Adenosine Group Research Articles

Behavioral changes induced through adenosine A2A receptor ligands in a rat depression model induced by olfactory bulbectomy.

BackgroundMajor depressive disorders are characterized by their severity and long‐lasting symptoms, which make such disorders highly disabling illnesses. Unfortunately, 50% of major depressive patients experience relapses, perhaps partly because drug research has been performed only in animal models that screen for antidepressant drugs that appear to only ameliorate acute depression symptoms. The bilateral olfactory bulbectomy (OBX) animal model presents the advantage of mimicking the symptoms of chronic depression by means of brain surgery. Adenosine purinergic receptors A2A (A2AR) have been the target of interest in the field of psychiatric diseases. This study aimed to show which A2A receptor ligands exert antidepressive‐like effects in the OBX rat model.MethodsForty Sprague‐Dawley male rats were divided into four groups: control, OBX + vehicle, OBX + ZM 241385, and OBX + adenosine groups. Pharmacological treatment was administered for 14 days, and the rats were examined via the forced swim test (FST), open field test (OFT), and sucrose preference test (SPT).ResultsThe OBX + ZM 241385 group exhibited decreased immobility time in the FST, decreased isolation time in the OFT, and reversed anhedonia behavior in the SPT compared to the vehicle group. However, no significant differences for adenosine treatment were found.Conclusions ZM 241385 administration (2 mg/kg i.p.) restored behavioral changes associated with OBX‐induced depression.

THE EFFECTIVENESS OF PRECONDITIONING AND POSTCONDITIONING WITH ADENOSINE IN PREVENTION OF REPERFUSION DAMAGE IN PATIENTS WITH ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION

The study aimed to evaluate the effectiveness of pharmacological preconditioning and postconditioning with sublingual adenosine in prevention of reperfusion damage in patients with ST-segment elevation myocardial infarction. Material and methods. In prospective trial 166 patients with STEMI were randomized to sublingual adenosine prior and after percutaneous coronary intervention (n=82) or standard therapy (n=84). Reperfusion arrhythmia, blood level of troponin T and effectiveness of reperfusion was assessed. Results . According to PCI results angiographic success was achieved in 88.1% patients of adenosine group and 92.7% patients of standard therapy group (p > 0.05). The reperfusion arrhythmias rate was significantly low in adenosine group (78%) compared to control (92.9%, p = 0.013). The use of adenosine was associated with 25.4% risk reduction in life-threatening reperfusion arrhythmias (p<0.01). During 24 h after PCI troponin T level decreased in both groups more significantly in adenosine (p < 0.05). The use of adenosine was associated with 8.3% risk reduction in myocardial reperfusion damage (p < 0.05). Conclusions . The pharmacological preconditioning and postconditioning with sublingual adenosine in the perioperative period of PCI in patients with STEMI is usefull to prevent myocardial reperfusion damage but does not affect the efficiency of reperfusion.

Efficacy and safety of higenamine hydrochloride stress echocardiography for diagnosis of coronary artery disease

Objective To evaluate the efficacy and safety of higenamine hydrochloride(HG) stress echocardiography for diagnosis of coronary artery disease (CAD). Methods The study was designed as prospective, randomized, open-labled, positively controlled and crossover phase II multi-center clinical research. Ninety subjects who were suspected to have CAD were enrolled.HG dosage was titrated at 0.5, 1, 2, 4 μg·kg-1·min-1 every 3 min. Adenosine was injected 140 μg·kg-1·min-1 for 6 min with total dosage 0.8 mg/kg. Visual assessment of the left ventricle wall motionand 17-segment model were used for analysis of stress echocardiography. CAD was defined as identifying >50% diameter stenosis in at least one major coronary artery by coronary angiogram. All adverse reaction were recorded. Results For HG group, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value were 28.9%, 89.7%, 57.1%, 76.5% and 47.8%, respectively; for adenosine group, they were 26.7%, 94.9%, 58.3%, 85.7% and 47.1%, respectively. There was no significant difference between the two groups(P>0.05). The diagnostic sensitivities of HG and adenosine echocardiography for single vessel stenosis were 11.1% and 5.6%, respectively(P>0.05). Both HG and adenosine echocardiography have the same sensitivity with 37.5% for double vessel stenosis and 44.4% for triple vessel stenosis. Advers reaction rate was 84.4% in HG group and 92.2% in adenosine group(P>0.05). Conclusions HG stress echocardiography for CAD diagnosis has high specificity, good safety and low sensitivity, which are similar to adenosine echo. Key words: Echocardiography, stress; Coronary artery disease; Higenamine hydrochloride; Adenosine

Does adenosine testing after second-generation cryoballoon ablation improve clinical success rate for paroxysmal atrial fibrillation?

