Investigations with GMC2021 in experimental models predictive of antimigraine activity and coronary side-effect potential

Abstract Several acutely acting antimigraine drugs, including sumatriptan and other second generation 5-HT1D receptor agonists, have the ability to constrict porcine carotid arteriovenous anastomoses as well as the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, for the therapeutic and coronary side-effect potential of the compounds. Using these two models, we have now investigated the effects of GMC2021 (3-[2-(dimethylanimo)ethyl]-5-[(trifluoromethyl)sulfonyl]oxy][1 H]indole oxalate, a close analogue of sumatriptan. GMC2021 (30, 100, 300 and 1000 μg · kg−1, i.v.) decreased the total carotid blood flow by exclusively decreasing arteriovenous anastomotic blood flow; capillary blood flow to the skin and ears was moderately increased. The mean ± S.E.M. dose of GMC2021 eliciting a 50% decrease (ED50) in the porcine carotid arteriovenous anastomotic blood flow was found to be 1.1 ± 0.3 μmol · kg−1 and the highest dose (1000 μg · kg−1) produced a 67 ± 4% reduction. The carotid haemodynamic effects of GMC2021 were reduced by the selective 5-HT1D receptor antagonist, GR127935 (N-[methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1-biphenyl]-4-carbboxamide hydrochloride), which completely antagonizes porcine carotid haemodynamic responses to sumatriptan (ED50: 0.16 μmol · kg−1, i.v.). Compared to sumatriptan (pD2: 6.12 ± 0.15; Emax: 31.3 ± 12.3% of contractions to 100 mM K+), GMC2021 was less potent in constricting the human isolated coronary artery (pD2: 5.45 ± 0.2; Emax: 21.0 ± 4.8% of contractions to 100 mM K+). The above results suggest that GMC2021 constricts carotid arteriovenous anastomoses partly by a 5-HT1D receptor and partly by another, probably novel, receptor and that GMC2021 should be able to abort migraine headaches in patients, with perhaps a less propensity for coronary side effects

Prognostic implications of left ventricular myocardial work indices in patients with secondary mitral regurgitation

Background: Assessment of left ventricular (LV) function in patients with secondary mitral regurgitation (SMR) remains challenging but is an important parameter for risk stratification. The association of LV myocardial work components (work index [GWI], constructive [GCW] and wasted [GWW] work, and work efficiency) derived from pressure-strain loops obtained with speckle tracking echocardiography, and all-cause mortality in patients with SMR was investigated. Methods: LV myocardial GWI, GCW, GWW, and global work efficiency were measured with speckle tracking strain echocardiography in 373 patients (72% men, median age 68 years) with various grades of SMR. All-cause mortality was the primary end point. Results: Mild SMR was observed in 143 patients, 128 had moderate SMR, and 102 had severe SMR. Patients with severe SMR had the largest LV volumes and the worst LV ejection fraction and LV global longitudinal strain. In patients with severe SMR, LV GWI and GCW were more impaired (500 mm Hg% versus 680 mm Hg% P=0.024 and 678 mm Hg% versus 851 mm Hg% P=0.006, respectively), while GWW was lower (130 mm Hg% versus 260 mm Hg% P<0.001, respectively) and global work efficiency was significantly higher (82% versus 76%, P=0.001) compared with patients with mild SMR. After a median follow-up of 56 months, 161 patients died. LV GWI <= 500 mm Hg%, LV GCW <= 750 mm Hg%, and LV GWW Conclusions: Patients with severe SMR had the worst LV GWI and LV GCW but better LV GWW and global work efficiency reflecting the unloading of the LV in the low-pressure left atrial chamber. These parameters were independently associated with worse long-term survival in patients with SMR.Cardiolog

Changes in global left ventricular myocardial work indices and stunning detection 3 months after ST-segment elevation myocardial infarction

Global left ventricular (LV) myocardial work (MW) indices (GLVMWI) are derived from speckle tracking echocardiographic strain data in combination with non-invasive blood pressure measurements. Changes in global work index (GWI), global constructive work (GCW), global wasted work (GWW) and global work efficiency (GWE) after ST-segment elevation myocardial infarction (STEMI) have not been explored. The aim of present study was to assess the evolution of GLVMWI in STEMI patients from baseline (index infarct) to 3 months' follow-up. Three-hundred and fifty patients (265 men; mean age 61 +/- 10 years) with STEMI treated with primary percutaneous coronary intervention (PCI) and guideline-based medical therapy were retrospectively evaluated. Clinical variables, conventional echocardiographic measures and GLVMWI were recorded at baseline within 48 hours post-primary PCI and 3 months' follow-up. LV ejection fraction (from 54 +/- 10% to 57 +/- 10%, p < 0.001), GWI (from 1449 +/- 451 mm Hg% to 1953 +/- 492 mm Hg%, p < 0.001), GCW (from 1624 +/- 519 mm Hg% to 2228 +/- 563 mm Hg%, p < 0.001) and GWE (from 93% (interquartile range (IQR) 86%-95%) to 95% (IQR 91%-96%), p < 0.001) improved significantly at 3 months' follow-up with no significant difference in GWW (from 101 mm Hg% (IQR 63-155 mm Hg%) to 96 mm Hg% (IQR 64-155 mm Hg %); p = 0.535). On multivariable linear regression analysis, lower values of troponin T at baseline, increase in systolic blood pressure and improvement in LV global longitudinal strain were independently associated with higher GWI and GCW at 3 months' follow-up. In conclusion, the evolution of GWI, GCW and GWE in STEMI patients may reflect myocardial stunning, whereas the stability in GWW may reflect permanent myocardial damage and the development of non-viable scar tissue. (C) 2021 The Authors. Published by Elsevier Inc.Cardiolog

