Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Alpha Adrenergic Induction of Transport of Lysosomal Enzyme across the Blood-Brain Barrier.

The impermeability of the adult blood-brain barrier (BBB) to lysosomal enzymes impedes the ability to treat the central nervous system manifestations of lysosomal storage diseases. Here, we found that simultaneous stimulation of the alpha1 and alpha2 adrenoreceptor restores in adult mice the high rate of transport for the lysosomal enzyme P-GUS that is seen in neonates but lost with development. Beta adrenergics, other monoamines, and acetylcholine did not restore this transport. A high dose (500 microg/mouse) of clonidine, a strong alpha2 and weak alpha1 agonist, was able to act as monotherapy in the stimulation of P-GUS transport. Neither use of alpha1 plus alpha2 agonists nor the high dose clonidine disrupted the BBB to albumin. In situ brain perfusion and immunohistochemistry studies indicated that adrengerics act on transporters already at the luminal surface of brain endothelial cells. These results show that adrenergic stimulation, including monotherapy with clonidine, could be key for CNS enzyme replacement therapy

Supplemental Material - Predicting opioid use disorder before and after the opioid prescribing peak in the United States: A machine learning tool using electronic healthcare records

Supplemental Material for Predicting Opioid Use Disorder before and after the Opioid Prescribing Peak in the United States: A Machine Learning Tool using Electronic Healthcare Records by Tyler J. Banks, Jeffrey F. Scherrer, Tung D. Nguyen, Jeffery K. Uhlmann, and Satish S. Nair in Health Informatics Journal</p

Combined effect of alpha1 (cirazoline) and alpha2 (clonidine) adrenergic receptor agonists on I-PGUS transport across the BBB.

<p>Neither drug alone affected I-PGUS uptake, but combined they effectively increased transport across the BBB. ***p<0.001 in comparison to control; n = 12/group.</p

Blood-brain barrier disruption and brain pharmacokinetics of PGUS at two doses of epinephrine.

<p>(A) shows that the 120 nmol/mouse dose of epinephrine decreased the vascular space of I-Alb. (B) shows that neither dose disrupted the BBB. (C) shows that both doses reduced vascular space of I-PGUS and that the 120 nmol/mouse dose also slowed clearance from blood. (D) shows that I-PGUS did not cross the BBB, but that both doses of epinephrine induced transport of I-PGUS across the BBB. n = 7/group.</p

Expression of M6P receptor on nonpermeablized primary monolayer cultures of mouse brain endothelial cells.

<p>Receptor was detected on cells not treated with epinephrine and treatment did not enhance intensity of staining.</p

Effect of monoamines and acetylcholine on I-PGUS uptake.

<p><b>Only epinephrine enhanced BBB penetration.</b> **P<0.01; n = 7-10/group.</p