Topical Potassium Channel Blockage Improves Pharyngeal Collapsibility: A Translational, Placebo-Controlled Trial.

BACKGROUND: Potassium (K+) channel inhibition has been identified in animal models as a potential target to increase pharyngeal dilator muscle activity and to treat OSA. However, these findings have not yet been translated to humans. RESEARCH QUESTION: Does a novel, potent, tandem of P domains in a weak inward rectifying K+ channel (TWIK)-related acid-sensitive K+ (TASK) 1/3 channel antagonist, BAY2586116, improve pharyngeal collapsibility in pigs and humans, and secondarily, what is the optimal dose and method of topical application? STUDY DESIGN AND METHODS: In the preclinical study, pharyngeal muscle activity and upper-airway collapsibility via transient negative pressure application was quantified in 13 anesthetized pigs during administration of placebo, 0.3 µg, 3 µg, and 30 µg nasal drops of BAY2586116. In the clinical study, 12 people with OSA instrumented with polysomnography equipment, an epiglottic pressure catheter, pneumotachograph, and nasal mask to monitor sleep and breathing performed up to four detailed upper airway sleep physiology studies. Participants received BAY2586116 (160 µg) or placebo nasal spray before sleep via a double-masked, randomized, crossover design. Most participants also returned for three additional overnight visits: (1) nasal drops (160 µg), (2) half-dose nasal spray (80 µg), and (3) direct endoscopic application (160 µg). The upper-airway critical closing pressure (Pcrit) during sleep was quantified at each visit. RESULTS: Consistent and sustained improvements in pharyngeal collapsibility to negative pressure were found with 3 and 30 µg of BAY2586116 vs placebo in pigs. Similarly, BAY2586116 improved pharyngeal collapsibility by an average of approximately 2 cm H2O vs placebo, regardless of topical application method and dose (P < .008, mixed model) in participants with OSA. INTERPRETATION: Acute topical application of BAY2586116 improves upper-airway collapsibility in anesthetized pigs and sleeping humans with OSA. These novel physiologic findings highlight the therapeutic potential to target potassium channel mechanisms to treat OSA. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04236440; URL: www. CLINICALTRIALS: gov.

Antitumor effects of regorafenib and sorafenib in preclinical models of hepatocellular carcinoma.

The purpose of this study was to investigate the antitumor activity of regorafenib and sorafenib in preclinical models of HCC and to assess their mechanism of action by associated changes in protein expression in a HCC-PDX mouse model. Both drugs were administered orally once daily at 10 mg/kg (regorafenib) or 30 mg/kg (sorafenib), which recapitulate the human exposure at the maximally tolerated dose in mice. In a H129 hepatoma model, survival times differed significantly between regorafenib versus vehicle (p=0.0269; median survival times 36 vs 27 days), but not between sorafenib versus vehicle (p=0.1961; 33 vs 28 days). Effects on tumor growth were assessed in 10 patient-derived HCC xenograft (HCC-PDX) models. Significant tumor growth inhibition was observed in 8/10 models with regorafenib and 7/10 with sorafenib; in four models, superior response was observed with regorafenib versus sorafenib which was deemed not to be due to lower sorafenib exposure. Bead-based multiplex western blot analysis was performed with total protein lysates from drug- and vehicle-treated HCC-PDX xenografts. Protein expression was substantially different in regorafenib- and sorafenib-treated samples compared with vehicle. The pattern of upregulated proteins was similar with both drugs and indicates an activated RAF/MEK/ERK pathway, but more proteins were downregulated with sorafenib versus regorafenib. Overall, both regorafenib and sorafenib were effective in mouse models of HCC, although several cases showed better regorafenib activity which may explain the observed efficacy of regorafenib in sorafenib-refractory patients.

What tendon pathology is seen on imaging in people who have taken fluoroquinolones? A systematic review.

Fluoroquinolones (FQs) are highly effective broad-spectrum antibiotics. Clinical data reveal an increased incidence of tendon pain and rupture in those taking FQs, yet little is known about tendon structural changes. This review synthesises published data on tendon structural changes in people who have taken FQs. Eight databases were searched for potentially relevant articles (Medline, CINAHL, Biological Abstracts, AMED, Web of Knowledge, SCOPUS, SportDiscus and EMBASE) using MeSH and free-text searches. Inclusion and exclusion criteria determined which articles were used for this review. Twenty-six papers met the eligibility criteria. The Achilles tendon was most commonly affected, and ciprofloxacin and levofloxacin were the most commonly implicated FQs. Mean time to onset of symptoms was 16 days following first FQ dose. Imaging modalities used included magnetic resonance imaging (MRI), B-mode ultrasound (US) and computed tomography (CT). Tendon measurements were rarely reported, and intratendinous imaging findings were not reported in a consistent manner. Few studies imaged tendons bilaterally, and only two studies were longitudinal in design. Future studies should report imaging measures such as thickness and cross-sectional area and use consistent descriptions of intratendinous changes during and post-FQ treatment.

Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based in Vivo Probe (BAY-598) for the Protein Lysine Methyltransferase SMYD2.

Protein lysine methyltransferases have recently emerged as a new target class for the development of inhibitors that modulate gene transcription or signaling pathways. SET and MYND domain containing protein 2 (SMYD2) is a catalytic SET domain containing methyltransferase reported to monomethylate lysine residues on histone and nonhistone proteins. Although several studies have uncovered an important role of SMYD2 in promoting cancer by protein methylation, the biology of SMYD2 is far from being fully understood. Utilization of highly potent and selective chemical probes for target validation has emerged as a concept which circumvents possible limitations of knockdown experiments and, in particular, could result in an improved exploration of drug targets with a complex underlying biology. Here, we report the development of a potent, selective, and cell-active, substrate-competitive inhibitor of SMYD2, which is the first reported inhibitor suitable for in vivo target validation studies in rodents.