Adenosine administration after pulmonary vein (PV) isolation using radiofrequency, can unmask PVs dormant conductions and predict atrial fibrillation (AF) recurrence. Our study evaluates whether adenosine-guided pulmonary vein isolation following second-generation cryoballoon (CB-2G) ablation may improve the success rate for paroxysmal AF. One hundred and one consecutive patients scheduled for a first ablation with (CB-2G) were prospectively included between January 2013 and November 2015 in two centers. Intravenous adenosine was administered after PV isolation to unmask dormant conductions (DC) in the first 51 patients and additional applications were performed to ablate DC. The 50 next patients underwent cryoablation without adenosine testing. Symptomatic atrial fibrillation recurrence was evaluated after 3, and 12 months. Acute PV isolation was achieved in all 402 PVs of 101 patients. Moreover, 8/204 VPPV (3,9%) involving 11,7% of patients with adenosine testing showed dormant reconduction, including 1 left superior pulmonary vein, 3 left inferior pulmonary vein, 4 right superior pulmonary vein, and no right inferior pulmonary vein. After a single procedure, success rates for cryoablation were 78,5% in adenosine group and 70% in the group without adenosine ( P = 0.22), with a mean follow-up of 422 days. Mean procedure duration for adenosine and without adenosine group were respectively 151 and 117 minutes ( P = 0.0009), and mean fluroscopy time 36 and 33 minutes ( P = 0.3). Adenosine testing after second-generation cryoballoon ablation can unmask a low rate of DC but does not improve success rate. However, this strategy increases procedural time.

Adenosine versus intravenous calcium channel antagonists for supraventricular tachycardia.

People with supraventricular tachycardia (SVT) frequently are symptomatic and present to the emergency department for treatment. Although vagal manoeuvres may terminate SVT, they often fail, and subsequently adenosine or calcium channel antagonists (CCAs) are administered. Both are known to be effective, but both have a significant side effect profile. This is an update of a Cochrane review previously published in 2006. To review all randomised controlled trials (RCTs) that compare effects of adenosine versus CCAs in terminating SVT. We identified studies by searching CENTRAL, MEDLINE, Embase, and two trial registers in July 2017. We checked bibliographies of identified studies and applied no language restrictions. We planned to include all RCTs that compare adenosine versus a CCA for patients of any age presenting with SVT. We used standard methodological procedures as expected by Cochrane. Two review authors independently checked results of searches to identify relevant studies and resolved differences by discussion with a third review author. At least two review authors independently assessed each included study and extracted study data. We entered extracted data into Review Manager 5. Primary outcomes were rate of reversion to sinus rhythm and major adverse effects of adenosine and CCAs. Secondary outcomes were rate of recurrence, time to reversion, and minor adverse outcomes. We measured outcomes by calculating odds ratios (ORs) and assessed the quality of primary outcomes using the GRADE approach through the GRADEproGDT website. We identified two new studies for inclusion in the review update; the review now includes seven trials with 622 participants who presented to an emergency department with SVT. All included studies were RCTs, but only three described the randomisation process, and none had blinded participants, personnel, or outcome assessors to the intervention given. Moderate-quality evidence shows no differences in the number of people reverting to sinus rhythm who were treated with adenosine or CCA (89.7% vs 92.9%; OR 1.51, 95% confidence interval (CI) 0.85 to 2.68; participants = 622; studies = 7; I2 = 36%). Low-quality evidence suggests no appreciable differences in major adverse event rates between CCAs and adenosine. Researchers reported only one case of hypotension in the CCA group and none in the adenosine group (0.66% vs 0%; OR 3.09, 95% CI 0.12 to 76.71; participants = 306; studies = 3; I2 = 0%). Included trials did not report length of stay in hospital nor patient satisfaction. Moderate-quality evidence shows no differences in effects of adenosine and calcium channel antagonists for treatment of SVT on reverting to sinus rhythm, and low-quality evidence suggests no appreciable differences in the incidence of hypotension. A study comparing patient experiences and prospectively studied adverse events would provide evidence on which treatment is preferable for management of SVT.

