Limited neuromuscular input results in muscle weakness in neuromuscular disease either because of a reduction in the density of muscle innervation, the rate of neuromuscular junction activation or the efficiency of synaptic transmission1. We developed a small molecule fast skeletal troponin activator, CK-2017357, as a means to increase muscle strength by amplifying the response of muscle when neuromuscular input is diminished secondary to a neuromuscular disease. Binding selectively to the fast skeletal troponin complex, CK-2017357 slows the rate of calcium release from troponin C and sensitizes muscle to calcium. As a consequence, the force-calcium relationship of muscle fibers shifts leftwards as does the force-frequency relationship of a nerve-muscle pair. In vitro and in vivo, CK-2017357 increases the production of force at sub-maximal stimulation rates. Importantly, we show that sensitization of the fast skeletal troponin complex to calcium improves muscle force and grip strength immediately after single doses of CK-2017357 in a model of neuromuscular disease, myasthenia gravis. Troponin activation may provide a new therapeutic approach to improve physical activity in diseases where neuromuscular function is compromised.
The
identification and optimization of the first activators of
fast skeletal muscle are reported. Compound 1 was identified
from high-throughput screening (HTS) and subsequently found to improve
muscle function via interaction with the troponin complex. Optimization
of 1 for potency, metabolic stability, and physical properties
led to the discovery of tirasemtiv (25), which has been
extensively characterized in clinical trials for the treatment of
amyotrophic lateral sclerosis.
Objective
To highlight the role of interventional radiology (IR) in the treatment of patients hospitalized with coronavirus disease 2019 (COVID-19).
Methods
Retrospective review of hospitalized patients who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and had one or more IR procedures at a tertiary referral hospital in New York City during a 6-week period in April and May of 2020.
Results
Of the 724 patients admitted with COVID-19, 92 (12.7%) underwent 124 interventional radiology procedures (79.8% in IR suite, 20.2% at bedside). The median age of IR patients was 63 years (range 24–86 years); 39.1% were female; 35.9% in the intensive care unit. The most commonly performed IR procedures were central venous catheter placement (31.5%), inferior vena cava filter placement (9.7%), angiography/embolization (4.8%), gastrostomy tube placement (9.7%), image-guided biopsy (10.5%), abscess drainage (9.7%), and cholecystostomy tube placement (6.5%). Thoracentesis/chest tube placement and nephrostomy tube placement were also performed as well as catheter-directed thrombolysis of massive pulmonary embolism and thrombectomy of deep vein thrombosis. General anesthesia (10.5%), monitored anesthesia care (18.5%), moderate sedation (29.8%), or local anesthetic (41.1%) was utilized. There were 3 (2.4%) minor complications (SIR adverse event class B), 1 (0.8%) major complication (class C), and no procedure-related death. With a median follow-up of 4.3 months, 1.1% of patients remain hospitalized, 16.3% died, and 82.6% were discharged.
Conclusion
Interventional radiology participated in the care of hospitalized COVID-19 patients by performing a wide variety of necessary procedures.
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