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K P Minneman - One of the best experts on this subject based on the ideXlab platform.
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transcriptional responses to growth factor and g protein coupled Receptors in pc12 cells comparison of alpha 1 Adrenergic Receptor subtypes
Journal of Neurochemistry, 2002Co-Authors: K P Minneman, Debbie Lee, Hongying Zhong, Alf Berts, Karen L Abbott, T J MurphyAbstract:Transcriptional responses to growth factor and G protein-coupled Receptors were compared in PC12 cells using retroviral luciferase reporters. In cells stably expressing alpha(1A)-Adrenergic Receptors, norepinephrine activated all five reporters [AP1 (activator protein-1), SRE (serum response element), CRE (cyclic AMP response element), NFkappaB) (nuclear factor-kappaB), and NFAT (nuclear factor of activated T cells)], whereas nerve growth factor (NGF) and epidermal growth factor activated only AP1 and SRE. Activation of P2Y2 Receptors by UTP did not activate any reporters. Protein kinase C inhibition blocked NFkappaB activation by norepinephrine, but potentiated CRE. Mitogen-activated protein kinase kinase inhibition blocked AP1 activation by norepinephrine, but also potentiated CRE. p38 mitogen-activated protein kinase inhibition reduced most norepinephrine responses, but not NGF responses. inhibition of Src eliminated SRE responses to norepinephrine and NGF, and reduced all responses except CRE. Phosphatidylinositol 3-kinase inhibitors markedly potentiated CRE activation by norepinephrine, with only small effects on the other responses. Comparison of the three human subtypes showed that the alpha(1A) activated all five reporters, the alpha(1B) showed smaller effects, and the alpha(1D) was ineffective. Cell differentiation caused by norepinephrine, but not NGF, was reduced by all inhibitors studied. These experiments suggest that alpha(1A)-Adrenergic Receptors activate a wider array of transcriptional responses than do growth factors in PC12 cells. These responses are not linearly related to second messenger production, and different subtypes show different patterns of activation.
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coupling efficiencies of human alpha 1 Adrenergic Receptor subtypes titration of Receptor density and responsiveness with inducible and repressible expression vectors
Molecular Pharmacology, 1996Co-Authors: T L Theroux, T A Esbenshade, R D Peavy, K P MinnemanAbstract:We compared the efficiencies with which human alpha 1-Adrenergic Receptor (AR) subtypes activate inositol phosphate (InsP) formation and increase intracellular Ca2+ in transfected cell lines. Expression of human alpha 1a-, alpha 1b-, and alpha 1d-AR cDNAs under the repressible control of anhydrotetracycline in human embryonic kidney (HEK) 293 cells, which normally express no alpha 1-ARs, was used to compare responses to norepinephrine (NE) at different Receptor densities. Maximal NE-stimulated InsP formation was found to increase with increasing density of each subtype, whereas basal levels and responses to sodium fluoride did not change. A comparison of multiple subclones over equivalent ranges of Receptor expression showed that activation of each subtype resulted in different maximal responses (alpha 1a > alpha 1b > alpha 1d) in HEK 293 cells. Analogous studies were carried out in human SK-N-MC cells, which normally express low levels of all three alpha 1-AR subtypes, using an isopropyl-beta-D-thiogalactoside-inducible expression system. Induction with isopropyl-beta-D-thiogalactoside increased the density of individual alpha 1-AR subtypes by 4-6-fold over the level of endogenous expression. Increased expression of each of these subtypes in SK-N-MC cells did not alter the EC50 value for NE in stimulating InsP formation or releasing [Ca2+]i but did increase maximal responses to NE. Similar to our findings in HEK 293 cells, a comparison of responses at similar expression levels in SK-N-MC cells showed different maximal responses stimulated by each subtype, for both InsP (alpha 1a > alpha 1b > or = alpha 1d) and [Ca2+]i (alpha 1a > alpha 1b > alpha 1d) responses. These studies show that agonist-occupied human alpha 1-AR subtypes have different efficiencies in activating phospholipase C in human cell lines. In both HEK 293 and SK-N-MC cells, alpha 1a-ARs couple most efficiently, whereas alpha 1d-ARs couple very poorly.