Templated polycondensation of aminopropyltrimethoxysilane on DNA

The polycondensation of a silane derivative such as aminopropyltrimethoxysilane (ATMS) in the presence of DNA was investigated in an organic solvent for the first time. Here, NMR observation showed that the hydrolysis step of ATMS before polycondensation was faster when the reaction was carried out in presence of double stranded DNA (146 bp) in chloroform. In order to test the specificity of this enhancement effect, the influence of the different components of DNA on ATMS hydrolysis and/or polycondensation was then investigated using different bases, nucleosides and nucleotides. The results showed that the kinetics of ATMS hydrolysis was affected by the type of nucleotide units used, the faster hydrolysis reaction rate being observed with molecules containing adenosine group, and that in the absence of water the amino group of deoxyadenosine units can react with ATMS methoxy groups.

Rational design of substrate binding pockets in polyphosphate kinase for use in cost-effective ATP-dependent cascade reactions.

Adenosine-5'-triphosphate (ATP) is the energy equivalent of the living system. Polyphosphate (polyP) is the ancient energy storage equivalent of organisms. Polyphosphate kinases (PPKs) catalyze the polyP formation or ATP formation, to store energy or to regenerate ATP, respectively. However, most PPKs are active only in the presence of long polyPs, which are more difficult and more expensive to generate than the short polyPs. We investigated the PPK preference towards polyPs by site-directed mutagenesis and computational simulation, to understand the mechanism and further design enzymes for effective ATP regeneration using short polyPs for in vitro cascade reactions, which are highly desired for research and applications. The results suggest that the short polyPs inhibit PPK by blocking the ADP-binding pocket. Structural comparison between PPK (Corynebacterium glutamicum) and PPK (Sinorhizobium meliloti) indicates that three amino acid residues, i.e., lysine, glutamate, and threonine, are involved in the activity towards short polyP by fixing the adenosine group of ADP in between the subunits of the dimer, while the terminal phosphate group of ADP still offers an active site, which presents a binding pocket for ADP. A proposed triple mutant PPK (SMc02148-KET) demonstrates significant activity towards short polyP to form ATP from ADP. The obtained high glutathione titer (38.79mM) and glucose-6-phosphate titer (87.35mM) in cascade reactions with ATP regeneration using the triple mutant PPK (SMc02148-KET) reveal that the tailored PPK establishes the effective ATP regeneration system for ATP-dependent reactions.

Adenosine for postoperative analgesia: A systematic review and meta-analysis.

PurposePerioperative infusion of adenosine has been suggested to reduce the requirement for inhalation anesthetics, without causing serious adverse effects in humans. We conducted a meta-analysis of randomized controlled trials evaluating the effect of adenosine on postoperative analgesia.MethodsWe retrieved articles in computerized searches of Scopus, Web of Science, PubMed, EMBASE, and Cochrane Library databases, up to July 2016. We used adenosine, postoperative analgesia, and postoperative pain(s) as key words, with humans, RCT, and CCT as filters. Data of eligible studies were extracted, which included pain scores, cumulative opioid consumption, adverse reactions, and vital signs. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed-effects or random-effects models, depending on the heterogeneity of the included trials.ResultsIn total, 757 patients from 9 studies were included. The overall effect of adenosine on postoperative VAS/VRS scores and postoperative opioid consumption was not significantly different from that of controls (P >0.1). The occurrence of PONV and pruritus was not statistically significantly different between an adenosine and nonremifentanil subgroup (P >0.1), but the rate of PONV occurrence was greater in the remifentanil subgroup (P <0.01). Time to first postoperative analgesic requirement in the adenosine group was not significantly difference from that of the saline group (SMD = 0.07, 95%CI: −0.28 to 0.41, P = 0.71); but this occurred significantly later than with remifentanil (SMD = 1.10, 95%CI: 2.48 to 4.06, P < 0.01). Time to hospital discharge was not significantly different between the control and adenosine groups (P = 0.78). The perioperative systolic blood pressure was significantly lower in the adenosine than in the control group in the mannitol subgroup (P < 0.01). The incidence of bradycardia, transient first- degree atrioventricular block, and tachycardia was not significantly different between the adenosine and control groups (P > 0.1).ConclusionAdenosine has no analgesic effect or prophylactic effect against PONV, but reduce systolic blood pressure and heart rates. Adenosine may benefit patients with hypertension, ischemic heart disease, and tachyarrhythmia, thereby improving cardiac function.