Left ventricular myocardial work in patients with severe aortic stenosis

Background: Left ventricular myocardial work (LVMW) is a novel method to assess left ventricular (LV) function using pressure-strain loops that takes into consideration LV afterload. The estimation of LV afterload in patients with severe aortic stenosis (AS) may be challenging, and no study so far has investigated LVMW in this setting. The aim of this study was to develop a method to calculate LVMW in patients with severe AS and to analyze its relationship with heart failure symptoms.Methods: Indices of LVMW were calculated in 120 patients with severe AS who underwent transcatheter aortic valve replacement and invasive LV and aortic pressure measurements. LV systolic pressure was also derived by adding the mean aortic valve gradient to the aortic systolic pressure. LV global longitudinal strain and echocardiography-derived LV systolic pressure were then incorporated to construct pressure-strain loops of the left ventricle.Results: An excellent correlation was observed between LVMW indices calculated using the invasive and echocardiography-derived LV systolic pressure. Patients in New York Heart Association functional class III or IV (n = 97 [73%]) had lower LV global longitudinal strain, LV global work index, LV global constructive work, and right ventricular free wall strain compared with those in New York Heart Association functional class I or II. In contrast to LV global longitudinal strain, LV global work index (odds ratio per 100 mm Hg% increase, 0.91; 95% CI, 0.85-0.98; P = .012) and LV global constructive work showed independent associations with New York Heart Association functional class III or IV heart failure symptoms.Conclusions: The calculation of echocardiography-based LVMW indices is feasible in patients with severe AS. In particular, LV global work index and global constructive work showed independent associations with heart failure symptoms and may provide additional information on myocardial remodeling and function in patients with severe AS.Cardiolog

Global left ventricular myocardial work efficiency and Long-term prognosis in patients after ST-segment-elevation myocardial infarction

Background:Left ventricular (LV) global longitudinal strain has demonstrated incremental prognostic value over LV ejection fraction in patients with ST-segment-elevation myocardial infarction. However, LV global longitudinal strain does not take into consideration the effect of afterload. Novel speckle-tracking echocardiographic indices of myocardial work integrate blood pressure measurements (afterload) with LV global longitudinal strain. The present study aimed to investigate the prognostic value of global LV myocardial work efficiency (GLVMWE; reflecting LV performance) obtained from pressure-strain loops with echocardiography in patients with ST-segment-elevation myocardial infarction.Methods:A total of 507 ST-segment-elevation myocardial infarction patients (mean age, 61 +/- 11 years; 76% men) were retrospectively analyzed. LV ejection fraction and GLVMWE were measured by transthoracic echocardiography within 48 hours of admission. GLVMWE was defined as the ratio of constructive work divided by the sum of constructive and wasted work in all LV segments and expressed as a percentage. Spline curve analysis was used to define the association between reduced GLVMWE and all-cause death.Results:After a median follow-up of 80 months (interquartile range, 67-97 months), 40 (8%) patients died. Patients with reduced GLVMWE (= 86%). Reduced GLVMWE (<86%) showed an independent association with all-cause mortality (hazard ratio, 3.167 [95% CI, 1.679-5.972]; P<0.001).Conclusions:Reduced GLVMWE (<86%) measured by transthoracic echocardiography within 48 hours of admission in ST-segment-elevation myocardial infarction patients is associated with worse long-term survival.Cardiolog

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men

Modern NMR spectroscopy of proteins and peptides in solution and its relevance to drug design

The knowledge of the three-dimensional (3D) structures and conformational dynamics of proteins and peptides is important for the understanding of biochemical and genetic data derived for these molecules. This understanding can ultimately be of help in drug design. We describe here the role of Nuclear Magnetic Resonance (NMR) spectroscopy in this process for three distinct situations: for small proteins, where relatively simple NMR methods can be used for full 3D structure determination; for larger proteins that require multinuclear multidimensional NMR but for which full 3D structures can still be obtained; and for small peptides that are studied in interaction with macromolecules (receptors) using specialized NMR techniques. A fourth situation, pertaining to large systems where only partial structural information can be obtained from NMR data, is briefly discussed. Molecules of interest to the biomedical field (C5a and stromelysin) are discussed as examples.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43356/1/11091_2005_Article_BF02174537.pd

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

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation &lt;92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p&lt;0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p&lt;0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

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

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research