at least 850 mg/day, at least 900 mg/day, at least 950 mg/day, or at least 1 ,000 mg/day. In some embodiments, a therapeutically effective amount of a therapeutic sleep agent disclosed herein is, e.g., at most 1 mg/day, at most 5 mg/day, at most 10 mg/day, at most 15 mg/day, at most 20 mg/day, at most 25 mg/day, at most 30 mg/day, at most 40 mg/day, at most 50 mg/day, at most 75 mg/day, at most 100 mg/day, at most 125 mg/day, at most 150 mg/day, at most 175 mg/day, at most 200 mg/day, at most 225 mg/day, at most 250 mg/day, at most 275 mg/day, at most 300 mg/day, at most 325 mg/day, at most 350 mg/day, at most 375 mg/day, at most 400 mg/day, at most 425 mg/day, at most 450 mg/day, at most 475 mg/day, at most 500 mg/day, at most 525 mg/day, at most 550 mg/day, at most 575 mg/day, at most 600 mg/day, at most 625 mg/day, at most 650 mg/day, at most 675 mg/day, at most 700 mg/day, at most 750 mg/day, at most 800 mg/day, at most 850 mg/day, at most 900 mg/day, at most 950 mg/day, or at most 1 ,000 mg/day.

[046] In some embodiments, a therapeutically effective amount of a therapeutic sleep agent disclosed herein is, e.g., about 1 mg/day to about 5 mg/day, about 1 mg/day to about 10 mg/day, about 1 mg/day to about 15 mg/day, about 1 mg/day to about 20 mg/day, about 1 mg/day to about 25 mg/day, about 1 mg/day to about 30 mg/day, about 1 mg/day to about 35 mg/day, about 1 mg/day to about 40 mg/day, about 1 mg/day to about 45 mg/day, about 1 mg/day to about 50 mg/day, about 1 mg/day to about 60 mg/day, about 1 mg/day to about 70 mg/day, about 1 mg/day to about 80 mg/day, about 1 mg/day to about 90 mg/day, about 1 mg/day to about 100 mg/day, about 1 mg/day to about 110 mg/day, about 1 mg/day to about 120 mg/day, about 1 mg/day to about 130 mg/day, about 1 mg/day to about 140 mg/day, about 1 mg/day to about 150 mg/day, about 5 mg/day to about 10 mg/day, about 5 mg/day to about 15 mg/day, about 5 mg/day to about 20 mg/day, about 5 mg/day to about 25 mg/day, about 5 mg/day to about 30 mg/day, about 5 mg/day to about 35 mg/day, about 5 mg/day to about 40 mg/day, about 5 mg/day to about 45 mg/day, about 5 mg/day to about 50 mg/day, about 5 mg/day to about 60 mg/day, about 5 mg/day to about 70 mg/day, about 5 mg/day to about 80 mg/day, about 5 mg/day to about 90 mg/day, about 5 mg/day to about 100 mg/day, about 5 mg/day to about 110 mg/day, about 5 mg/day to about 120 mg/day, about 5 mg/day to about 130 mg/day, about 5 mg/day to about 140 mg/day, about 5 mg/day to about 150 mg/day, about 10 mg/day to about 15 mg/day, about 10 mg/day to about 20 mg/day, about 10 mg/day to about 25 mg/day, about 10 mg/day to about 30 mg/day, about 10 mg/day to about 35 mg/day, about 10 mg/day to about 40 mg/day, about 10 mg/day to about 45 mg/day, about 10 mg/day to about 50 mg/day, about 10 mg/day to about 60 mg/day, about 10 mg/day to about 70 mg/day, about 10 mg/day to about 80 mg/day, about 10 mg/day to about 90 mg/day, about 10 mg/day to about 100 mg/day, about 10 mg/day to about 110 mg/day, about 10 mg/day to about 120 mg/day, about 10 mg/day to about 130 mg/day, about 10 mg/day to about 140 mg/day, about 10 mg/day to about 150 mg/day, about 25 mg/day to about 50 mg/day, about 25 mg/day to about 100 mg/day, about 25 mg/day to about 150 mg/day, about 25 mg/day to about 200 mg/day, about 25 mg/day to about 250 mg/day, about 25 mg/day to about 300 mg/day, about 25 mg/day to about 350 mg/day, about 25 mg/day to about 400 mg/day, about 25 mg/day to about 450 mg/day, about 25 mg/day to about 500 mg/day, about 50 mg/day to about 100 mg/day, about 50 mg/day to about 150 mg/day, about 50 mg/day to about 200 mg/day, about 50 mg/day to about 250 mg/day, about 50 mg/day to about 300 mg/day, about 50 mg/day to about 350 mg/day, about 50 mg/day to about 400 mg/day, about 50 mg/day to about 450 mg/day, about 50 mg/day to about 500 mg/day, about 100 mg/day to about 200 mg/day, about 100 mg/day to about 300 mg/day, about 100 mg/day to about 400 mg/day, about 100 mg/day to about 500 mg/day, about 100 mg/day to about 600 mg/day, about 100 mg/day to about 700 mg/day, about 100 mg/day to about 800 mg/day, about 100 mg/day to about 900 mg/day, about 100 mg/day to about 1 ,000 mg/day, about 200 mg/day to about 300 mg/day, about 200 mg/day to about 400 mg/day, about 200 mg/day to about 500 mg/day, about 200 mg/day to about 600 mg/day, about 200 mg/day to about 700 mg/day, about 200 mg/day to about 800 mg/day, about 200 mg/day to about 900 mg/day, about 200 mg/day to about 1 ,000 mg/day, about 300 mg/day to about 400 mg/day, about 300 mg/day to about 500 mg/day, about 300 mg/day to about 600 mg/day, about 300 mg/day to about 700 mg/day, about 300 mg/day to about 800 mg/day, about 300 mg/day to about 900 mg/day, about 300 mg/day to about 1 ,000 mg/day, about 400 mg/day to about 500 mg/day, about 400 mg/day to about 600 mg/day, about 400 mg/day to about 700 mg/day, about 400 mg/day to about 800 mg/day, about 400 mg/day to about 900 mg/day, about 400 mg/day to about 1 ,000 mg/day, about 500 mg/day to about 600 mg/day, about 500 mg/day to about 700 mg/day, about 500 mg/day to about 800 mg/day, about 500 mg/day to about 900 mg/day, about 500 mg/day to about 1 ,000 mg/day, about 600 mg/day to about 700 mg/day, about 600 mg/day to about 800 mg/day, about 600 mg/day to about 900 mg/day, about 600 mg/day to about 1 ,000 mg/day, about 700 mg/day to about 800 mg/day, about 700 mg/day to about 900 mg/day, about 700 mg/day to about 1 ,000 mg/day, about 800 mg/day to about 900 mg/day, about 800 mg/day to about 1 ,000 mg/day, or about 800 mg/day to about 1 ,000 mg/day.

[047] In some embodiments, a therapeutically effective amount of at least one other therapeutic sleep agent disclosed herein when used in combination with a potassium channel modulator disclosed herein is at a sub-therapeutically effective amount if that at least one other therapeutic sleep agent was administered without the potassium channel modulator disclosed herein.

[048] In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 25 mg/day to about 500 mg/day of a potassium channel modulator in combination with about 25 mg/day to about 400 mg/day of at least one other therapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 25 mg/day to about 500 mg/day of a triaminopyridine in combination with about 25 mg/day to about 400 mg/day of at least one other therapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 25 mg/day to about 500 mg/day of a triaminopyridine in combination with about 25 mg/day to about 400 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 25 mg/day to about 500 mg/day of a retigabine in combination with about 25 mg/day to about 400 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder.

[049] In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 25 mg/day to about 400 mg/day of a potassium channel modulator in combination with about 25 mg/day to about 300 mg/day of at least one other therapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 25 mg/day to about 400 mg/day of a triaminopyridine in combination with about 25 mg/day to about 300 mg/day of at least one other therapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 25 mg/day to about 400 mg/day of a triaminopyridine in combination with about 25 mg/day to about 300 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 25 mg/day to about 400 mg/day of a retigabine in combination with about 25 mg/day to about 300 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder.

[050] In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof, comprises administering about 50 mg/day to about 400 mg/day of a potassium channel modulator in combination with about 25 mg/day to about 250 mg/day of at least one other therapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a triaminopyridine in combination with about 25 mg/day to about 250 mg/day of at least one other therapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a triaminopyridine in combination with about 25 mg/day to about 250 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a retigabine in combination with about 25 mg/day to about 250 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder.

[051] In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a potassium channel modulator in combination with about 25 mg/day to about 200 mg/day of at least one other therapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a triaminopyridine in combination with about 25 mg/day to about 200 mg/day of at least one other therapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a triaminopyridine in combination with about 25 mg/day to about 200 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a retigabine in combination with about 25 mg/day to about 200 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder.

[052] In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a potassium channel modulator in combination with about 25 mg/day to about 150 mg/day of at least one other therapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a triaminopyridine in combination with about 25 mg/day to about 150 mg/day of at least one other therapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a triaminopyridine in combination with about 25 mg/day to about 150 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a retigabine in combination with about 25 mg/day to about 150 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder.

