Introduction: There are at the minimum two major, quite different approaches to advance drug discovery. The first being the target-based drug discovery (TBDD) approach that is commonly referred to as the molecular approach. The second approach is the phenotype-based drug discovery (PBDD), also known as physiology-based drug discovery or empirical approach.
Area covered: The authors discuss, herein, the need for developing radiation countermeasure agents for various sub-syndromes of acute radiation syndromes (ARS) following TBDD and PBDD approaches. With time and continuous advances in radiation countermeasure drug development research, the expectation is to have multiple radiation countermeasure agents for each sub-syndrome made available to radiation exposed victims.
Expert opinion: The majority of the countermeasures currently being developed for ARS employ the PBDD approach, while the TBDD approach is clearly under-utilized. In the future, an improved drug development strategy might be a ‘hybrid’ strategy that is more reliant on TBDD for the initial drug discovery via large-scale screening of potential candidate agents, while utilizing PBDD for secondary screening of those candidates, followed by tertiary analytics phase in order to pinpoint efficacious candidates that target the specific sub-syndromes of ARS. 相似文献
Etomidate is frequently selected over propofol for induction of anaesthesia because of a putatively favourable haemodynamic profile, but data confirming this perception are limited.
Methods
Patients undergoing cardiac surgery were randomised to induction of anaesthesia with propofol or etomidate. Phase I (n=75) was conducted as open-label, whereas Phase II (n=75) was double blind. Mean arterial blood pressure (MAP) and boluses of vasopressor administered after induction were recorded. The primary endpoint was the area under the curve below baseline MAP (MAP-time integral) during the 10 min after induction. Secondary endpoints were the use of vasopressors over the same period, and the effect of blinding on the aforementioned endpoints. Groups were compared using regression models with phase and anaesthetist as factors.
Results
The mean difference between etomidate and propofol in the MAP-time integral below baseline was 2244 mm Hg s (95% confidence interval, 581–3906; P=0.009), representing a 34% greater reduction with propofol. Overall, vasopressors were used in 10/75 patients in the etomidate group vs 21/75 in the propofol group (P=0.38), and in 20/74 patients during the blinded phase vs 11/76 during the open-label phase (P=0.31). The interaction between randomisation and phase (open-labelled or blinded) was not significant for either primary (P=0.73) or secondary endpoints (P=0.90).
Conclusions
Propofol caused a 34% greater reduction in MAP-time integral from baseline after induction of anaesthesia than etomidate, despite more frequent use of vasopressors with propofol, confirming the superior haemodynamic profile of etomidate in this context. The proportion of patients receiving vasopressors increased slightly, albeit not significantly, in both groups in the blinded phase.
Clinical trial registration
Australian and New Zealand Clinical Trials Registry, ACTRN12614000717651. 相似文献
Acute myocardial infarction (AMI) causes irreversible myocardial damage and release of inflammatory mediators, including cytokines, chemokines and miRNAs. We aimed to investigate changes in the levels of cytokines (IL-6, TNF-α and IL-10), miRNAs profiles (miR-146 and miR-155) and distribution of different monocyte subsets (CD14++CD16-, CD14++CD16+, CD14+CD16++) in the acute and post-healing phases of AMI.
Methods
In eighteen consecutive AMI patients (mean age 56.78?±?12.4 years, mean left ventricle ejection fraction – LVEF: 41.9?±?9.8%), treated invasively, monocyte subsets frequencies were evaluated (flow cytometry), cytokine concentrations were analyzed (ELISA) as well as plasma miRNAs were isolated twice – on admission and after 19.2?±?5.9 weeks of follow-up. Measurements were also performed among healthy volunteers.
Results
AMI patients presented significantly decreased frequencies of classical cells in comparison to healthy controls (median 71.22% [IQR: 64.4–79.04] vs. 84.35% [IQR: 81.2–86.7], p?=?0.001) and higher percent of both intermediate and non-classical cells, yet without statistical significance (median 6.54% [IQR: 5.14–16.64] vs. 5.87% [IQR: 4.48–8.6], p?=?0.37 and median 5.99% [IQR: 3.39–11.5] vs. 5.26% [IQR: 3.62–6.2], p?=?0.42, respectively). In AMI patients both, analyzed plasma miRNA concentrations were higher than in healthy subjects (miR-146: median 5.48 [IQR: 2.4–11.27] vs. 1.84 [IQR: 0.87–2.53], p?=?0.003; miR-155: median 25.35 [IQR: 8.17–43.15] vs. 8.4 [IQR: 0.08–16.9], p?=?0.027, respectively), and returned back to the values found in the control group in follow-up. miR-155/miR-146 ratio correlated with the frequencies of classical monocytes (r=0.6, p?=?0.01) and miR-155 correlated positively with the concentration of inflammatory cytokines ? IL-6 and TNF-α.
