Drug treatments for covid-19: living systematic review and network meta-analysis

BMJ, Journal Year: 2020, Volume and Issue: unknown, P. m2980 - m2980

Published: July 30, 2020

To compare the effects of treatments for coronavirus disease 2019 (covid-19). Living systematic review and network meta-analysis. WHO covid-19 database, a comprehensive multilingual source global literature, up to 3 December 2021 six additional Chinese databases 20 February 2021. Studies identified as 1 were included in analysis. Randomised clinical trials which people with suspected, probable, or confirmed randomised drug treatment standard care placebo. Pairs reviewers independently screened potentially eligible articles. After duplicate data abstraction, bayesian meta-analysis was conducted. Risk bias studies assessed using modification Cochrane risk 2.0 tool, certainty evidence grading recommendations assessment, development, evaluation (GRADE) approach. For each outcome, interventions classified groups from most least beneficial harmful following GRADE guidance. 463 enrolling 166 581 patients included; 267 (57.7%) 89 814 (53.9%) are new previous iteration; 265 (57.2%) evaluating at 100 events met threshold inclusion analyses. Compared care, three drugs reduced mortality mostly severe moderate certainty: systemic corticosteroids (risk difference 23 fewer per 1000 patients, 95% credible interval 40 7 fewer, certainty), interleukin-6 receptor antagonists when given (23 1000, 36 Janus kinase inhibitors (44 64 high certainty). two probably reduce hospital admission non-severe disease: nirmatrelvir/ritonavir (36 41 26 certainty) molnupiravir (19 29 5 Remdesivir may (29 6 low Only had quality reduction time symptom resolution (3.3 days 4.8 1.6 certainty); several others showed possible benefit. Several increase adverse leading discontinuation; hydroxychloroquine increases mechanical ventilation (moderate Corticosteroids, antagonists, confer other important benefits covid-19. Molnupiravir This not registered. The protocol is publicly available supplementary material. article living that will be updated reflect emerging evidence. Updates occur years date original publication. fifth version published on 30 July 2020 (BMJ 2020;370:m2980), versions can found supplements. When citing this paper please consider adding number access clarity.

Language: Английский

---

The roles of calcium and ATP in the physiology and pathology of the exocrine pancreas

Physiological Reviews, Journal Year: 2021, Volume and Issue: 101(4), P. 1691 - 1744

Published: May 5, 2021

This review deals with the roles of calcium ions and ATP in control normal functions different cell types exocrine pancreas as well these molecules pathophysiology acute pancreatitis. Repetitive rises local cytosolic ion concentration apical part acinar cells not only activate exocytosis but also, via an increase intramitochondrial concentration, stimulate formation that is needed to fuel energy-requiring secretion process. However, intracellular overload, resulting a global sustained elevation has opposite effect decreasing mitochondrial production, this initiates processes lead necrosis. In last few years it become possible image signaling events simultaneously acinar, stellate, immune intact lobules pancreas. disclosed by which interact each other, particularly relation initiation development By unraveling molecular mechanisms underlying disease, several promising therapeutic intervention sites have been identified. provides hope we may soon be able effectively treat often fatal disease.

Language: Английский

---

Orai1 Inhibitors as Potential Treatments for Pulmonary Arterial Hypertension

Circulation Research, Journal Year: 2022, Volume and Issue: 131(9)

Published: Sept. 27, 2022

Background: Pulmonary arterial hypertension (PAH) is characterized by progressive distal pulmonary artery (PA) obstruction, leading to right ventricular hypertrophy and failure. Exacerbated intracellular calcium (Ca 2+ ) signaling contributes abnormalities in PA smooth muscle cells (PASMCs), including aberrant proliferation, apoptosis resistance, exacerbated migration, contractility. Store-operated Ca entry involved homeostasis PASMCs, but its properties PAH are unclear. Methods: Using a combination of imaging, molecular biology, vitro, ex vivo, vivo approaches, we investigated the roles Orai1 SOC channel remodeling determined consequences pharmacological inhibition using experimental models (PH). Results: mRNA protein were increased human PASMCs (hPASMCs) from patients with (PAH-hPASMCs). We found that MEK1/2 (mitogen-activated kinase 1/2), NFAT (nuclear factor activated T cells), NFκB factor-kappa B) contribute upregulation expression PAH-hPASMCs. small interfering RNA (siRNA) inhibitors, reduced store-operated entry, mitochondrial uptake, excessive calcineurin activity inhibitors agonist-evoked constriction PAs. In rat PH evoked chronic hypoxia, monocrotaline, or Sugen/hypoxia, administration (N-{4-[3,5-bis(Trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-4-methyl-1,2,3-thiadiazole-5-carboxamide [BTP2], 4-(2,5-dimethoxyphenyl)-N-[(pyridin-4-yl)methyl]aniline [JPIII], 5J4) protected against PH. Conclusions: PH, increased. normalizes PAH-hPASMCs phenotype attenuates models. These results suggest should be considered as relevant therapeutic target for PAH.