[053] In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a potassium channel modulator in combination with about 25 mg/day to about 100 mg/day of at least one other therapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a triaminopyridine in combination with about 25 mg/day to about 100 mg/day of at least one other therapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a triaminopyridine in combination with about 25 mg/day to about 100 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a retigabine in combination with about 25 mg/day to about 100 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder.

[054] In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a potassium channel modulator in combination with about 25 mg/day to about 75 mg/day of at least one othertherapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a triaminopyridine in combination with about 25 mg/day to about 75 mg/day of at least one other therapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a triaminopyridine in combination with about 25 mg/day to about 75 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a retigabine in combination with about 25 mg/day to about 75 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder.

[055] In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a potassium channel modulator in combination with about 1 mg/day to about 150 mg/day of at least one othertherapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a triaminopyridine in combination with about 1 mg/day to about 150 mg/day of at least one other therapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a triaminopyridine in combination with about 1 mg/day to about 150 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a retigabine in combination with about 1 mg/day to about 150 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder.

[056] In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a potassium channel modulator in combination with about 1 mg/day to about 100 mg/day of at least one other therapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a triaminopyridine in combination with about 1 mg/day to about 100 mg/day of at least one other therapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a triaminopyridine in combination with about 1 mg/day to about 100 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a retigabine in combination with about 1 mg/day to about 100 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder.

[057] In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a potassium channel modulator in combination with about 1 mg/day to about 75 mg/day of at least one other therapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a triaminopyridine in combination with about 1 mg/day to about 75 mg/day of at least one other therapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a triaminopyridine in combination with about 1 mg/day to about 75 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a retigabine in combination with about 1 mg/day to about 75 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder.

[058] In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a potassium channel modulator in combination with about 1 mg/day to about 50 mg/day of at least one other therapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a triaminopyridine in combination with about 1 mg/day to about 50 mg/day of at least one other therapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a triaminopyridine in combination with about 1 mg/day to about 50 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a retigabine in combination with about 1 mg/day to about 50 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder.

[059] In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a potassium channel modulator in combination with about 1 mg/day to about 25 mg/day of at least one other therapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a triaminopyridine in combination with about 1 mg/day to about 25 mg/day of at least one other therapeutic sleep agent disclosed herein to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a triaminopyridine in combination with about 1 mg/day to about 25 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder. In some embodiments, a combinatorial method for treating a sleep or an anxiety disorder in a patient in need thereof comprises administering about 50 mg/day to about 400 mg/day of a retigabine in combination with about 1 mg/day to about 25 mg/day of trazodone and/or suvorexant to the patient to manage one or more symptoms of a sleep or an anxiety disorder.

[060] The actual therapeutic effective amount of a potassium channel modulator or therapeutic sleep agent disclosed herein to be used or administered to an individual can be determined by a person of ordinary skill in the art by taking into account factors that include, without limitation, the type of sleep or anxiety disorder, the particular physiological conditions or symptoms associated with the sleep or anxiety disorder, the cause of the sleep or anxiety disorder, the severity of the sleep or anxiety disorder, the degree of relief desired for the sleep or anxiety disorder, the duration of relief desired for the sleep or anxiety disorder, the particular potassium channel modulator and/or therapeutic sleep agent used, the rate of excretion of the particular potassium channel modulator and/or therapeutic sleep agent used, the pharmacodynamics of the potassium channel modulator and/or therapeutic sleep agent used, the nature of the other compounds to be included in the therapy, the particular route of administration used, the particular characteristics, history and risk factors of the individual, such as, e.g., age, weight, general health and the like, or any combination thereof. [061] The actual effective amount of a potassium channel modulator ortherapeutic sleep agent disclosed herein is determined by routine screening procedures employed to evaluate an activity and efficacy of a potassium channel modulator ortherapeutic sleep agent disclosed herein. Such screening procedures are well known by those skilled in the art. For example, it is known by a person of ordinary skill in the art that an effective amount of a potassium channel modulator ortherapeutic sleep agent disclosed herein can be extrapolated from in-vitro assays and in-vivo administration studies using animal models prior to administration to humans. Variations in dosage levels can be adjusted using standard empirical routines of optimization, which are well-known to a person of ordinary skill in the art. It is expected that a potassium channel modulator or therapeutic sleep agent disclosed herein having a higher level of activity and/or efficacy can be used in smaller amounts and concentrations, while those having a lower level of activity and/or efficacy may require larger amounts or concentrations in order to achieve the same controlling effect. Such amounts can be determined by routine assays/measurements of activity and/or efficacy for a potassium channel modulator or therapeutic sleep agent disclosed herein. The precise therapeutically effective dosage levels and patterns are preferably determined by the attending healthcare professional in consideration of the above-identified factors.

[062] The present specification discloses, in part, a sleep disorder. Sleep is a complex biological process. While you are sleeping, you are unconscious, but your brain and body functions are still active. They are doing a number of important jobs that help you stay healthy and function at your best. So when you don't get enough quality sleep, it does more than just make you feel tired. It can affect your physical and mental health, thinking, and daily functioning. A sleep disorder is a condition in which disturb a normal sleep pattern of an individual. There are different causes for different sleep disorders, including 1) other conditions, such as heart disease, lung disease, nerve disorders, and pain; 2) mental illnesses, including depression and anxiety; 3) side effects associated with medicines; and 4) a genetic predisposition.

[063] There are more than 80 different recognized sleep disorders. Non-limiting examples of a sleep disorder include insomnia, hypersomnia, parasomnia, sleep apnea, jet lag, restless leg syndrome, sleepwalking (somnambulism or noctambulism), narcolepsy, night terrors, rhythmic movement disorder, sleep paralysis, sundowning, and rapid eye movement sleep behavior disorder.

[064] The International Classification of Sleep Disorders are organized these sleep disorders into seven categories: insomnia, sleep-related breathing disorders, central disorders of hypersomnolence, circadian rhythm sleep-wake disorders, parasomnias, sleep-related movement disorders, miscellaneous sleep disorders. Insomnias are a sleep disorder in which an individual has trouble falling and/or staying asleep. The most common sleep disorder, insomnias fall into two major categories: trouble falling asleep and difficulty maintaining sleep through the night. Sleep-related breathing disorders are a sleep disorder in which an individual experiences stoppage of breathing while asleep, is a period when someone stops breathing with obstructive sleep apnea being a major example. Central disorders of hypersomnolence are a sleep disorder in which an individual experiences excessive daytime sleepiness despite sufficient nighttime sleep with narcolepsy being the most familiar example. Circadian rhythm sleep-wake disorders are a sleep disorder in which affect the timing of sleep; such as when sleep times are out of alignment with an individual’s normal biological clock of being active during the day and sleeping at night, or differing from accustomed sleep patterns, including jet lag and shift work sleep disorders. Parasomnias are a sleep disorder which involve abnormal or unusual movements, behaviors, emotions, perceptions, and dreams that occur while falling asleep, sleeping, between sleep stages, or during arousal from sleep with sleepwalking, night terrors, sleep paralysis and REM sleep behavior disorders being common examples. Sleep-related movement disorders are a sleep disorder in which involve repetitive movements that affect sleep with restless legs syndrome being the classic example. Miscellaneous sleep disorder are a sleep disorder defined by conditions that don't fit into the categories above. One example is sundowning - when people with dementia become more confused in the evening, often leading to sleep disruption.

[065] The symptoms of sleep disorders depend on the specific disorder. Some signs that you may have a sleep disorder include 1) consistently requiring more than 30 minutes to fall asleep; 2) regularly waking up multiple times during the night and having difficulty falling back asleep; 3) regularly waking up too early in the morning; 4) being sleepy during the day; 5) taking frequent naps; 6) falling asleep at the wrong times during the day; 7) loud snoring, snorts, gasps; 8) making choking sounds; 9) stop breathing for short periods; 10) creeping, tingling, or crawling feelings in legs or arms that are relieved by moving or massaging; 11) frequent leg or arm jerking during sleep; 12) experiencing vivid, dreamlike experiences while falling asleep or dozing; 13) episodes of sudden muscle weakness when you are angry or fearful, or when you laugh; and 14) experience sensations of not being able to move when first waking up.

[066] The present specification discloses, in part, an anxiety disorder. An anxiety disorder is an umbrella term for a group of mental disorders characterized by significant emotions of unease, fear and panic. These behavioral symptoms can become so serve and/or chronic in an individual that physical symptoms can occur, such as a fast heart rate, shakiness, hyperthyroidism, and heart disease. Other problems such as caffeine, alcohol, or cannabis use and withdrawal from certain drugs are common. In addition, anxiety disorders often occur with other mental disorders, particularly a major depressive disorder, an obsessive- compulsive disorder, a personality disorder, or other disorder like substance use disorder, seasonal effective disorder, and premenstrual dysphoric disorder, as well as with trauma-related syndromes such as post-traumatic stress disorder.