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selectivity of agonists for cloned alpha 1 Adrenergic Receptor subtypes
Molecular Pharmacology, 1994Co-Authors: K P Minneman, T L Theroux, S Hollinger, Chide Han, T A EsbenshadeAbstract:The potencies and intrinsic activities of agonists in activating cloned alpha 1-Adrenergic Receptor (AR) subtypes were compared. The hamster alpha 1B-, bovine alpha 1C-, or rat alpha 1A/D-ARs were expressed at high levels in human embryonic kidney 293 cells. Catecholamines and phenylethylamines, but not lower efficacy agonists, were more potent in inhibiting radioligand binding to the expressed alpha 1A/D subtype than to the alpha 1B or alpha 1C subtypes; this selectivity remained in the presence of different buffers, nucleotides, and cations. Activation of all three subtypes caused substantial increases in [3H]inositol phosphate formation in cells grown in 96-well plates. Pretreatment with phenoxybenzamine decreased maximal responses to norepinephrine (NE) with only small decreases in apparent potency, suggesting similar small Receptor reserves for all three subtypes. The catecholamines NE, epinephrine, and 6-fluoro-NE were full agonists with similar potencies at the three subtypes; alpha-methyl-NE was also a full agonist but was about 20-fold less potent at alpha 1B-ARs than at alpha 1C- or alpha 1A/D-ARs. Phenylephrine had similar potencies at all three subtypes but gave a submaximal response at alpha 1B-ARs. Methoxamine was a full agonist at alpha 1C- and alpha 1A/D-ARs, with about 20-fold greater potency at the alpha 1C subtype, but showed lower intrinsic activity at alpha 1B-ARs. A number of imidazolines, amidephrine, and SKF 89748 had substantial intrinsic activity at alpha 1C-ARs but little or no intrinsic activity at the other two subtypes. We conclude that the potencies of many agonists in competing for radioligand binding sites are related to their potencies in activating functional responses but that this relationship is not the same for all subtypes. NE and epinephrine activate all three cloned alpha 1-AR subtypes with similar potencies and intrinsic activities, but many widely used agonists show significant selectivity for different alpha 1-AR subtypes.
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alpha 1 Adrenergic Receptor subtypes
Annual Review of Pharmacology and Toxicology, 1994Co-Authors: K P Minneman, T A EsbenshadeAbstract:Investigators have not yet reached a consensus on the number and signaling mechanisms of alpha 1-Adrenergic Receptor (AR) subtypes. Two native subtypes (alpha 1A and alpha 1B) can be distinguished pharmacologically, and three subtypes (alpha 1B, alpha 1C, and alpha 1D) have been cloned. One of the cloned subtypes (alpha 1D) was originally thought to encode the pharmacologically defined alpha 1A subtype. However, recent data suggest otherwise, and many investigators now agree that the alpha 1A subtype has probably not yet been cloned. The relationship between the cloned Receptors and the native subtypes must be understood, and any additional cDNA clones obtained, before the drug specificities and second messenger pathways of alpha 1-AR subtypes can be clearly defined. Little is yet known about the cellular and tissue distribution of these subtypes, their developmental profiles, or their functional importance. Molecular cloning of complementary DNA sequences for the remaining subtypes will help to clarify the number and properties of these subtypes. Identification of drugs that can selectively target particular subtypes is an important goal that may result in therapeutic advances in numerous disease states, including benign prostatic hyperplasia. The newly recognized complexity of the Adrenergic Receptors presents us with both important challenges and new therapeutic targets. The potential impact of this field on medical therapeutics remains to be clearly defined.
Paul C Simpson - One of the best experts on this subject based on the ideXlab platform.