Conclusions
These results may suggest cooperation of both pro-inflammatory and anti-inflammatory signals in AMI in order to promote appropriate healing of the infarcted myocardium. 相似文献
ObjectiveAir pollution, weather condition and influenza are known risk factors of acute coronary syndrome (ACS) among elderly people. The influenza vaccine (IV) has been shown to reduce major cardiovascular events. The purpose of this study was to compare resistance to air pollution and weather factors causing ACS between vaccinated and less-vaccinated elderly people.MethodsA case–crossover design was applied to 1835 elderly ACS patients who were obtained from the 1-million sample of Taiwan National Health Insurance Research Data with inclusion criteria: (1) the first diagnosis of ACS was in cold season and at age 68 or more, (2) had received the free IV program at least once during the period 3 years before the ACS. They were stratified into two groups: 707 had received flu vaccinations for all the 3 years and the remaining 1128 had not. The measurements of air pollutants, temperature, and humidity corresponding to each of the 3 days prior to the ACS diagnosis date were retrieved from the data banks of the Taiwan Environmental Protection Administration and Central Weather Bureau.FindingsIncreases in air pollution concentrations of CO, NO2, PM10 or PM2.5 and decreases in temperature significantly influenced the risk of ACS for the non-continuously vaccinated elderly population; however, less significant effects were observed for the continuously vaccinated population.ConclusionConsecutive influenza vaccination may potentially offer resistance against the detrimental effects of air pollution and changes in temperature in frail elderly adults with ACS. Future studies are needed to directly assess the interaction effect between the vaccination and environmental factors on ACS. 相似文献
Gyromitra esculenta, also known as “false morel” is one of the most poisonous mushrooms. This species is found all over the world, growing in coniferous forest in early spring time. Common manifestation of poisoning includes gastrointestinal symptoms which include varied degrees of liver impairment.We describe three cases: acute liver injury, acute liver failure and acute-on-chronic liver failure due to G. esculenta poisoning. At admission patients presented with encephalopathy and features of liver failure. Two of them recovered completely following supportive management while the remaining patient who also had preexisting liver disease developed multiorgan failure and subsequently died.Although a rare occurrence, G. esculenta poisoning should be considered in the differential diagnosis of acute liver failure. 相似文献
Acute myeloid leukemia (AML) remains a therapeutically challenging malignancy with high rate of relapse and poor outcomes. There has been increased understanding of the molecular characteristics of AML and the various roles of the immune system in its pathogenesis, the result of which has led to the study and development of multiple immune-based approaches for this disease. In this review, we aim to provide an overview of the recent advancements made in antibody-based approaches to the treatment of AML including monoclonal antibodies, antibody-drug conjugates, and immune checkpoint inhibition. In addition, we provide insight and discuss the promise of these agents, some of which may soon enter the therapeutic armamentarium we currently employ against this lethal disease. 相似文献
BackgroundDistal radial access (DRA) has been proposed to improve procedure ergonomics and favor radial artery patency. Although promising data, nothing is known on evolving hand function after DRA.ObjectivesThis study sought to comprehensively evaluate hand function in patients undergoing DRA.MethodsReal-world patients undergoing DRA undertook a thorough multimodality assessment of hand function implementing multidomain questionnaires (Disabilities of the Arm, Shoulder and Hand and Levine-Katz), and motor (pinch grip test) and sensory (Semmes-Weinstein monofilaments test) examinations of both hands. All assessments were performed at preprocedural baseline and planned at 1-, 6-, and 12-month follow-up (FU). Adverse clinical and procedural events were documented too.ResultsData of 313 patients (220 men, age 66 ± 10 years) from 9 international centers were analyzed. The Disabilities of the Arm, Shoulder and Hand and the Levine-Katz scores slightly improved from baseline to FU (P = 0.008 and P = 0.029, respectively). Pinch strength mildly improved from baseline to FU (P < 0.001 for both the left and right hands). Similarly, touch pressure threshold appeared to faintly improve in both the left and right hands (P < 0.012 for all the sites). For both motor and sensory function tests, comparable findings were found for the DRA hand and the contralateral one, with no significant differences between them. Repeated assessment of all tests over all FU time points similarly showed lack of worsening hand function. Access-related adverse events included 19 harmless bleedings and 3 forearm radial artery and 3 distal radial artery occlusions. None affected hand function at FU.ConclusionsIn a systematic multidimensional assessment, DRA was not associated with hand function impairment. Moreover, DRA emerges as a safe alternative vascular access. 相似文献