Bioorganometallic chemistry: Co-factor regeneration, enzyme recognition of biomimetic 1,4-NADH analogs, and organic synthesis; tandem catalyzed regioselective formation of N-substituted-1,4-dihydronicotinamide derivatives with [Cp*Rh(bpy)H]+, coupled to chiral S-alcohol formation with HLADH, and engineered cytochrome P450s, for selective C-H oxidation reactions

Two novel tandem catalysis approaches for the chiral synthesis of S-alcohols from reduction of their prochiral ketones with Horse Liver Alcohol Dehydrogenase (HLADH), and selective C-H oxidation reactions with protein engineered Cytochrome P450s, are presented. We utilized a co-factor regeneration procedure with three biomimetic NAD+ models that do not contain the pyrophosphate, nor the adenosine group, and either/or a ribose, N-1-benzylnicotinamide triflate, 1, N-4-methoxybenzylnicotinamide triflate, 2, and β-nicotinamide-5′-ribose methyl phosphate, 3, in conjunction with in situ formed [Cp*Rh(bpy)H]+ from [Cp*Rh(bpy)(H2O)]2+ (Cp* = η5-C5Me5, bpy = 2,2'-bipyridyl) and the hydride source, sodium formate, to regioselectively provide their 1,4-NADH analogs, N-benzyl-1,4-dihydronicotinamide, 4, N-4-methoxybenzyl-1,4-dihydronicotinamide, 5, and 1,4-dihydronicotinamide-5′-ribose methylphosphate, 6. Surprisingly, the 1,4-NADH biomimics, 4 and 6, were recognized, in the second tandem catalysis approach, by the natural 1,4-NADH dependent enzyme, HLADH, for catalyzed, highly enantioselective conversions of prochiral ketones to chiral S-alcohols. For example, with phenethylmethyl ketone and benzylmethyl ketone, the corresponding chiral alcohols were formed in >93% ee (S-enantiomer). Thus, 1,4-NADH biomimetic model recognition by HLADH does not significantly depend on the presence of the ribose, pyrophosphate, or adenosine groups to provide chiral products. We will also propose a plausible active site (HLADH)Zn-H intermediate, generated via a hydride transfer from bound 4/6 to Zn, for the enzymatic reduction of prochiral aryl/alkyl ketones to their chiral aryl/alkyl S-alcohols. Furthermore, the use of protein engineered cytochrome P450 enzymes provided improved molecular recognition of the above mentioned 1,4-NADH biomimetic co-factors, 4 and 5, for selective C-H oxidation reactions. For example, 1,4-NADH dependent mutants of natural 1,4-NAD(P)H dependent P450 BM-3 and 1,4-NADH dependent P450 CAM, with biomimetic co-factors 4 and 5, provided selective oxidation of p-nitrophenoxydecanoic acid to ω-oxydecanocarboxylic acid and p-nitrophenol, via C-H hydroxylation and β-hydrogen elimination, while oxidation of camphor provided hydroxycamphor, respectively. We will discuss the various parameters that effect molecular recognition of the biomimics, including protein engineering of both P450 BM-3 and P450 CAM enzymes, while determining the effect of the co-factor regeneration procedure on HLADH and P450 enzyme activity. These important observations have created new paradigms for the synthesis of organic compounds of interest, with the economically more favorable biomimics of NAD+, 1,4-NADH, and 1,4-NAD(P)H as co-factors, in tandem with the use of [Cp*Rh(bpy)(H)]+ as a regioselective catalytic reagent for co-factor regeneration.

New tools in nucleoside toolbox of tick-borne encephalitis virus reproduction inhibitors

Design and development of nucleoside analogs is an established strategy in the antiviral drug discovery field. Nevertheless, for many viruses the coverage of structure-activity relationships (SAR) in the nucleoside chemical space is not sufficient. Here we present the nucleoside SAR exploration for tick-borne encephalitis virus (TBEV), a member of Flavivirus genus. Promising antiviral activity may be achieved by introduction of large hydrophobic substituents in the position 6 of adenosine or bulky silyl groups to the position 5′. Introduction of methyls to the ribose moiety does not lead to inhibition of TBEV reproduction. Possible mechanisms of action of these nucleosides include the inhibition of viral entry or interaction with TBEV non-structural protein 5 methyltransferase or RNA-dependent RNA polymerase domains.