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the alpha 1d is the predominant alpha 1 Adrenergic Receptor subtype in human epicardial coronary arteries
Journal of the American College of Cardiology, 2009Co-Authors: Brian C Jensen, Philip M Swigart, Marie Eve Laden, Teresa Demarco, Charles W Hoopes, Paul C SimpsonAbstract:Objectives The goal was to identify Alpha-1-Adrenergic Receptor (AR) subtypes in human coronary arteries. Background The α1-ARs regulate human coronary blood flow. The α1-ARs exist as 3 molecular subtypes, α1A, α1B, and α1D, and the α1D subtype mediates coronary vasoconstriction in the mouse. However, the α1A is thought to be the only subtype in human coronary arteries. Methods We obtained human epicardial coronary arteries and left ventricular (LV) myocardium from 19 transplant recipients and 6 unused donors (age 19 to 70 years; 68% male; 32% with coronary artery disease). We cultured coronary rings and human coronary smooth muscle cells. We assayed α1- and β-AR subtype messenger ribonucleic acid (mRNA) by quantitative real-time reverse transcription polymerase chain reaction and subtype proteins by radioligand binding and extracellular signal-regulated kinase (ERK) activation. Results The α1D subtype was 85% of total coronary α1-AR mRNA and 75% of total α1-AR protein, and α1D stimulation activated ERK. In contrast, the α1D was low in LV myocardium. Total coronary α1-AR levels were one-third of β-ARs, which were 99% the β2 subtype. Conclusions The α1D subtype is predominant and functional in human epicardial coronary arteries, whereas the α1A and α1B are present at very low levels. This distribution is similar to the mouse, where myocardial α1A- and α1B-ARs mediate beneficial functional responses and coronary α1Ds mediate vasoconstriction. Thus, α1D-selective antagonists might mediate coronary vasodilation, without the negative cardiac effects of nonselective α1-AR antagonists in current use. Furthermore, it could be possible to selectively activate beneficial myocardial α1A- and/or α1B-AR signaling without causing coronary vasoconstriction.
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ten commercial antibodies for alpha 1 Adrenergic Receptor subtypes are nonspecific
Naunyn-schmiedebergs Archives of Pharmacology, 2009Co-Authors: Brian C Jensen, Philip M Swigart, Paul C SimpsonAbstract:Commercial antibodies are used widely to quantify and localize the α1-Adrenergic Receptor (AR) subtypes, α1A, α1B, and α1D. We tested ten antibodies, from abcam and Santa Cruz, using western blot with heart and brain tissue from wild-type (WT) mice and mice with systemic knockout (KO) of one or all three subtypes. We found that none of the antibodies detected a band in WT that was absent in the appropriate KO or in the KO that was null for all α1-ARs (ABDKO). We conclude that the antibodies we tested are not specific for α1-ARs. These results raise caution with prior studies using these reagents. For now, competition radioligand binding is the only reliable approach to quantify the α1-AR subtype proteins. Receptor protein localization remains a challenge.
T A Esbenshade - One of the best experts on this subject based on the ideXlab platform.
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coupling efficiencies of human alpha 1 Adrenergic Receptor subtypes titration of Receptor density and responsiveness with inducible and repressible expression vectors
Molecular Pharmacology, 1996Co-Authors: T L Theroux, T A Esbenshade, R D Peavy, K P MinnemanAbstract:We compared the efficiencies with which human alpha 1-Adrenergic Receptor (AR) subtypes activate inositol phosphate (InsP) formation and increase intracellular Ca2+ in transfected cell lines. Expression of human alpha 1a-, alpha 1b-, and alpha 1d-AR cDNAs under the repressible control of anhydrotetracycline in human embryonic kidney (HEK) 293 cells, which normally express no alpha 1-ARs, was used to compare responses to norepinephrine (NE) at different Receptor densities. Maximal NE-stimulated InsP formation was found to increase with increasing density of each subtype, whereas basal levels and responses to sodium fluoride did not change. A comparison of multiple subclones over equivalent ranges of Receptor expression showed that activation of each subtype resulted in different maximal responses (alpha 1a > alpha 1b > alpha 1d) in HEK 293 cells. Analogous studies were carried out in human SK-N-MC cells, which normally express low levels of all three alpha 1-AR subtypes, using an isopropyl-beta-D-thiogalactoside-inducible expression system. Induction with isopropyl-beta-D-thiogalactoside increased the density of individual alpha 1-AR subtypes by 4-6-fold over the level of endogenous expression. Increased expression of each of these subtypes in SK-N-MC cells did not alter the EC50 value for NE in stimulating InsP formation or releasing [Ca2+]i but did increase maximal responses to NE. Similar to our findings in HEK 293 cells, a comparison of responses at similar expression levels in SK-N-MC cells showed different maximal responses stimulated by each subtype, for both InsP (alpha 1a > alpha 1b > or = alpha 1d) and [Ca2+]i (alpha 1a > alpha 1b > alpha 1d) responses. These studies show that agonist-occupied human alpha 1-AR subtypes have different efficiencies in activating phospholipase C in human cell lines. In both HEK 293 and SK-N-MC cells, alpha 1a-ARs couple most efficiently, whereas alpha 1d-ARs couple very poorly.