[067] For an individual to be clinically diagnosed with an anxiety disorder, symptoms typically need to be present for at least 6 months, the emotions experienced by the individual are more intense than what would be expected for the situation, and the individual exhibits decreased functioning. Individuals often have more than one anxiety disorder. Like other forms of mental illness, the cause(s) of an anxiety disorder stem from a combination of things, including changes in the brain, environmental stress and genetic factors are suspected in playing a role.

[068] There are several categories of anxiety disorders, typically classified by the symptoms. These include a generalized anxiety disorder, a specific phobia, a panic disorder, a social anxiety disorder, a separation anxiety disorder, a selective mutism. The disorder differs by what results in the symptoms. About 12% of people are affected by an anxiety disorder in a given year, and between 5% and 30% are affected over a lifetime. These disorders occur in females about twice as often as in males, and generally begin before age 25 years. The most common are specific phobias, which affect nearly 12%, and social anxiety disorder, which affects 10%. Phobias mainly affect people between the ages of 15 and 35, and become less common after age 55. Rates appear to be higher in the United States and Europe.

[069] Generalized anxiety disorder (GAD) is the most common disorder to affect older adults, and is characterized by long-lasting, intense, unrealistic fear and worry which is not focused on any one object or situation. An individual with GAD becomes overly concerned with everyday matters. Besides having nonspecific, persistent, excessive anxiety, GAD is accompanied by three or more of the following symptoms: restlessness, fatigue, concentration problems, irritability, muscle tension, and sleep disturbance.

[070] Specific phobias are the single largest category of anxiety disorders, and is characterized by intense, unrealistic fear and worry that is triggered by a specific stimulus or situation. When exposed to a trigger, an individual with a specific phobia experiences trembling, shortness of breath, or rapid heartbeat, typically causing the individual to avoid ordinary situations. The individual understands that the anxiety is not proportional to the actual or potential danger but is still overwhelmed by it.

[071] A panic disorder is characterized by brief, intense, unrealistic fear and worry that abruptly arises. Although a panic disorder can be triggered, for example, by stress, irrational thoughts, general fear or fear of the unknown, or even exercise, sometimes the trigger is unclear or absent and a panic disorder can occur randomly and without warning. In addition to recurrent unexpected anxiety, a diagnosis of a panic disorder requires chronic symptoms that last beyond the specific panic episodes of anxiety. Such chronic symptoms include worry over the anxiety’s potential implications, persistent fear of future episodes of anxiety, or significant changes in behavior related to the anxiety.

[072] A social anxiety disorder (SAD), also called social phobia, is characterized by intense, unrealistic fear and worry of negative public scrutiny, public embarrassment, humiliation, or social interaction. An individual with SAD feels overwhelmed about everyday social situations and fixates on being judged by others or on being embarrassed or ridiculed. SAD can be specific to particular social situations (such as public speaking) or, more typically, is experienced in most (or all) social interactions. As with all phobic disorders, an individual suffering from SAD will often attempt to avoid the specific stimulus or situation that triggers the anxiety. With respect to SAD this is particularly problematic as such avoidance can lead to complete social isolation.

[073] A selective mutism is when an individual who is normally capable of speech does not in specific situation or to specific people. An individual with selective mutism stays silent even when the consequences of the silence include shame, social ostracism or even punishment. Selective mutism affects about 0.8% of people at some point in their life.