Promotive effects of adenosine on human hair follicle growth and angiogenin expression

Objective To evaluate the promotive effects of adenosine on human hair follicle growth and angiogenin expression. Methods Intact human hair follicles in the anagen phase were isolated from the scalp, and then divided into 6 groups to be treated with adenosine at different concentrations of 0, 0.1, 1, 10, 100 and 1 000 μmol/L respectively. Each adenosine group was further divided into 2 subgroups to be treated either with or without 0.8 mg/L anti-human angiogenin antibody, and hair follicles receiving no treatment served as the control group. The growth length of hair follicles during 6-day culture was measured by using a microscope. Human dermal papilla cells were isolated by a two-step enzyme digestion method, and then classified into the same groups as above. After 48-hour culture, methyl thiazolyl tetrazolium (MTT) assay was performed to evaluate cellular proliferative activity, flow cytometry to analyze cell cycle, reverse transcription (RT)-PCR to measure the mRNA expression of angiogenin in dermal papilla cells, and enzyme-linked immunosorbent assay (ELISA) to measure the protein expression of angiogenin in the culture supernatant of dermal papilla cells. Results Compared with the control group, the 10-1 000 μmol/L adenosine-treated groups showed significantly increased growth of hair follicles in vitro (F = 377.776, P < 0.05), and 100 μmol/L adenosine had the strongest promotive effect (P < 0.05). However, anti-human angiogenin antibody could partly antagonize the promotive effect. Compared with the control group, the proliferative activity of human dermal papilla cells was significantly enhanced in the 0.1-1 000 μmol/L adenosine-treated groups (F = 230.067, P < 0.05), and adenosine at 10 and 100 μmol/L had the strongest enhancing effects (both P < 0.05). Similarly, anti-human angiogenin antibody could partly antagonize the enhancing effects of adenosine on cell proliferation. As flow cytometry showed, compared with the control group, the 10-1 000 μmol/L adenosine-treated groups showed significantly lower proportions of dermal papilla cells in G1 phase (F = 75.5, P < 0.05), but higher proportions of cells in G2 phase (F = 15.7, P < 0.05) and S phase (F = 81.8, P < 0.05). In addition, the mRNA and protein expressions of angiogenin were significantly up-regulated in human dermal papilla cells treated by 10 and 100 μmol/L adenosine compared with the control group (F = 942.630, 148.544, respectively, both P < 0.05). Conclusion Adenosine can promote the growth of human hair follicles and proliferation of dermal papilla cells, likely by up-regulating angiogenin expression. Key words: Adenosine; Angiogenins; Hair follicle; Cell proliferation; Cell cycle; Dermal papilla cells

The REFLO-STEMI (REperfusion Facilitated by LOcal adjunctive therapy in ST-Elevation Myocardial Infarction) trial: a randomised controlled trial comparing intracoronary administration of adenosine or sodium nitroprusside with control for attenuation of microvascular obstruction during primary percutaneous coronary intervention

