2 research outputs found
Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19)
The SARS-CoV-2 virus spreading across the world has led to surges of COVID-19 illness, hospitalizations, and
death. The complex and multifaceted pathophysiology of life-threatening COVID-19 illness including viral mediated
organ damage, cytokine storm, and thrombosis warrants early interventions to address all components of the devastating
illness. In countries where therapeutic nihilism is prevalent, patients endure escalating symptoms and without
early treatment can succumb to delayed in-hospital
care and death. Prompt early initiation of sequenced multidrug
therapy (SMDT) is a widely and currently available
solution to stem the tide of hospitalizations and death. A
multipronged therapeutic approach includes 1) adjuvant
nutraceuticals, 2) combination intracellular anti-infective
therapy, 3) inhaled/oral corticosteroids, 4) antiplatelet
agents/anticoagulants, 5) supportive care including supplemental
oxygen, monitoring, and telemedicine. Randomized
trials of individual, novel oral therapies have not
delivered tools for physicians to combat the pandemic in
practice. No single therapeutic option thus far has been
entirely effective and therefore a combination is required
at this time. An urgent immediate pivot from single drug to
SMDT regimens should be employed as a critical strategy
to deal with the large numbers of acute COVID-19 patients
with the aim of reducing the intensity and duration
of symptoms and avoiding hospitalization and death
Sphingosine kinase modulates microvascular tone and myogenic responses through activation of Rhoa/Rho kinase
Background - RhoA and Rho kinase are important modulators of microvascular tone. Methods and Results - We tested whether sphingosine kinase (Sphk1) that generates the endogenous sphingolipid mediator sphingosine-1-phosphate (S1P) is part of a signaling cascade to activate the RhoA/Rho kinase pathway. Using a new transfection model, we report that resting tone and myogenic responses of isolated resistance arteries increased with forced expression of Sphk1 in smooth muscle cells of these arteries. Overexpression of a dominant negative Sphk1 mutant or coexpression of dominant negative mutants of RhoA or Rho kinase together with Sphk1 completely inhibited development of tone and myogenic responses. Conclusions - The tone-increasing effects of a Sphk1 overexpression suggest that Sphk1 may play an important role in the control of peripheral resistance