[074] Aspects of the present specification may also be described by the following embodiments: A method for treating a sleep or anxiety disorder in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a potassium channel modulator, thereby treating the sleep or anxiety disorder of the individual. The method of embodiment 1 , wherein the potassium channel modulator modulates one or more Kv7 members of voltage-gated potassium channels. The method of embodiment 1 or 2, wherein the potassium channel modulator is a neuronal Kv7 activator. The method of embodiment 3, wherein the neuronal Kv7 activator is a Triaminopyridine or one of its derivatives, an Acrylamide, a Benzamide, a Fenamate, a Dimethoxypyrimidine or one of its derivatives, Oxindole, Celecoxib, zinc pyrithione, ML213, QO58, QO58 lysine, NS1643, Benzbromarone, ZG1732 and ZG2083. The method of embodiment 4, wherein the Triaminopyridine includes a flupirtine, or retigabine or a derivative thereof, or any combination thereof. The method of embodiment 5, wherein the retigabine derivative is NS15370, P-Retigabine, SF0034 or RL648_81 or any combination thereof. The method of any one of embodiments 1-6, wherein the therapeutically effective amount of the potassium channel modulator is between about 25 mg/day to about 50 mg/day, about 25 mg/day to about 100 mg/day, about 25 mg/day to about 150 mg/day, about 25 mg/day to about 200 mg/day, about 25 mg/day to about 250 mg/day, about 25 mg/day to about 300 mg/day, about 25 mg/day to about 350 mg/day, about 25 mg/day to about 400 mg/day, about 25 mg/day to about 450 mg/day, about 25 mg/day to about 500 mg/day, about 50 mg/day to about 100 mg/day, about 50 mg/day to about 150 mg/day, about 50 mg/day to about 200 mg/day, about 50 mg/day to about 250 mg/day, about 50 mg/day to about 300 mg/day, about 50 mg/day to about 350 mg/day, about 50 mg/day to about 400 mg/day, about 50 mg/day to about 450 mg/day, about 50 mg/day to about 500 mg/day, about 100 mg/day to about 200 mg/day, about 100 mg/day to about 300 mg/day, about 100 mg/day to about 400 mg/day, about 100 mg/day to about 500 mg/day, about 100 mg/day to about 600 mg/day, about 100 mg/day to about 700 mg/day, about 100 mg/day to about 800 mg/day, about 100 mg/day to about 900 mg/day, about 100 mg/day to about 1 ,000 mg/day, about 200 mg/day to about 300 mg/day, about 200 mg/day to about 400 mg/day, about 200 mg/day to about 500 mg/day, about 200 mg/day to about 600 mg/day, about 200 mg/day to about 700 mg/day, about 200 mg/day to about 800 mg/day, about 200 mg/day to about 900 mg/day, about 200 mg/day to about 1 ,000 mg/day, about 300 mg/day to about 400 mg/day, about 300 mg/day to about 500 mg/day, about 300 mg/day to about 600 mg/day, about 300 mg/day to about 700 mg/day, about 300 mg/day to about 800 mg/day, about 300 mg/day to about 900 mg/day, about 300 mg/day to about 1 ,000 mg/day, about 400 mg/day to about 500 mg/day, about 400 mg/day to about 600 mg/day, about 400 mg/day to about 700 mg/day, about 400 mg/day to about 800 mg/day, about 400 mg/day to about 900 mg/day, about 400 mg/day to about 1 ,000 mg/day, about 500 mg/day to about 600 mg/day, about 500 mg/day to about 700 mg/day, about 500 mg/day to about 800 mg/day, about 500 mg/day to about 900 mg/day, about 500 mg/day to about 1 ,000 mg/day, about 600 mg/day to about 700 mg/day, about 600 mg/day to about 800 mg/day, about 600 mg/day to about 900 mg/day, about 600 mg/day to about 1 ,000 mg/day, about 700 mg/day to about 800 mg/day, about 700 mg/day to about 900 mg/day, about 700 mg/day to about 1 ,000 mg/day, about 800 mg/day to about 900 mg/day, about 800 mg/day to about 1 ,000 mg/day, or about 800 mg/day to about 1 ,000 mg/day. The method of any one of embodiments 1-7, wherein administration of the potassium channel modulator by an enteral, a parenteral or a topical route of administration. The method of any one of embodiments 1-8, wherein administration of the potassium channel modulator is by a route of administration that is oral, nasal, sublingual, rectal, dermal, transdermal, or by injection. The combinatorial method according to any one of embodiments 1-8, wherein the individual suffers from a form of age-related cognitive impairment, a neurological disease or a psychiatric disease. The method according to any one of embodiments 1-10, wherein the individual suffers from a post- traumatic stress syndrome, a traumatic brain injury, or an autism spectrum disorder. The method according to any one of embodiments 1-11 , wherein the individual is at least 50 years of age. A combinatorial method for treating a sleep or anxiety disorder in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a potassium channel modulator in combination with an amount of at least one other therapeutic sleep agent utilized to treat the sleep or anxiety disorder, thereby treating the sleep or anxiety disorder of the individual. The combinatorial method of embodiment 13, wherein the potassium channel modulator modulates one or more Kv7 members of voltage-gated potassium channels. The combinatorial method of embodiment 13 or 14, wherein the potassium channel modulator is a neuronal Kv7 activator. The combinatorial method of embodiment 15, wherein the neuronal Kv7 activator is a Triaminopyridine or one of its derivatives, an Acrylamide, a Benzamide, a Fenamate, a Dimethoxypyrimidine or one of its derivatives, Oxindole, Celecoxib, zinc pyrithione, ML213, QO58, QO58 lysine, NS1643, Benzbromarone, ZG1732 and ZG2083. The combinatorial method of embodiment 16, wherein the Triaminopyridine includes a flupirtine or retigabine or a derivative thereof, or any combination thereof. The combinatorial method of embodiment 16, wherein the retigabine derivative is NS15370, P- Retigabine, SF0034 or RL648_81 or any combination thereof. The combinatorial method of any one of embodiments 13-18, wherein the at least one therapeutic sleep agent is an antidepressant or an antianxiety medication. The combinatorial method of any one of embodiments 13-19, wherein the at least one other therapeutic sleep agent is at least one of doxepin, estazo!am, eszopicione, mirtazapine and its enantiomers, ramelteon, suvorexant, temazepam, trazodone, triazolam, zalepion, or zolpidem. The combinatorial method of any one of embodiments 13-20, wherein the amount of the least one other therapeutic sleep agent is an amount that is a therapeutically ineffective amount of the at least one other therapeutic sleep agent if the at least one other therapeutic sleep agent was administered without the potassium channel modulator. The combinatorial method of 21 , wherein the amount of the least one other therapeutic sleep agent is an amount that is about half of a regulatory agency-approved dosage of the least one other therapeutic sleep agent. The method of any one of embodiments 13-22, wherein the therapeutically effective amount of the potassium channel modulator is between about 25 mg/day to about 50 mg/day, about 25 mg/day to about 100 mg/day, about 25 mg/day to about 150 mg/day, about 25 mg/day to about 200 mg/day, about 25 mg/day to about 250 mg/day, about 25 mg/day to about 300 mg/day, about 25 mg/day to about 350 mg/day, about 25 mg/day to about 400 mg/day, about 25 mg/day to about 450 mg/day, about 25 mg/day to about 500 mg/day, about 50 mg/day to about 100 mg/day, about 50 mg/day to about 150 mg/day, about 50 mg/day to about 200 mg/day, about 50 mg/day to about 250 mg/day, about 50 mg/day to about 300 mg/day, about 50 mg/day to about 350 mg/day, about 50 mg/day to about 400 mg/day, about 50 mg/day to about 450 mg/day, about 50 mg/day to about 500 mg/day, about 100 mg/day to about 200 mg/day, about 100 mg/day to about 300 mg/day, about 100 mg/day to about 400 mg/day, about 100 mg/day to about 500 mg/day, about 100 mg/day to about 600 mg/day, about 100 mg/day to about 700 mg/day, about 100 mg/day to about 800 mg/day, about 100 mg/day to about 900 mg/day, about 100 mg/day to about 1 ,000 mg/day, about 200 mg/day to about 300 mg/day, about 200 mg/day to about 400 mg/day, about 200 mg/day to about 500 mg/day, about 200 mg/day to about 600 mg/day, about 200 mg/day to about 700 mg/day, about 200 mg/day to about 800 mg/day, about 200 mg/day to about 900 mg/day, about 200 mg/day to about 1 ,000 mg/day, about 300 mg/day to about 400 mg/day, about 300 mg/day to about 500 mg/day, about 300 mg/day to about 600 mg/day, about 300 mg/day to about 700 mg/day, about 300 mg/day to about 800 mg/day, about 300 mg/day to about 900 mg/day, about 300 mg/day to about 1 ,000 mg/day, about 400 mg/day to about 500 mg/day, about 400 mg/day to about 600 mg/day, about 400 mg/day to about 700 mg/day, about 400 mg/day to about 800 mg/day, about 400 mg/day to about 900 mg/day, about 400 mg/day to about 1 ,000 mg/day, about 500 mg/day to about 600 mg/day, about 500 mg/day to about 700 mg/day, about 500 mg/day to about 800 mg/day, about 500 mg/day to about 900 mg/day, about 500 mg/day to about 1 ,000 mg/day, about 600 mg/day to about 700 mg/day, about 600 mg/day to about 800 mg/day, about 600 mg/day to about 900 mg/day, about 600 mg/day to about 1 ,000 mg/day, about 700 mg/day to about 800 mg/day, about 700 mg/day to about 900 mg/day, about 700 mg/day to about 1 ,000 mg/day, about 800 mg/day to about 900 mg/day, about 800 mg/day to about 1 ,000 mg/day, or about 800 mg/day to about 1 ,000 mg/day. The method of any one of embodiments 13-23, wherein the therapeutically effective amount ofthe least one other therapeutic sleep agent is between about 1 mg/day to about 5 mg/day, about 1 mg/day to about 10 mg/day, about 1 mg/day to about 15 mg/day, about 1 mg/day to about 20 mg/day, about 1 mg/day to about 25 mg/day, about 1 mg/day to about 30 mg/day, about 1 mg/day to about 35 mg/day, about 1 mg/day to about 40 mg/day, about 1 mg/day to about 45 mg/day, about 1 mg/day to about 50 mg/day, about 1 mg/day to about 60 mg/day, about 1 mg/day to about 70 mg/day, about 1 mg/day to about 80 mg/day, about 1 mg/day to about 90 mg/day, about 1 mg/day to about 100 mg/day, about 1 mg/day to about 110 mg/day, about 1 mg/day to about 120 mg/day, about 1 mg/day to about 130 mg/day, about 1 mg/day to about 140 mg/day, about 1 mg/day to about 150 mg/day, about 5 mg/day to about 10 mg/day, about 5 mg/day to about 15 mg/day, about 5 mg/day to about 20 mg/day, about 5 mg/day to about 25 mg/day, about 5 mg/day to about 30 mg/day, about 5 mg/day to about 35 mg/day, about 5 mg/day to about 40 mg/day, about 5 mg/day to about 45 mg/day, about 5 mg/day to about 50 mg/day, about 5 mg/day to about 60 mg/day, about 5 mg/day to about 70 mg/day, about 5 mg/day to about 80 mg/day, about 5 mg/day to about 90 mg/day, about 5 mg/day to about 100 mg/day, about 5 mg/day to about 110 mg/day, about 5 mg/day to about 120 mg/day, about 5 mg/day to about 130 mg/day, about 5 mg/day to about 140 mg/day, about 5 mg/day to about 150 mg/day, about 10 mg/day to about 15 mg/day, about 10 mg/day to about 20 mg/day, about 10 mg/day to about 25 mg/day, about 10 mg/day to about 30 mg/day, about 10 mg/day to about 35 mg/day, about 10 mg/day to about 40 mg/day, about 10 mg/day to about 45 mg/day, about 10 mg/day to about 50 mg/day, about 10 mg/day to about 60 mg/day, about 10 mg/day to about 70 mg/day, about 10 mg/day to about 80 mg/day, about 10 mg/day to about 90 mg/day, about 10 mg/day to about 100 mg/day, about 10 mg/day to about 110 mg/day, about 10 mg/day to about 120 mg/day, about 10 mg/day to about 130 mg/day, about 10 mg/day to about 140 mg/day, about 10 mg/day to about 150 mg/day, about 25 mg/day to about 50 mg/day, about 25 mg/day to about 100 mg/day, about 25 mg/day to about 150 mg/day, about 25 mg/day to about 200 mg/day, about 25 mg/day to about 250 mg/day, about 25 mg/day to about 300 mg/day, about 25 mg/day to about 350 mg/day, about 25 mg/day to about 400 mg/day, about 25 mg/day to about 450 mg/day, about 25 mg/day to about 500 mg/day, about 50 mg/day to about 100 mg/day, about 50 mg/day to about 150 mg/day, about 50 mg/day to about 200 mg/day, about 50 mg/day to about 250 mg/day, about 50 mg/day to about 300 mg/day, about 50 mg/day to about 350 mg/day, about 50 mg/day to about 400 mg/day, about 50 mg/day to about 450 mg/day, about 50 mg/day to about 500 mg/day, about 100 mg/day to about 200 mg/day, about 100 mg/day to about 300 mg/day, about 100 mg/day to about 400 mg/day, about 100 mg/day to about 500 mg/day, about 100 mg/day to about 600 mg/day, about 100 mg/day to about 700 mg/day, about 100 mg/day to about 800 mg/day, about 100 mg/day to about 900 mg/day, about 100 mg/day to about 1 ,000 mg/day, about 200 mg/day to about 300 mg/day, about 200 mg/day to about 400 mg/day, about 200 mg/day to about 500 mg/day, about 200 mg/day to about 600 mg/day, about 200 mg/day to about 700 mg/day, about 200 mg/day to about 800 mg/day, about 200 mg/day to about 900 mg/day, about 200 mg/day to about 1 ,000 mg/day, about 300 mg/day to about 400 mg/day, about 300 mg/day to about 500 mg/day, about 300 mg/day to about 600 mg/day, about 300 mg/day to about 700 mg/day, about 300 mg/day to about 800 mg/day, about 300 mg/day to about 900 mg/day, about 300 mg/day to about 1 ,000 mg/day, about 400 mg/day to about 500 mg/day, about 400 mg/day to about 600 mg/day, about 400 mg/day to about 700 mg/day, about 400 mg/day to about 800 mg/day, about 400 mg/day to about 900 mg/day, about 400 mg/day to about 1 ,000 mg/day, about 500 mg/day to about 600 mg/day, about 500 mg/day to about 700 mg/day, about 500 mg/day to about 800 mg/day, about 500 mg/day to about 900 mg/day, about 500 mg/day to about 1 ,000 mg/day, about 600 mg/day to about 700 mg/day, about 600 mg/day to about 800 mg/day, about 600 mg/day to about 900 mg/day, about 600 mg/day to about 1 ,000 mg/day, about 700 mg/day to about 800 mg/day, about 700 mg/day to about 900 mg/day, about 700 mg/day to about 1 ,000 mg/day, about 800 mg/day to about 900 mg/day, about 800 mg/day to about 1 ,000 mg/day, or about 800 mg/day to about 1 ,000 mg/day. The combinatorial method of any one of embodiments 13-24, wherein the at least one other therapeutic sleep agent is Trazodone and the amount administered is about 25 mg/day to about 150 mg/day. The combinatorial method of any one of embodiments 13-24, wherein the at least one other therapeutic sleep agent is Suvorexant and the amount administered is about 1 mg/day to about 5 mg/day. The combinatorial method of any one of embodiments 13-26, wherein administration of the therapeutically effective amount of a potassium channel modulator is orally, nasally, intravenously or sublingually. 28. The method of any one of embodiments 13-27, wherein administration of the potassium channel modulator is by a route of administration that is oral, nasal, sublingual, rectal, dermal, transdermal, or by injection.