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selectivity of agonists for cloned alpha 1 Adrenergic Receptor subtypes
Molecular Pharmacology, 1994Co-Authors: K P Minneman, T L Theroux, S Hollinger, Chide Han, T A EsbenshadeAbstract:The potencies and intrinsic activities of agonists in activating cloned alpha 1-Adrenergic Receptor (AR) subtypes were compared. The hamster alpha 1B-, bovine alpha 1C-, or rat alpha 1A/D-ARs were expressed at high levels in human embryonic kidney 293 cells. Catecholamines and phenylethylamines, but not lower efficacy agonists, were more potent in inhibiting radioligand binding to the expressed alpha 1A/D subtype than to the alpha 1B or alpha 1C subtypes; this selectivity remained in the presence of different buffers, nucleotides, and cations. Activation of all three subtypes caused substantial increases in [3H]inositol phosphate formation in cells grown in 96-well plates. Pretreatment with phenoxybenzamine decreased maximal responses to norepinephrine (NE) with only small decreases in apparent potency, suggesting similar small Receptor reserves for all three subtypes. The catecholamines NE, epinephrine, and 6-fluoro-NE were full agonists with similar potencies at the three subtypes; alpha-methyl-NE was also a full agonist but was about 20-fold less potent at alpha 1B-ARs than at alpha 1C- or alpha 1A/D-ARs. Phenylephrine had similar potencies at all three subtypes but gave a submaximal response at alpha 1B-ARs. Methoxamine was a full agonist at alpha 1C- and alpha 1A/D-ARs, with about 20-fold greater potency at the alpha 1C subtype, but showed lower intrinsic activity at alpha 1B-ARs. A number of imidazolines, amidephrine, and SKF 89748 had substantial intrinsic activity at alpha 1C-ARs but little or no intrinsic activity at the other two subtypes. We conclude that the potencies of many agonists in competing for radioligand binding sites are related to their potencies in activating functional responses but that this relationship is not the same for all subtypes. NE and epinephrine activate all three cloned alpha 1-AR subtypes with similar potencies and intrinsic activities, but many widely used agonists show significant selectivity for different alpha 1-AR subtypes.
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alpha 1 Adrenergic Receptor subtypes
Annual Review of Pharmacology and Toxicology, 1994Co-Authors: K P Minneman, T A EsbenshadeAbstract:Investigators have not yet reached a consensus on the number and signaling mechanisms of alpha 1-Adrenergic Receptor (AR) subtypes. Two native subtypes (alpha 1A and alpha 1B) can be distinguished pharmacologically, and three subtypes (alpha 1B, alpha 1C, and alpha 1D) have been cloned. One of the cloned subtypes (alpha 1D) was originally thought to encode the pharmacologically defined alpha 1A subtype. However, recent data suggest otherwise, and many investigators now agree that the alpha 1A subtype has probably not yet been cloned. The relationship between the cloned Receptors and the native subtypes must be understood, and any additional cDNA clones obtained, before the drug specificities and second messenger pathways of alpha 1-AR subtypes can be clearly defined. Little is yet known about the cellular and tissue distribution of these subtypes, their developmental profiles, or their functional importance. Molecular cloning of complementary DNA sequences for the remaining subtypes will help to clarify the number and properties of these subtypes. Identification of drugs that can selectively target particular subtypes is an important goal that may result in therapeutic advances in numerous disease states, including benign prostatic hyperplasia. The newly recognized complexity of the Adrenergic Receptors presents us with both important challenges and new therapeutic targets. The potential impact of this field on medical therapeutics remains to be clearly defined.
Juan Jesus Carrero - One of the best experts on this subject based on the ideXlab platform.