BackgroundMicrovascular obstruction (MVO) predicts short- and longer-term outcomes following primary percutaneous coronary intervention (PPCI) treatment of ST-elevation myocardial infarction (STEMI). The evidence base supporting the role of adenosine and sodium nitroprusside (SNP), the most evaluated adjunctive therapies aimed at attenuating MVO and infarct size, remains weak as the trials involved have had variable end points and used differing drug doses and modes of delivery.ObjectiveTo determine whether intracoronary administration of adenosine or SNP following thrombus aspiration reduces infarct size and/or MVO measured by cardiac magnetic resonance (CMR) imaging in patients undergoing PPCI within 6 hours of onset of STEMI.DesignMulticentre, prospective, parallel, randomised controlled and open-label trial with blinded end point analysis.SettingFour high-volume UK PPCI centres.ParticipantsPatients with STEMI undergoing PPCI with Thrombolysis in Myocardial Infarction (TIMI) flow grade 0/1 in the infarct-related artery and no significant bystander coronary artery disease on angiography.InterventionsParticipants were anticoagulated with bivalirudin and allocated by an automated 24-hour telephone randomisation service to one of three groups: (1) standard PPCI (control), (2) PPCI with adjunctive adenosine 1–2 mg or (3) PPCI with adjunctive SNP 250 µg. The study drugs were delivered intracoronary immediately following thrombus aspiration and again following successful stenting.Main outcome measuresThe primary outcome was infarct size (% total left ventricular end-diastolic mass; %LVM) measured by CMR imaging undertaken 48–96 hours post PPCI. Secondary outcome measures included MVO (hypoenhancement within the infarct core) on CMR imaging, electrocardiographic and angiographic markers of microvascular perfusion and major adverse cardiac events (MACEs) during a median of 6 months’ follow-up. The study aimed to recruit 240 patients (powered at 80% to detect a 5% absolute reduction in infarct size).ResultsThe trial completed recruitment in April 2014 having randomised 247 patients (standard PPCI group,n = 86; PPCI + adenosine group,n = 82; PPCI + SNP group,n = 79). In total, 79% of participants were male and the mean ± standard deviation age of participants was 59.3 ± 12.3 years. CMR imaging was completed in 197 (80%) patients (standard PPCI,n = 65; PPCI + adenosine,n = 63; PPCI + SNP,n = 69) for the primary outcome. There was no significant difference in infarct size [%LVM, median, interquartile range (IQR)] between the adenosine group (10.1, 4.7–16.2), the SNP group (10.0, 4.2–15.8) and the control group (8.3, 1.9–14.0) (p = 0.062 andp = 0.160 vs. control, respectively). MVO (%LVM, median, IQR) was similar across the groups [1.0, 0.0–3.7 (p = 0.205) and 0.6, 0.0–2.4 (p = 0.244) for adenosine and SNP, respectively, vs. 0.3, 0.0–2.8 for the control]. Using per-protocol analysis, infarct size (%LVM) was increased in adenosine-treated patients compared with control patients (12.0 vs. 8.3;p = 0.031). Increased left ventricular volume and reduced left ventricular ejection fraction were also observed in the adenosine arm. There was a significant increase in MACEs in patients undergoing adenosine-facilitated PPCI compared with control patients, driven by heart failure, at 30 days [hazard ratio (HR) 5.39, 95% confidence interval (CI) 1.18 to 24.60;p = 0.04] and 6 months (HR 6.53, 95% CI 1.46 to 29.2;p = 0.01) post randomisation.ConclusionsHigh-dose intracoronary adenosine and SNP during PPCI did not reduce infarct size or MVO measured by CMR imaging. Furthermore, adenosine may adversely affect mid-term clinical outcome and should not be used during PPCI to prevent reperfusion injury.Trial registrationClinicalTrials.gov NCT01747174 and EudraCT 2010–023211–34.FundingThis project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and NIHR partnership.

Effect of continuous low-dose infusion of adenosine into hepatic artery on hepatic arterial flow of li-ver graft

Objective To assess the effect of continuous low-dose infusion of adenosine on hepatic arterial flow (HAF) of patients with liver graft during surgery. Methods From Jan 2009 to Aug 2009, 44 patients underwent orthotopic liver transplantation (OLT). 10 patients were enrolled to receive adenosine treatment and 34 patients served as controls. Following arterial reperfusion, a 16G central venous catheter was placed into the gastroduodenal artery and adenosine was continuously infused at doses ranging from 0.7 to 4.2 μg·kg-1·min-1 for 30 min. HAF and portal vein flow (PVF) were measured using a real-time time flow meter prior to, during and 10 min after adenosine infusion. Data on gender, age, postoperative hospital stay, ICU stay, hepatic biochemical indicators and 1-year survival rate were compared between the two groups. Results Adenosine significantly increased HAF at doses from 1.4 to 2.8 μg·kg-1·min-1. Doses>2.8 μg·kg-1·min-1 did not further increase HAF. HAF increased by 150.3%±161.2% (P 0.05) during adenosine infusion. No significant differences were found on MAP [(85.6±13.0) vs 84.0±13.6, P>0.05] and HR [(74.5±10.0) vs (74.1±9.6), P>0.05] before and after adenosine infusion. In addition, there were no significant differences between the adenosine group and the control group on patients’ gender, age, postoperative hospital stay, ICU stay, hepatic biochemical indicators and 1-year survival rate. Conclusion This pilot study concluded that adenosine administration directly into the HA significantly increased HAF of liver grafts without systemic side effects. Key words: Liver transplantation; Small-for-size syndrome; Adenosine; Hepatic artery flow

Evaluation of Short- and Long-Term Efficacy of Combined Intracoronary Administration of High-Dose Adenosine and Tirofiban during Primary Percutaneous Coronary Intervention.