29. The combinatorial method according to any one of embodiments 13-28, wherein administration of the potassium channel modulator results in a decrease in a frequency and/or an intensity of an undesired side effect brought on by administration of the at least one other therapeutic sleep agent.

30. The combinatorial method according to embodiment 29, wherein the undesired side effect is at least one of headache, next day drowsiness, dizziness, abnormal dreams, diarrhea, dry mouth, cough, upper respiratory tract infection, blurred vision, constipation, trouble urinating, urinary retention problems, nausea, vomiting, upset stomach, symptoms of anxiety, panic attacks, thoughts about suicide or dying, feelings of restlessness, feelings of agitation, irritability or weight gain.

31 . The combinatorial method according to any one of embodiments 13-30, wherein the individual suffers from a form of age-related cognitive impairment, neurological disease or psychiatric disease.

32. The method according to any one of embodiments 13-31 , wherein the individual suffers from post- traumatic stress syndrome, traumatic brain injury, or an autism spectrum disorder.

33. The method according to any one of embodiments 13-32, wherein the individual is at least 50 years of age.

EXAMPLES

[075] The following non-limiting examples are provided for illustrative purposes only in order to facilitate a more complete understanding of representative embodiments now contemplated. These examples should not be construed to limit any of the embodiments described in the present specification, including those pertaining to the compounds, pharmaceutical compositions, or methods and uses disclosed herein.

Example 1

Potassium Channel Modulator Efficacy for Reducing Sleep Fragmentation in AD Transgenic Mice

[076] Studies using Alzheimer disease (AD) mouse models have demonstrated a clear relationship between abnormal Amyloid-beta (Ab) processing and sleep disturbance, in agreement with human studies. Specifically, transgenic mice which overexpress amyloid precursor protein, leading to Ab accumulation demonstrate sleep fragmentation, decreased slow wave and REM sleep, and abnormal EEG synchrony. In particular, the 5XFAD mice display very severe neuronal loss, substantial Ab accumulation, and cognitive impairment, along with well-characterized sleep perturbation. Importantly, 5XFAD mice have a robust 14- 26% reduction in sleep bout length with no total changes in time spent asleep, indicating increased sleep fragmentation. These preclinical data illustrate that 5XFAD mice are a good model to evaluate sleep abnormalities.

[077] In one series of experiments, the efficacy of retigabine will be assessed by a dose-response study using 1 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg and 30 mg/kg at the start of lights on phase (zt-0). For each dosage evaluated, two animal groups will be designated with one group to receive retigabine (Experimental Group) and one group to receive a saline placebo (Control Group). Ten 5XFAD mice consisting of 5 males and 5 females will be randomly assigned to each group. The mice are between 4-6 months of age, a period in which sleep defects are characterized in 5XFAD animals. Ten days prior to any experimental treatments, animals are implanted with custom built electroencephalography (EEG)/electromyography (EMG) recording unit by securing within the skull using dental cement two stainless steel screws over the left frontal bone (AP:1 .0 mm, ML: -1.5 mm) and the right parietal bone (AP: -2.5 mm ML: -2.5 mm) and secured within the skull using dental cement, threading two wires into the neck muscle, and cementing atop of the skull an electrode interface hub. Animals are tethered to the EEG/EMG recording cables 1 day prior to the experiment to allow habituation.

[078] The experiments are initiated by first recording animal sleep for 24 hours to establish baseline sleep levels. On day 2, at the start of lights on phase (zt-0), animals received an intraperitoneal injection with the prescribed dosage of retigabine or saline placebo. This injection time point was chosen given the animals natural inclination to sleep mimicking the period in which patients would receive treatment. Following the injection day, animals will be recorded for an additional day (day 3) to monitor any prolonged effects during drug washout. Following each experimental trial EEG recordings will be scored for sleep stage by trained individuals blinded to treatment conditions. The effectiveness of retigabine will be assessed by evaluating the primary endpoints of duration and frequency of NREM sleep bouts at 3-hours and 12-hours postinjection relative to baseline and Control Group animals. In addition, secondary endpoints of retigabine efficacy will include latency to NREM following injection, REM and wake bout duration and frequency, and spectral analysis. Spectral analysis included examining the ratiometric changes of delta power or slow waves (0.5-4 Hz), as well as the frequency of sleep spindles at 3-hours and 12-hours post-injection relative to baseline and Control Group animals. To ensure that the effect is not a result of reduced seizure occurrence and thus, a higher quality sleep, seizure count during treatment will be examined. Seizures can be identified electrographically and will be defined as a clustering of spikes with amplitudes typically greater than 3-fold basal EEG background activity. To be considered a seizure, more than 10 spikes must cluster together temporally and demonstrate a clear beginning and end of activity. Since there are many types of seizures, each with different rhythmic patterns, an assessment was made on the EEG recordings to identify the most characteristic seizure for these mice and build rule-based classifiers for subsequent seizure identification. Seizure incidence on each day of EEG recording will be tabulated for each animal and compared across treatments at 3-hours and 12-hours post-injection.

[079] In a second series of experiments, the efficacy of retigabine will be assessed by a 20 mg/kg dose at the start of lights off phase (zt-12). Experimental and Control Groups will be established as described for the first series of experiments, with Experimental group animals receiving 20 mg/kg retigabine and Control Group animals receiving a saline placebo. The experimental timeline and effectiveness of retigabine will be assessed by evaluating the primary and secondary endpoints as discussed above.

[080] Following identification of the lowest retigabine dose required to achieve statistical efficacy on the primary endpoints at 3-hours post-injection (herein referred to as low dose retigabine), a third series of experiments will be initiated to assess the efficacy of low dose retigabine and trazodone combinations at the start of lights on phase (zt-0). In these dose-response studies, low dose retigabine will be coadministered with either 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 5 mg/kg, or 10 mg/kg trazodone. In addition, in a separate dose-effect study, 30 mg/kg retigabine (high dose retigabine) will be co-administered with either 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 5 mg/kg, or 10 mg/kg trazodone. Experimental and Control Groups will be established as described for the first series of experiments except that each group will consist of 20 animals (10 males and 10 females). The experimental timeline and effectiveness of retigabine/trazodone will be assessed by evaluating the primary and secondary endpoints as discussed above.

[081] It is expected that animals treated with retigabine will show, in a dose-response manner, efficacy starting at 1 mg/kg and peaking at the higher dose of 30 mg/kg in the sleep and anxiety outcomes compared with placebo treated animals. Specifically, we expect to observe that animals treated with retigabine will show a longer duration and higher frequency of NREM sleep bouts and reduced latency to NREM, increased REM and wake bout duration and frequency, and spectral analysis compared with placebo.

[082] In addition, it is expected that combination of lower and high dose of retigabine with trazodone will show significantly higher benefits than a monotherapy with retigabine. Specifically, animals treated with low dose retigabine and trazodone combinations will show a longer duration and higher frequency of NREM sleep bouts and reduced latency to NREM, increased REM and wake bout duration and frequency, and spectral analysis compared with placebo, with higher efficacy for the higher doses of the combination. Similar outcomes are expected from animals treated with high dose retigabine and trazodone combinations.

Example 2

Potassium Channel Modulator Efficacy for Reducing Ab1-42 Levels in AD Transgenic Mice

[083] Once parameters surrounding short-term efficacy of retigabine in reducing sleep abnormalities has been established as described in Example 1 , the long-term impact retigabine therapy on sleep will be assessed.