Language: Английский

---

Calcium Signals during SARS-CoV-2 Infection: Assessing the Potential of Emerging Therapies

Cells, Journal Year: 2022, Volume and Issue: 11(2), P. 253 - 253

Published: Jan. 12, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense single-stranded RNA virus that causes disease 2019 (COVID-19). This illness was declared pandemic by the world health organization (WHO) in March 2020, just few weeks after being described for first time. Since then, global research effort has considerably increased humanity’s knowledge about both viruses and disease. It also spawned several vaccines have proven to be key tools attenuating spread of severity COVID-19. However, with vaccine-related skepticism on rise, as well breakthrough infections vaccinated population threat complete immune escape variant, alternative strategies fight against SARS-CoV-2 are urgently required. Calcium signals long been known play an essential role infection diverse thus constitute promising avenue further therapeutic strategies. In this review, we introduce pivotal calcium signaling viral cascades. Based this, discuss prospective calcium-related treatment targets cure COVID-19 exploit dependence signals.

Language: Английский

---

Regulation of neuropathic pain by microglial Orai1 channels

Science Advances, Journal Year: 2023, Volume and Issue: 9(4)

Published: Jan. 27, 2023

Microglia are important mediators of neuroinflammation, which underlies neuropathic pain. However, the molecular checkpoints controlling microglial reactivity not well-understood. Here, we investigated role Orai1 channels for microglia-mediated neuroinflammation following nerve injury and find that deletion in microglia attenuates Ca 2+ signaling production inflammatory cytokines by proalgesic agonists. Conditional attenuated proliferation dorsal horn, spinal cytokine levels, potentiation excitatory neurotransmission peripheral injury. These cellular effects were accompanied mitigation pain hyperalgesia knockout mice. A small-molecule inhibitor, CM4620, similarly mitigated allodynia male Unexpectedly, these protective seen female mice, revealing sexual dimorphism regulation hyperalgesia. Together, findings indicate key regulators sexually dimorphic

Language: Английский

---

Current evidence for COVID-19 therapies: a systematic literature review

European Respiratory Review, Journal Year: 2021, Volume and Issue: 30(159), P. 200384 - 200384

Published: March 17, 2021

Effective therapeutic interventions for the treatment and prevention of coronavirus disease 2019 (COVID-19) are urgently needed. A systematic review was conducted to identify clinical trials pharmacological COVID-19 published between 1 December 14 October 2020. Data regarding efficacy interventions, in terms mortality, hospitalisation need ventilation, were extracted from identified studies synthesised qualitatively. In total, 42 included. Interventions assessed included antiviral, mucolytic, antimalarial, anti-inflammatory immunomodulatory therapies. Some reductions ventilation seen with interferons remdesivir, particularly when administered early, mucolytic drug, bromhexine. Most lopinavir/ritonavir hydroxychloroquine did not show significant over standard care/placebo. Dexamethasone significantly reduced versus care, patients severe disease. Evidence other classes limited. Many had a moderate-to-high risk bias, blinding; most short-term some low patient numbers. This highlights well-designed increase quality available evidence. It also emphasises importance tailoring stage severity maximum efficacy.

