Liquid chromatographic methods for determination of the new antiepileptic drugs stiripentol,retigabine,rufinamide and perampanel:A comprehensive and critical review / 药物分析学报

The new antiepileptic drugs perampanel,retigabine,rufinamide and stiripentol have been recently approved for different epilepsy types.Being them an innovation in the antiepileptics armamentarium,a lot of investigations regarding their pharmacological properties are yet to be performed.Besides,considering their broad anticonvulsant activities,an extension of their therapeutic indications may be worthy of investigation,especially regarding other seizure types as well as other central nervous system disorders.Although different liquid chromatographic (LC) methods coupled with ultraviolet,fluores-cence,mass or tandem-mass spectrometry detection have already been developed for the determination of perampanel,retigabine,rufinamide and stiripentol,new and more cost-effective methods are yet required.Therefore,this review summarizes the main analytical aspects regarding the liquid chro-matographic methods developed for the analysis of perampanel,retigabine (and its main active metabolite),rufinamide and stiripentol in biological samples and pharmaceutical dosage forms.Furthermore,the physicochemical and stability properties of the target compounds will also be addressed.Thus,this review gathers,for the first time,important background information on LC methods that have been developed and applied for the determination of perampanel,retigabine,rufinamide and stiripentol,which should be considered as a starting point if new (bio)analytical techniques are aimed to be imnlemented for these drugs.

KCNQ Channels in the Mesolimbic Reward Circuit Regulate Nociception in Chronic Pain in Mice / 神经科学通报·英文版

Mesocorticolimbic dopaminergic (DA) neurons have been implicated in regulating nociception in chronic pain, yet the mechanisms are barely understood. Here, we found that chronic constructive injury (CCI) in mice increased the firing activity and decreased the KCNQ channel-mediated M-currents in ventral tegmental area (VTA) DA neurons projecting to the nucleus accumbens (NAc). Chemogenetic inhibition of the VTA-to-NAc DA neurons alleviated CCI-induced thermal nociception. Opposite changes in the firing activity and M-currents were recorded in VTA DA neurons projecting to the medial prefrontal cortex (mPFC) but did not affect nociception. In addition, intra-VTA injection of retigabine, a KCNQ opener, while reversing the changes of the VTA-to-NAc DA neurons, alleviated CCI-induced nociception, and this was abolished by injecting exogenous BDNF into the NAc. Taken together, these findings highlight a vital role of KCNQ channel-mediated modulation of mesolimbic DA activity in regulating thermal nociception in the chronic pain state.

Analgesic effects of aspirin combined with kv7 channel openers / 中国药理学通报

Aim To provide scientific evidence for clinical drug combination by exploring the analgesic effect of aspirin combined with Kv7 channel openers, retigabine and flupirtine. Methods The mice were randomly divided into control group, aspirin group, flupirtine group, retigabine group, aspirin + flupirtine group and aspirin + retigabine group. To assess the antinociceptive effects of each group, the acetic acid-induced abdominal constriction test and the hot-plate test were used. Results In the acetic acid-induced abdominal constriction test, compared to aspirin group, the amount of abdominal constriction in aspirin + flupirtine group was significantly reduced (P <0.01). The latent period of abdominal constriction in aspirin + retigabine group was significantly prolonged ( P < 0. 01) and the number of abdominal constriction was significantly reduced (P < 0. 01). In the hot-plate test, compared to aspirin group, the increment percentage of latent period in aspirin + flupirtine group and aspirin + retigabine group showed an increased trend. Among them, the increment percentage of latent period 30 and 60 minutes after injections in aspirin + retigabine group had a significant difference from that in aspirin group (P <0. 05). Conclusion Kv7 channel openers, retigabine and flupirtine, can enhance the analgesic effect of aspirin.

Role of Kv7 Channels in Vascular Dysfunction associated with Metabolic Syndrome

Vasoconstriction is regulated by various ion channels expressed in the plasma membrane of vascular smooth muscle cells. In particular, potassium (K+) channel activity determines resting membrane potential and regulates intracellular calcium (Ca2+) signaling. A number of studies have suggested that dysregulation of K+ channel activity is associated with increased myogenic tone or diminished vasorelaxation. Among the various families of K+ channels, voltage-dependent K+ channels (Kv channels) encoded by the KCNQ gene family (Kv7 channels or M channels) are widely expressed in various blood vessels isolated from mouse, rat, and human. Recent studies have demonstrated that a subunit of the Kv7 channel, Kv7.4, is down-regulated in the aorta and mesenteric and renal arteries of the Spontaneously Hypertensive Rat (SHR) model. Previous studies have also suggested that Kv7 channels play an important role in the regulation of vasorelaxation/vasoconstriction in response to activators/blockers. In addition, previous studies have indicated that hypertension, diabetes mellitus, and cerebrovascular disease result in development of vascular dysfunction associated with Kv7 abnormalities in various animal models. This review focuses on the potential role of the Kv7 channel in vascular dysfunction.

Kv7 channels in modulation of central monoaminergic neurotransmission / 中国药理学通报

The KCNQ gene family encodes five Kv7 channel sub-units(Kv7. 1-5) and four of these (Kv7. 2-5) channels are ex-pressed in the central nervous system ( CNS ) . Neuronal Kv7 channels participate in both pre-and post-synaptic modulation of neurotransmissions. Activation of neuronal Kv7 channels inhibits neuronal excitability and limits the release of monoaminergic neu-rotransmitter. Kv7 channel openers provide novel therapeutic op-tions in the treatment of disease states characterized by overactiv-ity of monoaminergic neurons ( e. g. schizophrenia, anxiety and drug abuse) . This review summarizes the studies on expression and functional role of Kv7 channels in monoaminergic neurotrans-mission in the CNS and the potential therapeutic effect of Kv7 channel openers on the disease characterized by overactivity of monoaminergic neurons.

Potassium channels in health, disease & development of channel modulators.

Ion channels present in the plasma membrane and intracellular organelles of all cells, play an important role in maintaining cellular integrity, smooth muscle contraction, secretion of hormones and neurotransmitters. Among the ion channels, potassium channels (K+) are the most abundant having important role in cardiac repolarization, smooth muscle relaxation and insulin release. These are also involved in the regulation of physiological functions like gastrointestinal peristalsis. These channels are the most diverse of all ion channels and are coded by at least 75 genes. Moreover, these have different subunits which co-assemble to form diverse functional channels. Abnormalities in K+ channels are associated with diseases like long QT syndrome, Anderson Tawil syndrome, epilepsy, type 2 diabetes mellitus, etc. A number of naturally occurring as well as synthetic compounds have been identified that modulate the opening and closure of KATP Channels. Some of the currently available K+ channel modulators like sulphonylureas, minoxidil, amiodarone, etc. lack tissue selectivity and have adverse effects. Hence, the success of KATP channel modulators depend on their tissue selectivity. Molecular level studies are needed to understand the type of K+ channels as this can lead to the development of newer drugs with tissue selectivity for various diseases.