[084] For each dosage evaluated, two animal groups will be designated with one group to receive retigabine or a retigabine/trazodone combination (Experimental Group) and one group to receive a saline placebo (Control Group). Four 5XFAD mice consisting of 2 males and 2 females, each between 4-6 months of age, will be randomly assigned to each group. Animals are implanted with an EEG/EMG recording unit as described in Example 1 . After this implantation, a guide cannula will be stereotactically placed into the right hippocampus with the following coordinates: AP: -3.1 mm, ML: 2.5 mm, and DV:1.2 mm (below dura). Following a 10-day recovery period microdialysis probes were inserted through the guide cannula until reaching the hippocampus (Bioanalytical Systems, Product ID MBR2-10). The membrane perfusion buffer will be artificial ISF containing 0.15% filtered bovine serum albumin with a flow rate of 0.5 pL/min. At the beginning of the study, mice will be attached to the flexible EEG recording cable and microdialysis started.

[085] The experiments are initiated by first recording animal sleep for 24 hours to establish baseline sleep levels. On day 2, at the start of lights on phase (zt-0), animals received an intraperitoneal injection with the prescribed dosage of retigabine alone or in combination with trazodone (Experimental Group) or saline placebo (Control Group). EEG/EMG recordings will be collected and the effectiveness of retigabine will be assessed by evaluating the primary and secondary endpoints as described in Example 1. In addition, microdialysis samples will be collected every 12 hours with a refrigerated fraction collector into polypropylene tubes (14 samples per animal). The samples will then be analyzed for Ab1-42 by sandwich ELISA (ThermoFisher Scientific, Catalog # KMB3441) at the completion of each experiment. Ab1-42 levels will be normalized for each animal by averaging the concentration of all samples collected on the baseline day before drug treatments and evaluating each concentration as a percentage of that mean.

[086] It is expected that 5XFAD animals treated with retigabine alone or in combination with trazodone will show, in a dose-response manner, a decrease in the levels of Ab1-42 in the ISF measured by microdialysis. In addition, it is expected that a significant correlation will be revealed between Ab1-42 levels and the duration and frequency of NREM sleep bouts, latency to NREM, REM and wake bout duration and frequency, and spectral analysis compared with placebo.

[087] In closing, foregoing descriptions of embodiments of the present invention have been presented for the purposes of illustration and description. It is to be understood that, although aspects of the present invention are highlighted by referring to specific embodiments, one skilled in the art will readily appreciate that these described embodiments are only illustrative of the principles comprising the present invention. As such, the specific embodiments are not intended to be exhaustive or to limit the invention to the precise forms disclosed. Therefore, it should be understood that embodiments of the disclosed subject matter are in no way limited to a particular element, compound, composition, component, article, apparatus, methodology, use, protocol, step, and/or limitation described herein, unless expressly stated as such.

[088] In addition, groupings of alternative embodiments, elements, steps and/or limitations of the present invention are not to be construed as limitations. Each such grouping may be referred to and claimed individually or in any combination with other groupings disclosed herein. It is anticipated that one or more alternative embodiments, elements, steps and/or limitations of a grouping may be included in, or deleted from, the grouping for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the grouping as modified, thus fulfilling the written description of all Markush groups used in the appended claims.

[089] Furthermore, those of ordinary skill in the art will recognize that certain changes, modifications, permutations, alterations, additions, subtractions and sub-combinations thereof can be made in accordance with the teachings herein without departing from the spirit of the present invention. Furthermore, it is intended that the following appended claims and claims hereafter introduced are interpreted to include all such changes, modifications, permutations, alterations, additions, subtractions and sub-combinations as are within their true spirit and scope. Accordingly, the scope of the present invention is not to be limited to that precisely as shown and described by this specification. [090] Certain embodiments ofthe present invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the present invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described embodiments in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[091] The words, language, and terminology used in this specification is for the purpose of describing particular embodiments, elements, steps and/or limitations only and is not intended to limit the scope ofthe present invention, which is defined solely by the claims. In addition, such words, language, and terminology are to be understood not only in the sense of their commonly defined meanings, but to include by special definition in this specification structure, material or acts beyond the scope of the commonly defined meanings. Thus, if an element, step or limitation can be understood in the context of this specification as including more than one meaning, then its use in a claim must be understood as being generic to all possible meanings supported by the specification and by the word itself.

[092] The definitions and meanings of the elements, steps or limitations recited in a claim set forth below are, therefore, defined in this specification to include not only the combination of elements, steps or limitations which are literally set forth, but all equivalent structure, material or acts for performing substantially the same function in substantially the same way to obtain substantially the same result. In this sense it is therefore contemplated that an equivalent substitution of two or more elements, steps or limitations may be made for any one of the elements, steps or limitations in a claim set forth below or that a single element, step or limitation may be substituted for two or more elements, steps or limitations in such a claim. Although elements, steps or limitations may be described above as acting in certain combinations and even initially claimed as such, it is to be expressly understood that one or more elements, steps or limitations from a claimed combination can in some cases be excised from the combination and that the claimed combination may be directed to a sub-combination or variation of a sub-combination. As such, notwithstanding the fact that the elements, steps and/or limitations of a claim are set forth below in a certain combination, it must be expressly understood that the invention includes other combinations of fewer, more or different elements, steps and/or limitations, which are disclosed in above even when not initially claimed in such combinations. Furthermore, insubstantial changes from the claimed subject matter as viewed by a person with ordinary skill in the art, now known or later devised, are expressly contemplated as being equivalently within the scope of the claims. Therefore, obvious substitutions now or later known to one with ordinary skill in the art are defined to be within the scope of the defined elements. Accordingly, the claims are thus to be understood to include what is specifically illustrated and described above, what is conceptually equivalent, what can be obviously substituted and also what essentially incorporates the essential idea of the invention. [093] Unless otherwise indicated, all numbers expressing a characteristic, item, quantity, parameter, property, term, and so forth used in the present specification and claims are to be understood as being modified in all instances by the term “about.” As used herein, the term “about” means that the characteristic, item, quantity, parameter, property, or term so qualified encompasses a range of plus or minus ten percent above and below the value of the stated characteristic, item, quantity, parameter, property, or term. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary. For instance, as mass spectrometry instruments can vary slightly in determining the mass of a given analyte, the term "about" in the context of the mass of an ion or the mass/charge ratio of an ion refers to +/-0.50 atomic mass unit. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indication should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[094] Notwithstanding that the numerical ranges and values setting forth the broad scope of the invention are approximations, the numerical ranges and values set forth in the specific examples are reported as precisely as possible. Any numerical range or value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Recitation of numerical ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate numerical value falling within the range. Unless otherwise indicated herein, each individual value of a numerical range is incorporated into the present specification as if it were individually recited herein.

[095] Use of the terms “may” or “can” in reference to an embodiment or aspect of an embodiment also carries with it the alternative meaning of “may not” or “cannot.” As such, if the present specification discloses that an embodiment or an aspect of an embodiment may be or can be included as part of the inventive subject matter, then the negative limitation or exclusionary proviso is also explicitly meant, meaning that an embodiment or an aspect of an embodiment may not be or cannot be included as part of the inventive subject matter. In a similar manner, use of the term “optionally” in reference to an embodiment or aspect of an embodiment means that such embodiment or aspect of the embodiment may be included as part of the inventive subject matter or may not be included as part of the inventive subject matter. Whether such a negative limitation or exclusionary proviso applies will be based on whether the negative limitation or exclusionary proviso is recited in the claimed subject matter.

[096] The terms “a,” “an,” “the” and similar references used in the context of describing the present invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Further, ordinal indicators - such as, e.g., “first,” “second,” “third,” etc. - for identified elements are used to distinguish between the elements, and do not indicate or imply a required or limited number of such elements, and do not indicate a particular position or order of such elements unless otherwise specifically stated. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the present invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the present specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[097] When used in the claims, whether as filed or added per amendment, the open-ended transitional term “comprising”, variations thereof such as, e.g., “comprise” and “comprises”, and equivalent open-ended transitional phrases thereof like “including,” “containing” and “having", encompass all the expressly recited elements, limitations, steps, integers, and/or features alone or in combination with unrecited subject matter; the named elements, limitations, steps, integers, and/or features are essential, but other unnamed elements, limitations, steps, integers, and/or features may be added and still form a construct within the scope of the claim. Specific embodiments disclosed herein may be further limited in the claims using the closed-ended transitional phrases “consisting of or “consisting essentially of (or variations thereof such as, e.g., “consist of, “consists of, “consist essentially of, and “consists essentially of) in lieu of or as an amendment for “comprising.” When used in the claims, whether as filed or added per amendment, the closed-ended transitional phrase “consisting of excludes any element, limitation, step, integer, or feature not expressly recited in the claims. The closed-ended transitional phrase “consisting essentially of limits the scope of a claim to the expressly recited elements, limitations, steps, integers, and/or features and any other elements, limitations, steps, integers, and/or features that do not materially affect the basic and novel characteristic(s) of the claimed subject matter. Thus, the meaning of the open-ended transitional phrase “comprising” is being defined as encompassing all the specifically recited elements, limitations, steps and/or features as well as any optional, additional unspecified ones. The meaning of the closed-ended transitional phrase “consisting of is being defined as only including those elements, limitations, steps, integers, and/or features specifically recited in the claim, whereas the meaning of the closed-ended transitional phrase “consisting essentially of is being defined as only including those elements, limitations, steps, integers, and/or features specifically recited in the claim and those elements, limitations, steps, integers, and/or features that do not materially affect the basic and novel characteristic(s) of the claimed subject matter. Therefore, the open-ended transitional phrase “comprising” (and equivalent open-ended transitional phrases thereof) includes within its meaning, as a limiting case, claimed subject matter specified by the closed-ended transitional phrases “consisting of or “consisting essentially of.” As such, the embodiments described herein or so claimed with the phrase “comprising” expressly and unambiguously provide description, enablement, and support for the phrases “consisting essentially of and “consisting of.”

