There is accumulating evidence that the subfamily of large-conductance potassium (“big”, “BK”) channels are involved in diverse, and perhaps coordinated, protective or counteractive responses to local or generaliz...There is accumulating evidence that the subfamily of large-conductance potassium (“big”, “BK”) channels are involved in diverse, and perhaps coordinated, protective or counteractive responses to local or generalized ischemia and hypoxia. Although widely distributed, the physiological differences among BK channels which results from posttranslational modification (alternative splicing) and co-assembly with auxiliary modulatory subunits (<em>β</em><sub>1-4</sub> and <em>γ</em><sub>1-4</sub>), bestows localized differences in subunit composition, distribution, 2<sup>nd</sup>-messenger coupling, and pharmacologic properties. Due to the ubiquitous nature of BK channels and the multiplicity of subtypes, they have many potential therapeutic applications in the maintenance of oxygen homeostasis, cerebro- and cardio-protection, and stimulation of respiration in response to drug-induced respiratory depression. BK channels may also offer other potentially broad and underrecognized promising targets for novel pharmaceutical development.展开更多
<span style="font-family:Verdana;">The </span><span style="font-family:Verdana;">“</span><span style="font-family:Verdana;">opioid crisis</span><sp...<span style="font-family:Verdana;">The </span><span style="font-family:Verdana;">“</span><span style="font-family:Verdana;">opioid crisis</span><span style="font-family:Verdana;">”</span><span style="font-family:""><span style="font-family:Verdana;"> has had a tremendous impact not only on its victims, but also on the practice of medicine, pain patients, and society in general. Unfortunately, efforts to “stem the tide” have not been successful at reducing overdose deaths. Counterbalancing the many ardent efforts to eliminate overdose deaths (such as the current widespread availability and use of opioid-receptor antagonists such as naloxone) is influx of the illicit fentanoids (</span><i><span style="font-family:Verdana;">i.e</span></i><span style="font-family:Verdana;">., fentanyl and analogs). In addition to their high-potency, the fentanoids differ in surprising ways from more “traditional” opioids such as morphine and heroin. This uniqueness contributes to a reduced effectiveness of opioid receptor antagonists in the treatment of opioid overdose. Further greatly complicating overdose treatment is polysubstance abuse (e.g., an opioid plus a benzodiaze</span><span style="font-family:Verdana;">pine). The non-opioid in the combination is not responsive to an opio</span><span style="font-family:Verdana;">id-recep</span></span><span style="font-family:Verdana;">- </span><span style="font-family:""><span style="font-family:Verdana;">tor antagonist, which imparts additional challenges. Thus, the new reality in</span><span style="font-family:Verdana;">troduces complications that negatively impact efforts to reverse </span></span><span style="font-family:Verdana;">“</span><span style="font-family:Verdana;">opioid</span><span style="font-family:Verdana;">”</span><span style="font-family:""><span style="font-family:Verdana;"> overdose. New approaches to improve outcomes in individuals who experience </span><span style="font-family:Verdana;">respiratory depression due to fentanoid-induced or polysubstance-induced</span><span style="font-family:Verdana;"> over</span></span><span style="font-family:Verdana;">- </span><span style="font-family:Verdana;">dose are needed. Approaches that harmonize with the new reality, perhaps something like a non-opioid </span><span style="font-family:Verdana;">“</span><span style="font-family:Verdana;">agnostic</span><span style="font-family:Verdana;">”</span><span style="font-family:Verdana;"> pharmacologic ventilatory stimulant, would provide a welcome addition to the current choices.</span>展开更多
文摘There is accumulating evidence that the subfamily of large-conductance potassium (“big”, “BK”) channels are involved in diverse, and perhaps coordinated, protective or counteractive responses to local or generalized ischemia and hypoxia. Although widely distributed, the physiological differences among BK channels which results from posttranslational modification (alternative splicing) and co-assembly with auxiliary modulatory subunits (<em>β</em><sub>1-4</sub> and <em>γ</em><sub>1-4</sub>), bestows localized differences in subunit composition, distribution, 2<sup>nd</sup>-messenger coupling, and pharmacologic properties. Due to the ubiquitous nature of BK channels and the multiplicity of subtypes, they have many potential therapeutic applications in the maintenance of oxygen homeostasis, cerebro- and cardio-protection, and stimulation of respiration in response to drug-induced respiratory depression. BK channels may also offer other potentially broad and underrecognized promising targets for novel pharmaceutical development.
文摘<span style="font-family:Verdana;">The </span><span style="font-family:Verdana;">“</span><span style="font-family:Verdana;">opioid crisis</span><span style="font-family:Verdana;">”</span><span style="font-family:""><span style="font-family:Verdana;"> has had a tremendous impact not only on its victims, but also on the practice of medicine, pain patients, and society in general. Unfortunately, efforts to “stem the tide” have not been successful at reducing overdose deaths. Counterbalancing the many ardent efforts to eliminate overdose deaths (such as the current widespread availability and use of opioid-receptor antagonists such as naloxone) is influx of the illicit fentanoids (</span><i><span style="font-family:Verdana;">i.e</span></i><span style="font-family:Verdana;">., fentanyl and analogs). In addition to their high-potency, the fentanoids differ in surprising ways from more “traditional” opioids such as morphine and heroin. This uniqueness contributes to a reduced effectiveness of opioid receptor antagonists in the treatment of opioid overdose. Further greatly complicating overdose treatment is polysubstance abuse (e.g., an opioid plus a benzodiaze</span><span style="font-family:Verdana;">pine). The non-opioid in the combination is not responsive to an opio</span><span style="font-family:Verdana;">id-recep</span></span><span style="font-family:Verdana;">- </span><span style="font-family:""><span style="font-family:Verdana;">tor antagonist, which imparts additional challenges. Thus, the new reality in</span><span style="font-family:Verdana;">troduces complications that negatively impact efforts to reverse </span></span><span style="font-family:Verdana;">“</span><span style="font-family:Verdana;">opioid</span><span style="font-family:Verdana;">”</span><span style="font-family:""><span style="font-family:Verdana;"> overdose. New approaches to improve outcomes in individuals who experience </span><span style="font-family:Verdana;">respiratory depression due to fentanoid-induced or polysubstance-induced</span><span style="font-family:Verdana;"> over</span></span><span style="font-family:Verdana;">- </span><span style="font-family:Verdana;">dose are needed. Approaches that harmonize with the new reality, perhaps something like a non-opioid </span><span style="font-family:Verdana;">“</span><span style="font-family:Verdana;">agnostic</span><span style="font-family:Verdana;">”</span><span style="font-family:Verdana;"> pharmacologic ventilatory stimulant, would provide a welcome addition to the current choices.</span>