Language: Английский

---

Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

PLoS ONE, Journal Year: 2021, Volume and Issue: 16(3), P. e0248132 - e0248132

Published: March 11, 2021

Background COVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of are urgently needed. This second edition living systematic review randomized clinical trials assessing effects all treatment interventions for participants in age groups with COVID-19. Methods findings We planned conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, individual patient meta-analyses. Our was based on PRISMA Cochrane guidelines, our eight-step procedure better validation significance meta-analysis results. performed both fixed-effect random-effects Primary outcomes were all-cause mortality serious adverse events. Secondary admission intensive care, mechanical ventilation, renal replacement therapy, quality life, non-serious According number outcome comparisons, we adjusted threshold p = 0.033. used GRADE assess certainty evidence. searched relevant databases websites published unpublished until November 2, 2020. Two reviewers independently extracted assessed methodology. included 82 enrolling total 40,249 participants. 81 out at overall high risk bias. Meta-analyses showed no evidence difference between corticosteroids versus control (risk ratio [RR] 0.89; 95% confidence interval [CI] 0.79 1.00; 0.05; I 2 23.1%; eight trials; very low certainty), events (RR CI 0.80 0.99; 0.04; 39.1%; ventilation 0.86; 0.55 1.33; 0.49; 55.3%; two certainty). The meta-analyses indications beneficial effects. Trial analyses required information size three not reached. Meta-analysis 0.93; 0.82 1.07; 0.31; 0%; four moderate certainty) analysis (boundary futility crossed) could reject remdesivir reduced death by 20%. 0.82; 0.68 38.9%; (required reached) Fixed-effect effect 0.40; 0.19 0.87; 0.02; intravenous immunoglobulin mortality, but result severely underpowered confirm or realistic intervention 0.63; 0.35 1.14; 0.12; 77.4%; five tocilizumab 0.70; 0.51 0.96; 0.32; 0.15 0.69; < 0.00; bromhexine standard care events, hydroxychloroquine lopinavir-ritonavir death, All remaining comparisons did have enough Nine single statistically significant results outcomes, Due lack data, it perform possible Conclusions No evidence-based currently exists. Very indicates might reduce ventilation; events; immunoglobin More risks bias random errors will continuously inform best practice research Systematic registration PROSPERO CRD42020178787 .

Language: Английский

---

Auxora for the Treatment of Patients With Acute Pancreatitis and Accompanying Systemic Inflammatory Response Syndrome

Pancreas, Journal Year: 2021, Volume and Issue: 50(4), P. 537 - 543

Published: April 1, 2021

Objectives To assess the safety of Auxora in patients with acute pancreatitis (AP), systemic inflammatory response syndrome (SIRS), and hypoxemia, identify efficacy endpoints to prospectively test future studies. Methods This phase 2, open-label, dose-response study randomized AP, accompanying SIRS, hypoxemia (n = 21) receive low-dose or high-dose plus standard care (SOC) SOC alone. All received pancreatic contrast-enhanced computed tomography scans at screenings, day 5/discharge, as clinically required 90 days postrandomization; were blinded centrally read determine AP severity using index. Solid food tolerance was assessed every meal SIRS 12 hours. Results The number experiencing serious adverse events not increased versus Three (36.5%) moderate receiving improved mild AP; no index improvements observed SOC. By end, better tolerated solid foods, had less persistent reduced hospitalization Conclusions favorable profile patient outcomes suggest may be an appropriate early treatment for SIRS. Clinical development will continue a randomized, controlled, blinded, dose-ranging study.

Language: Английский

---

Auxora vs. placebo for the treatment of patients with severe COVID-19 pneumonia: a randomized-controlled clinical trial

Critical Care, Journal Year: 2022, Volume and Issue: 26(1)

Published: April 8, 2022

Abstract Background Calcium release-activated calcium (CRAC) channel inhibitors block proinflammatory cytokine release, preserve endothelial integrity and may effectively treat patients with severe COVID-19 pneumonia. Methods CARDEA was a phase 2, randomized, double-blind, placebo-controlled trial evaluating the addition of Auxora, CRAC inhibitor, to corticosteroids standard care in adults Eligible were ≥ 1 symptom consistent infection, diagnosis confirmed by laboratory testing using polymerase chain reaction or other assay, pneumonia documented chest imaging. Patients also required be receiving oxygen therapy either high flow low nasal cannula at time enrolment have enrollment baseline imputed PaO 2 /FiO ratio > 75 ≤ 300. The from SpO determine pulse oximetry non-linear equation. could not non-invasive invasive mechanical ventilation enrolment. primary endpoint recovery through Day 60, secondary endpoints all-cause mortality 60 30. Due declining rates hospitalizations utilization medications prohibited regulatory guidance, stopped early. Results pre-specified efficacy set consisted 261 200 130 131 Auxora placebo groups, respectively. Time 7 vs. 10 days ( P = 0.0979) for who received placebo, rate 13.8% 20.6% 0.1449); 30 7.7% 17.6%, respectively 0.0165). Similar trends noted all randomized patients, on those 100. Serious adverse events (SAEs) less frequent treated occurred 34 (24.1%) 49 (35.0%) (P 0.0616). most common SAEs respiratory failure, acute distress syndrome, Conclusions safe well tolerated strong signals both Further studies are warranted. Trial registration NCT04345614.

Language: Английский

---

Store-operated calcium entry: From physiology to tubular aggregate myopathy

Current Opinion in Pharmacology, Journal Year: 2023, Volume and Issue: 68, P. 102347 - 102347

Published: Jan. 5, 2023

Language: Английский

---