[098] Lastly, all patents, patent publications, and other references cited and identified in the present specification are individually and expressly incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the compositions and methodologies described in such publications that might be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard is or should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates or contents of these documents.

Claims

1. A combinatorial method for treating a sleep or anxiety disorder in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a potassium channel modulator in combination with an amount of at least one other therapeutic sleep agent utilized to treat the sleep or anxiety disorder, thereby treating the sleep or anxiety disorder of the individual.

2. The combinatorial method of claim 1 , wherein the potassium channel modulator modulates one or more Kv7 members of voltage-gated potassium channels.

3. The combinatorial method of claim 1 or 2, wherein the potassium channel modulator is a neuronal Kv7 activator.

4. The combinatorial method of claim 3, wherein the neuronal Kv7 activator is a Triaminopyridine or one of its derivatives, an Acrylamide, a Benzamide, a Fenamate, a Dimethoxypyrimidine or one of its derivatives, Oxindole, Celecoxib, zinc pyrithione, ML213, QO58, QO58 lysine, NS1643, Benzbromarone, ZG1732 and ZG2083.

5. The combinatorial method of claim 4, wherein the Triaminopyridine includes a flupirtine or retigabine or a derivative thereof, or any combination thereof.

6. The combinatorial method of claim 5, wherein the retigabine derivative is NS15370, P-Retigabine, SF0034 or RL648_81 or any combination thereof.

7. The combinatorial method of any one of claims 1 -6, wherein the at least one therapeutic sleep agent is an antidepressant or an antianxiety medication.

8. The combinatorial method of any one of claims 1 -7, wherein the at least one other therapeutic sleep agent is at least one of doxepin, estazoiam, eszopiclone, mirtazapine and its enantiomers, rameiteon, suvorexant, temazepam, trazodone, triazolam, zaleplon, or zolpidem.

9. The combinatorial method of any one of claims 1-8, wherein the amount of the least one other therapeutic sleep agent is an amount that is a therapeutically ineffective amount of the at least one other therapeutic sleep agent if the at least one other therapeutic sleep agent was administered without the potassium channel modulator.

10. The combinatorial method of 9, wherein the amount of the least one other therapeutic sleep agent is an amount that is about half of a regulatory agency-approved dosage of the least one other therapeutic sleep agent.

11. The method of any one of claims 1-10, wherein the therapeutically effective amount of the potassium channel modulator is between about 25 mg/day to about 50 mg/day, about 25 mg/day to about 100 mg/day, about 25 mg/day to about 150 mg/day, about 25 mg/day to about 200 mg/day, about 25 mg/day to about 250 mg/day, about 25 mg/day to about 300 mg/day, about 25 mg/day to about 350 mg/day, about 25 mg/day to about 400 mg/day, about 25 mg/day to about 450 mg/day, about 25 mg/day to about 500 mg/day, about 50 mg/day to about 100 mg/day, about 50 mg/day to about 150 mg/day, about 50 mg/day to about 200 mg/day, about 50 mg/day to about 250 mg/day, about 50 mg/day to about 300 mg/day, about 50 mg/day to about 350 mg/day, about 50 mg/day to about 400 mg/day, about 50 mg/day to about 450 mg/day, about 50 mg/day to about 500 mg/day, about 100 mg/day to about 200 mg/day, about 100 mg/day to about 300 mg/day, about 100 mg/day to about 400 mg/day, about 100 mg/day to about 500 mg/day, about 100 mg/day to about 600 mg/day, about 100 mg/day to about 700 mg/day, about 100 mg/day to about 800 mg/day, about 100 mg/day to about 900 mg/day, about 100 mg/day to about 1 ,000 mg/day, about 200 mg/day to about 300 mg/day, about 200 mg/day to about 400 mg/day, about 200 mg/day to about 500 mg/day, about 200 mg/day to about 600 mg/day, about 200 mg/day to about 700 mg/day, about 200 mg/day to about 800 mg/day, about 200 mg/day to about 900 mg/day, about 200 mg/day to about 1 ,000 mg/day, about 300 mg/day to about 400 mg/day, about 300 mg/day to about 500 mg/day, about 300 mg/day to about 600 mg/day, about 300 mg/day to about 700 mg/day, about 300 mg/day to about 800 mg/day, about 300 mg/day to about 900 mg/day, about 300 mg/day to about 1 ,000 mg/day, about 400 mg/day to about 500 mg/day, about 400 mg/day to about 600 mg/day, about 400 mg/day to about 700 mg/day, about 400 mg/day to about 800 mg/day, about 400 mg/day to about 900 mg/day, about 400 mg/day to about 1 ,000 mg/day, about 500 mg/day to about 600 mg/day, about 500 mg/day to about 700 mg/day, about 500 mg/day to about 800 mg/day, about 500 mg/day to about 900 mg/day, about 500 mg/day to about 1 ,000 mg/day, about 600 mg/day to about 700 mg/day, about 600 mg/day to about 800 mg/day, about 600 mg/day to about 900 mg/day, about 600 mg/day to about 1 ,000 mg/day, about 700 mg/day to about 800 mg/day, about 700 mg/day to about 900 mg/day, about 700 mg/day to about 1 ,000 mg/day, about 800 mg/day to about 900 mg/day, about 800 mg/day to about 1 ,000 mg/day, or about 800 mg/day to about 1 ,000 mg/day.

12. The method of any one of claims 1-11 , wherein the therapeutically effective amount of the least one other therapeutic sleep agent is between about 1 mg/day to about 5 mg/day, about 1 mg/day to about 10 mg/day, about 1 mg/day to about 15 mg/day, about 1 mg/day to about 20 mg/day, about 1 mg/day to about 25 mg/day, about 1 mg/day to about 30 mg/day, about 1 mg/day to about 35 mg/day, about 1 mg/day to about 40 mg/day, about 1 mg/day to about 45 mg/day, about 1 mg/day to about 50 mg/day, about 1 mg/day to about 60 mg/day, about 1 mg/day to about 70 mg/day, about 1 mg/day to about 80 mg/day, about 1 mg/day to about 90 mg/day, about 1 mg/day to about 100 mg/day, about 1 mg/day to about 110 mg/day, about 1 mg/day to about 120 mg/day, about 1 mg/day to about 130 mg/day, about 1 mg/day to about 140 mg/day, about 1 mg/day to about 150 mg/day, about 5 mg/day to about 10 mg/day, about 5 mg/day to about 15 mg/day, about 5 mg/day to about 20 mg/day, about 5 mg/day to about 25 mg/day, about 5 mg/day to about 30 mg/day, about 5 mg/day to about 35 mg/day, about 5 mg/day to about 40 mg/day, about 5 mg/day to about 45 mg/day, about 5 mg/day to about 50 mg/day, about 5 mg/day to about 60 mg/day, about 5 mg/day to about 70 mg/day, about 5 mg/day to about 80 mg/day, about 5 mg/day to about 90 mg/day, about 5 mg/day to about 100 mg/day, about 5 mg/day to about 110 mg/day, about 5 mg/day to about 120 mg/day, about 5 mg/day to about 130 mg/day, about 5 mg/day to about 140 mg/day, about 5 mg/day to about 150 mg/day, about 10 mg/day to about 15 mg/day, about 10 mg/day to about 20 mg/day, about 10 mg/day to about 25 mg/day, about 10 mg/day to about 30 mg/day, about 10 mg/day to about 35 mg/day, about 10 mg/day to about 40 mg/day, about 10 mg/day to about 45 mg/day, about 10 mg/day to about 50 mg/day, about 10 mg/day to about 60 mg/day, about 10 mg/day to about 70 mg/day, about 10 mg/day to about 80 mg/day, about 10 mg/day to about 90 mg/day, about 10 mg/day to about 100 mg/day, about 10 mg/day to about 110 mg/day, about 10 mg/day to about 120 mg/day, about 10 mg/day to about 130 mg/day, about 10 mg/day to about 140 mg/day, about 10 mg/day to about 150 mg/day, about 25 mg/day to about 50 mg/day, about 25 mg/day to about 100 mg/day, about 25 mg/day to about 150 mg/day, about 25 mg/day to about 200 mg/day, about 25 mg/day to about 250 mg/day, about 25 mg/day to about 300 mg/day, about 25 mg/day to about 350 mg/day, about 25 mg/day to about 400 mg/day, about 25 mg/day to about 450 mg/day, about 25 mg/day to about 500 mg/day, about 50 mg/day to about 100 mg/day, about 50 mg/day to about 150 mg/day, about 50 mg/day to about 200 mg/day, about 50 mg/day to about 250 mg/day, about 50 mg/day to about 300 mg/day, about 50 mg/day to about 350 mg/day, about 50 mg/day to about 400 mg/day, about 50 mg/day to about 450 mg/day, about 50 mg/day to about 500 mg/day, about 100 mg/day to about 200 mg/day, about 100 mg/day to about 300 mg/day, about 100 mg/day to about 400 mg/day, about 100 mg/day to about 500 mg/day, about 100 mg/day to about 600 mg/day, about 100 mg/day to about 700 mg/day, about 100 mg/day to about 800 mg/day, about 100 mg/day to about 900 mg/day, about 100 mg/day to about 1 ,000 mg/day, about 200 mg/day to about 300 mg/day, about 200 mg/day to about 400 mg/day, about 200 mg/day to about 500 mg/day, about 200 mg/day to about 600 mg/day, about 200 mg/day to about 700 mg/day, about 200 mg/day to about 800 mg/day, about 200 mg/day to about 900 mg/day, about 200 mg/day to about 1 ,000 mg/day, about 300 mg/day to about 400 mg/day, about 300 mg/day to about 500 mg/day, about 300 mg/day to about 600 mg/day, about 300 mg/day to about 700 mg/day, about 300 mg/day to about 800 mg/day, about 300 mg/day to about 900 mg/day, about 300 mg/day to about 1 ,000 mg/day, about 400 mg/day to about 500 mg/day, about 400 mg/day to about 600 mg/day, about 400 mg/day to about 700 mg/day, about 400 mg/day to about 800 mg/day, about 400 mg/day to about 900 mg/day, about 400 mg/day to about 1 ,000 mg/day, about 500 mg/day to about 600 mg/day, about 500 mg/day to about 700 mg/day, about 500 mg/day to about 800 mg/day, about 500 mg/day to about 900 mg/day, about 500 mg/day to about 1 ,000 mg/day, about 600 mg/day to about 700 mg/day, about 600 mg/day to about 800 mg/day, about 600 mg/day to about 900 mg/day, about 600 mg/day to about 1 ,000 mg/day, about 700 mg/day to about 800 mg/day, about 700 mg/day to about 900 mg/day, about 700 mg/day to about 1 ,000 mg/day, about 800 mg/day to about 900 mg/day, about 800 mg/day to about 1 ,000 mg/day, or about 800 mg/day to about 1 ,000 mg/day.