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alpha 1 Adrenergic Receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection
eLife, 2021Co-Authors: Allison Koenecke, Michael Powell, Nicole Fischer, Sakibul Huq, Adham M Khalafallah, Ruoxuan Xiong, Zhu Shen, Marco Trevisan, Par Sparen, Juan Jesus CarreroAbstract:In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by hyperinflammation, which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that Alpha-1 Adrenergic Receptor (⍺1-AR) antagonists can prevent hyperinflammation and death in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n = 18,547) and three cohorts with pneumonia (n = 400,907). Federated across two ARD cohorts, we find that patients exposed to ⍺1-AR antagonists, as compared to unexposed patients, had a 34% relative risk reduction for mechanical ventilation and death (OR = 0.70, p = 0.021). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of ⍺1-AR antagonists ameliorates lower respiratory tract infection-associated hyperinflammation and death, as observed in COVID-19.
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alpha 1 Adrenergic Receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection
arXiv: Tissues and Organs, 2020Co-Authors: Allison Koenecke, Michael Powell, Nicole Fischer, Sakibul Huq, Adham M Khalafallah, Ruoxuan Xiong, Zhu Shen, Marco Trevisan, Par Sparen, Juan Jesus CarreroAbstract:In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by hyperinflammation, which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that Alpha-1 Adrenergic Receptor ($\alpha_1$-AR) antagonists can prevent hyperinflammation (cytokine storm syndrome) in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n=18,547) and three cohorts with pneumonia (n=400,907). Federated across two ARD cohorts, we find that patients exposed to $\alpha_1$-AR antagonists, as compared to unexposed patients, had a 34% relative risk reduction for mechanical ventilation and death (OR=0.70, p=0.021). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of $\alpha_1$-AR antagonists ameliorates lower respiratory tract infection-associated cytokine storm syndrome, as observed in COVID-19.
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alpha 1 Adrenergic Receptor antagonists to prevent acute respiratory distress syndrome and death from cytokine storm syndrome
arXiv: Tissues and Organs, 2020Co-Authors: Allison Koenecke, Michael Powell, Nicole Fischer, Sakibul Huq, Adham M Khalafallah, Ruoxuan Xiong, Zhu Shen, Marco Trevisan, Par Sparen, Juan Jesus CarreroAbstract:In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by hyperinflammation ('cytokine storm syndrome'), which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that Alpha-1 Adrenergic Receptor ($\alpha_1$-AR) antagonists can prevent cytokine storm syndrome in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n=19,659) and three cohorts with pneumonia (n=423,897). Federated across two ARD cohorts, our main result shows that patients using $\alpha_1$-AR antagonists, as compared to nonusers, had a 40% relative risk reduction for ventilation and dying (p=0.014). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to various sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of $\alpha_1$-AR antagonists ameliorates diseases associated with cytokine storm syndrome, such as COVID-19.
Allison Koenecke - One of the best experts on this subject based on the ideXlab platform.
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alpha 1 Adrenergic Receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection
eLife, 2021Co-Authors: Allison Koenecke, Michael Powell, Nicole Fischer, Sakibul Huq, Adham M Khalafallah, Ruoxuan Xiong, Zhu Shen, Marco Trevisan, Par Sparen, Juan Jesus CarreroAbstract:In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by hyperinflammation, which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that Alpha-1 Adrenergic Receptor (⍺1-AR) antagonists can prevent hyperinflammation and death in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n = 18,547) and three cohorts with pneumonia (n = 400,907). Federated across two ARD cohorts, we find that patients exposed to ⍺1-AR antagonists, as compared to unexposed patients, had a 34% relative risk reduction for mechanical ventilation and death (OR = 0.70, p = 0.021). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of ⍺1-AR antagonists ameliorates lower respiratory tract infection-associated hyperinflammation and death, as observed in COVID-19.
