Brief hypoxic episodes drive neuroplasticity in animal models and humans. Pretreatment with an allosteric α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (R) modulator ("ampakine") enables a single hypoxic exposure to induce sustained increases in phrenic motor activity ["phrenic motor facilitation" (pMF)]. Phrenic nerve activity was recorded in anesthetized rats to determine whether the ampakine-hypoxia (A-H) combination is unique in its ability to evoke pMF and to determine its underlying mechanisms. Pairing ampakine CX717 with brief moderate or severe hypercapnia failed to produce pMF. Pairing doxapram, a respiratory stimulant, with hypoxia did not produce pMF. We then sequentially tested the hypotheses that A-H-induced pMF requires spinal serotonin, adenosine, or NMDA receptor activation. Cervical intrathecal delivery of serotonin (methysergide) or adenosine 2 A receptor (MSX-3) antagonists before A-H failed to prevent pMF. In contrast, the NMDA-R blocker MK-801 prevented pMF when administered before but not after A-H. Finally, as a step in the translational pathway, we tested the safety and efficacy of acute A-H exposure in unanesthetized rats with indwelling diaphragm electromyogram (EMG) wires after cervical spinal cord injury (SCI). A-H was well tolerated, and at 3 mo after SCI, increased diaphragm EMG output. We conclude that the mechanism driving sustained increases in phrenic motor output after A-H is independent of spinal adenosine or serotonin receptor activation, but requires spinal NMDA-R activation for the induction, but not maintenance, of A-H pMF. Ampakine pretreatment may be useful to increase the efficacy of hypoxia-based rehabilitation paradigms after SCI, particularly since clinical trials report a substantial number of "low responders."NEW & NOTEWORTHY Rehabilitation paradigms using brief hypoxia exposure can improve recovery after spinal cord injury. A low dose of ampakines, which enhance AMPA neurotransmission, coupled with brief hypoxia (A-H), uniquely evokes respiratory neuroplasticity ("phrenic motor facilitation" or pMF) via a mechanism that requires spinal NMDA, but not serotonin or adenosine receptor activation. A-H also increased diaphragm activation in rats with chronic SCI, suggesting that the A-H pairing may be useful in neurorehabilitation.

The saga of antiarrhythmic drug (AAD) therapy reflects a field shaped by empiricism and burdened by challenges related to safety. The Singh-Vaughan-Williams classification was a timely necessity that eventually slowed pharmacological innovation by prioritizing electrophysiologic properties over arrhythmogenic mechanisms. The present, limited pharmacological armamentarium demands efforts to reassess legacy antiarrhythmics, repurpose non-antiarrhythmic agents as upstream or downstream therapy, and develop novel compounds. Flecainide, propafenone, and dronedarone have demonstrated their reliable efficacy and safety, even in patients with structural heart disease, which should allow clinicians to reduce their reliance on amiodarone. Previous concerns regarding the proarrhythmic risk of dofetilide and ibutilide are currently managed through careful patient selection and adequate QT interval monitoring. Novel targeted AADs are advancing through the development pipeline, of which etripamil and landiolol have already been approved. Other emerging drugs, such as SK channel blockers (AP30663 and AP31969), RyR2 blockers, CaMKII inhibitors, and TASK-1 blockers (doxapram), are aligned with the new paradigm of atrial fibrillation that focuses on triggers and re-entry. Once triggered, arrhythmias are perpetuated by the underlying substrate, which could be directly targeted by antifibrotic therapy. Developing concepts such as atrial cardiomyopathy allows clinicians to characterize substrate objectively, in order to assess disease severity and individualize antiarrhythmic treatment. The future of antiarrhythmic therapy will be reshaped by artificial intelligence and digital twinning, which allow precise phenotyping and a tailored approach based on individual patient profiles, complemented by rhythm monitoring through wearables.

Apnoea-the cessation of breathing-is a common condition in preterm infants due to the immaturity of their lungs, airway and brainstem respiratory drivers. Consequently, many preterm infants will receive pharmacological interventions for the treatment of apnoea. Caffeine (or in some developing countries, aminophylline or theophylline) is usually given as first-line treatment, whereas doxapram is sometimes used as an adjunct therapy. These treatments reduce apnoeas and improve neurodevelopmental outcomes. However, there is substantial variation in individual infants' requirement for treatment (not all infants will experience apnoea nor to the same degree). Moreover, there are considerable differences in how infants respond to treatment, for example, some infants continue to experience episodes of apnoea despite treatment. Clinical guidelines for pharmacological treatment (in particular, for caffeine) are often based on the age or weight of the infant, and there are currently no biomarkers for treatment requirement or dosing. There is a need for personalised treatment for apnoea of prematurity through the identification of suitable pharmacodynamic biomarkers. Here we narratively review current knowledge of the treatment of apnoea, focusing on caffeine, aminophylline and doxapram. We propose potential pharmacodynamic biomarkers and explore avenues for future research which will enable the testing and translation of these biomarkers for use in the neonatal unit. A personalised approach for apnoea treatment is essential to mitigate the negative short and long-term effects of both apnoea and its treatment in premature infants, ensuring that treatment can be provided at the right time and with the correct dose.

Drug-induced hypoxemia can occur with the immobilization of free-living moose (Alces alces). We describe the physiologic response of 12 adult females immobilized with thiafentanil and xylazine and exhibiting clinical signs of hypoxemia before (pretreatment) and after (posttreatment) nasal oxygen supplementation (4 L/min) with or without intravenous doxapram.

TASK-1 is a two-pore K[+] leak channel. The name, TASK-1, stands for TWIK-related acid-sensitive potassium channel 1, and this channel is encoded by the KCNK3 gene. TASK-1 channels are expressed in humans and modulate cell excitability in excitable cells such as neurons, cardiomyocytes, and vascular smooth muscle cells. TASK-1 inhibition is a mechanism of action for some respiratory stimulants, such as doxapram. TASK-1 channels have also been suggested to play a role in circumventing cell apoptosis in a population of non-small-cell lung cancer cells. We propose that the inner vestibule of the TASK-1 channel, a known binding site of known TASK-1 inhibitors, BAY10000493 and BAY2341237, can be exploited via virtual screening to find other novel TASK-1 inhibitors. Our results show that by targeting the inner vestibule site, we found an active TASK-1 inhibitor. We suspect that this region of interest can be further exploited to discover additional TASK-1 inhibitors. Our initial success lends validity to our virtual screening methodology and parameters. In this study, we identified a novel TASK-1 inhibitor, KU124, which we verified using an in vitro assay.

Direct oral anticoagulants (DOACs) reduce the rate of thromboembolism in patients with atrial fibrillation but the benefits and risks in survivors of intracerebral haemorrhage are uncertain. We aimed to determine whether DOACs reduce the risk of ischaemic stroke without substantially increasing the risk of recurrent intracerebral haemorrhage.