13. The combinatorial method of any one of claims 1-12, wherein the at least one other therapeutic sleep agent is Trazodone and the amount administered is about 25 mg/day to about 150 mg/day.

14. The combinatorial method of any one of claims 1-12, wherein the at least one other therapeutic sleep agent is Suvorexant and the amount administered is about 1 mg/day to about 5 mg/day.

15. The combinatorial method of any one of claims 1-14, wherein administration of the therapeutically effective amount of a potassium channel modulator is orally, nasally, intravenously or sublingually.

16. The method of any one of claims 1-15, wherein administration of the potassium channel modulator is by a route of administration that is oral, nasal, sublingual, rectal, dermal, transdermal, or by injection.

17. The combinatorial method according to anyone of claims 1-16, wherein administration of the potassium channel modulator results in a decrease in a frequency and/or an intensity of an undesired side effect brought on by administration of the at least one other therapeutic sleep agent.

18. The combinatorial method according to claim 17, wherein the undesired side effect is at least one of headache, next day drowsiness, dizziness, abnormal dreams, diarrhea, dry mouth, cough, upper respiratory tract infection, blurred vision, constipation, trouble urinating, urinary retention problems, nausea, vomiting, upset stomach, symptoms of anxiety, panic attacks, thoughts about suicide or dying, feelings of restlessness, feelings of agitation, irritability or weight gain.

19. The combinatorial method according to any one of claims 1-18, wherein the individual suffers from a form of age-related cognitive impairment, neurological disease or psychiatric disease.

20. The method according to any one of claims 11-19, wherein the individual suffers from post-traumatic stress syndrome, traumatic brain injury, or an autism spectrum disorder.

21 . The method according to any one of claims 1-10, wherein the individual is at least 50 years of age.

22 A method for treating a sleep or anxiety disorder in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a potassium channel modulator, thereby treating the sleep or anxiety disorder of the individual.

23. The method of claim 22, wherein the potassium channel modulator modulates one or more Kv7 members of voltage-gated potassium channels.

24. The method of claim 22 or 23, wherein the potassium channel modulator is a neuronal Kv7 activator.

25. The method of claim 24, wherein the neuronal Kv7 activator is a Triaminopyridine or one of its derivatives, an Acrylamide, a Benzamide, a Fenamate, a Dimethoxypyrimidine or one of its derivatives, Oxindole, Celecoxib, zinc pyrithione, ML213, QO58, QO58 lysine, NS1643, Benzbromarone, ZG1732 and ZG2083.

26. The method of claim 25, wherein the Triaminopyridine includes a flupirtine, or retigabine or a derivative thereof, or any combination thereof.

27. The method of claim 26, wherein the retigabine derivative is NS15370, P-Retigabine, SF0034 or RL648_81 or any combination thereof.

28. The method of any one of claims 22-27, wherein the therapeutically effective amount of the potassium channel modulator is between about 25 mg/day to about 50 mg/day, about 25 mg/day to about 100 mg/day, about 25 mg/day to about 150 mg/day, about 25 mg/day to about 200 mg/day, about 25 mg/day to about 250 mg/day, about 25 mg/day to about 300 mg/day, about 25 mg/day to about 350 mg/day, about 25 mg/day to about 400 mg/day, about 25 mg/day to about 450 mg/day, about 25 mg/day to about 500 mg/day, about 50 mg/day to about 100 mg/day, about 50 mg/day to about 150 mg/day, about 50 mg/day to about 200 mg/day, about 50 mg/day to about 250 mg/day, about 50 mg/day to about 300 mg/day, about 50 mg/day to about 350 mg/day, about 50 mg/day to about 400 mg/day, about 50 mg/day to about 450 mg/day, about 50 mg/day to about 500 mg/day, about 100 mg/day to about 200 mg/day, about 100 mg/day to about 300 mg/day, about 100 mg/day to about 400 mg/day, about 100 mg/day to about 500 mg/day, about 100 mg/day to about 600 mg/day, about 100 mg/day to about 700 mg/day, about 100 mg/day to about 800 mg/day, about 100 mg/day to about 900 mg/day, about 100 mg/day to about 1 ,000 mg/day, about 200 mg/day to about 300 mg/day, about 200 mg/day to about 400 mg/day, about 200 mg/day to about 500 mg/day, about 200 mg/day to about 600 mg/day, about 200 mg/day to about 700 mg/day, about 200 mg/day to about 800 mg/day, about 200 mg/day to about 900 mg/day, about 200 mg/day to about 1 ,000 mg/day, about 300 mg/day to about 400 mg/day, about 300 mg/day to about 500 mg/day, about 300 mg/day to about 600 mg/day, about 300 mg/day to about 700 mg/day, about 300 mg/day to about 800 mg/day, about 300 mg/day to about 900 mg/day, about 300 mg/day to about 1 ,000 mg/day, about 400 mg/day to about 500 mg/day, about 400 mg/day to about 600 mg/day, about 400 mg/day to about 700 mg/day, about 400 mg/day to about 800 mg/day, about 400 mg/day to about 900 mg/day, about 400 mg/day to about 1 ,000 mg/day, about 500 mg/day to about 600 mg/day, about 500 mg/day to about 700 mg/day, about 500 mg/day to about 800 mg/day, about 500 mg/day to about 900 mg/day, about 500 mg/day to about 1 ,000 mg/day, about 600 mg/day to about 700 mg/day, about 600 mg/day to about 800 mg/day, about 600 mg/day to about 900 mg/day, about 600 mg/day to about 1 ,000 mg/day, about 700 mg/day to about 800 mg/day, about 700 mg/day to about 900 mg/day, about 700 mg/day to about 1 ,000 mg/day, about 800 mg/day to about 900 mg/day, about 800 mg/day to about 1 ,000 mg/day, or about 800 mg/day to about 1 ,000 mg/day.

29. The method of any one of claims 22-28, wherein administration of the potassium channel modulator by an enteral, a parenteral or a topical route of administration.

30. The method of any one of claims 22-29, wherein administration of the potassium channel modulator is by a route of administration that is oral, nasal, sublingual, rectal, dermal, transdermal, or by injection.

31 . The combinatorial method according to any one of claims 22-30, wherein the individual suffers from a form of age-related cognitive impairment, a neurological disease or a psychiatric disease.

32. The method according to any one of claims 22-31 , wherein the individual suffers from a post-traumatic stress syndrome, a traumatic brain injury, or an autism spectrum disorder.

33. The method according to any one of claims 22-32, wherein the individual is at least 50 years of age.