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the association between alpha 1 Adrenergic Receptor antagonists and in hospital mortality from covid 19
medRxiv, 2020Co-Authors: Liam Rose, Michael Powell, Allison Koenecke, Ruoxuan Xiong, Zhu Shen, Kenneth W Kinzler, Laura A Graham, Chetan Bettegowda, Bert VogelsteinAbstract:Effective therapies for coronavirus disease 2019 (COVID-19) are urgently needed, and preclinical data suggest Alpha-1 Adrenergic Receptor antagonists (α 1 -AR antagonists) may be effective in reducing mortality related to hyperinflammation. Using a retrospective cohort design with patients in the Department of Veterans Affairs healthcare system, we use doubly robust regression and matching to estimate the association between use of α 1 -AR antagonists at time of hospitalization and likelihood of death due to COVID-19 during an inpatient stay. Having an active prescription for an α 1 -AR antagonist (tamsulosin, silodosin, prazosin, terazosin, doxazosin, or alfuzosin) at the time of admission had a significant negative association with in-hospital mortality (relative risk reduction 14%; odds ratio 0.75; 95% CI 0.66 to 0.86; p ≤ 0.001). These effects were also found in an expanded cohort of suspected COVID-19 patients, supporting the need for clinical trials.
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alpha 1 Adrenergic Receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection
arXiv: Tissues and Organs, 2020Co-Authors: Allison Koenecke, Michael Powell, Nicole Fischer, Sakibul Huq, Adham M Khalafallah, Ruoxuan Xiong, Zhu Shen, Marco Trevisan, Par Sparen, Juan Jesus CarreroAbstract:In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by hyperinflammation, which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that Alpha-1 Adrenergic Receptor ($\alpha_1$-AR) antagonists can prevent hyperinflammation (cytokine storm syndrome) in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n=18,547) and three cohorts with pneumonia (n=400,907). Federated across two ARD cohorts, we find that patients exposed to $\alpha_1$-AR antagonists, as compared to unexposed patients, had a 34% relative risk reduction for mechanical ventilation and death (OR=0.70, p=0.021). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of $\alpha_1$-AR antagonists ameliorates lower respiratory tract infection-associated cytokine storm syndrome, as observed in COVID-19.
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alpha 1 Adrenergic Receptor antagonists to prevent acute respiratory distress syndrome and death from cytokine storm syndrome
arXiv: Tissues and Organs, 2020Co-Authors: Allison Koenecke, Michael Powell, Nicole Fischer, Sakibul Huq, Adham M Khalafallah, Ruoxuan Xiong, Zhu Shen, Marco Trevisan, Par Sparen, Juan Jesus CarreroAbstract:In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by hyperinflammation ('cytokine storm syndrome'), which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that Alpha-1 Adrenergic Receptor ($\alpha_1$-AR) antagonists can prevent cytokine storm syndrome in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n=19,659) and three cohorts with pneumonia (n=423,897). Federated across two ARD cohorts, our main result shows that patients using $\alpha_1$-AR antagonists, as compared to nonusers, had a 40% relative risk reduction for ventilation and dying (p=0.014). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to various sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of $\alpha_1$-AR antagonists ameliorates diseases associated with cytokine storm syndrome, such as COVID-19.
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alpha 1 Adrenergic Receptor antagonists for preventing acute respiratory distress syndrome and death from cytokine storm syndrome
Unknown Journal, 2020Co-Authors: Joshua T Vogelstein, Michael Powell, Nicole Fischer, Sakibul Huq, Adham M Khalafallah, Allison Koenecke, Ruoxuan Xiong, Brian S Caffo, Elizabeth A Stuart, Nickolas PapadopoulosAbstract:In severe viral pneumonias, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by a hyperinflammatory reaction ('cytokine storm syndrome') that leads to acute respiratory distress syndrome and death, despite maximal supportive care Preventing hyperinflammation is key to avoiding these outcomes We previously demonstrated that Alpha-1 Adrenergic Receptor antagonists ($\alpha$-blockers) can prevent cytokine storm syndrome and death in mice Here, we conduct a retrospective analysis of patients with acute respiratory distress or pneumonia (n = 13,125 and n = 108,956, respectively) from all causes;patients who were incidentally taking $\alpha$-blockers had a reduced risk of requiring ventilation (by 35% and 16%, respectively), and a reduced risk of being ventilated and dying (by 56% and 20%, respectively), compared to non-users Beta-Adrenergic Receptor antagonists had no significant effects These results highlight the urgent need for prospective trials testing whether prophylactic $\alpha$-blockers improve outcomes in diseases with a prominent hyperinflammatory component such as COVID-19