To assess the influence of combined intracoronary application of high-dose adenosine and tirofiban in primary percutaneous coronary intervention (PCI) on clinical events and cardiac function. Our study evaluated consecutive patients with acute ST-segment elevation myocardial infarction undergoing primary PCI, who were randomly divided into adenosine group (n = 130) and control group (n = 128). Combined with thrombus aspiration and then intracoronary tirofiban, the adenosine group received intracoronary adenosine (2 mg) through the aspiration catheter 2 times. After thrombus aspiration and stenting of the infarct- related artery, the control group received placebo. The primary endpoint of our investigation was major adverse cardiac events (MACE) at the 1-year and 3-year marks. The secondary endpoint comprised left ventricular remodeling (LVR) at 6 months, myocardial blush grade (MBG), thrombolysis in myocardial infarction (TIMI) flow grade and corrected TIMI frame count (CTFC) after PCI. Our study found that TIMI flow grade post-PCI did not differ significantly between the 2 groups, while CTFC favored the adenosine-treated patients (21.6 ± 6.5 vs. 25.1 ± 7.8, p = 0.001). Although the adenosine group achieved a higher rate of MBG 3 (45.1% vs. 32.0%, p = 0.035) and MBG 2-3 (76.2% vs. 62.3%, p = 0.018) than the control group, the incidences of MACE at 1 year (20.0% vs. 25.0%, p = 0.373) and 3 years (26.9% vs. 32.0%, p = 0.413) were comparable. LVR occurred in 23.1% (27/117) of adenosine-treated patients and in 29.8% (43/114) of the controls (p = 0.296). Intracoronary administration of high-dose adenosine combined with intracoronary tirofiban and thrombus aspiration may further improve myocardial perfusion after primary PCI.

Ribosome-dependent activation of stringent control.

In order to survive, bacteria continually sense, and respond to, environmental fluctuations. Stringent control represents a key bacterial stress response to nutrient starvation1,2 that leads to a rapid and comprehensive reprogramming of metabolic and transcriptional patterns3. In general, transcription of genes for growth and proliferation are down-regulated, while those important for survival and virulence are favored4. Amino acid starvation is sensed by depletion of the aminoacyl-tRNA pools5, which results in accumulation of ribosomes stalled with non-aminoacylated (uncharged) tRNA in the ribosomal A-site6,7. RelA is recruited to stalled ribosomes, and activated to synthesize a hyperphosphorylated guanosine analog, (p)ppGpp8, which acts as a pleiotropic second messenger. However, structural information for how RelA recognizes stalled ribosomes and discriminates against aminoacylated tRNAs is missing. Here, we present the electron cryo-microscopy (cryo-EM) structure of RelA bound to the bacterial ribosome stalled with uncharged tRNA. The structure reveals that RelA utilizes a distinct binding site compared to the translational factors, with a multi-domain architecture that wraps around a highly distorted A-site tRNA. The TGS domain of RelA binds the CCA tail to orient the free 3’ hydroxyl group of the terminal adenosine towards a β-strand, such that an aminoacylated tRNA at this position would be sterically precluded. The structure supports a model where association of RelA with the ribosome suppresses auto-inhibition to activate synthesis of (p)ppGpp and initiate the stringent response. Since stringent control is responsible for the survival of pathogenic bacteria under stress conditions, and contributes to chronic infections and antibiotic tolerance, RelA represents a good target for the development of novel antibacterial therapeutics.

Prognostic implications of stress modality on mortality risk and cause of death in patients undergoing office-based SPECT myocardial perfusion imaging

BackgroundPatients requiring vasodilator single-photon emission computed-tomography myocardial perfusion imaging (SPECT-MPI) have a higher mortality risk than those selected for exercise or vasodilator with low-level exercise SPECT-MPI. However, it is unknown whether the increased mortality is driven by cardiac deaths alone or cardiac and non-cardiac deaths. MethodsIn a prospective cohort of 1,511 consecutive patients referred for SPECT-MPI, patients were classified according to stress test modality: exercise, adenosine with low-level exercise (AdenoEx), and adenosine. Subjects were followed for events of all-cause mortality and cause of death. Survival analyses using multivariate Cox regression and propensity score matching methods were performed. ResultsDuring a follow-up of 4.9 ± 0.9 years, a total of 68 (4.5%) deaths occurred: 50 non-cardiac and 18 cardiac. The adenosine group had the highest annual mortality (all-cause 3.65%, non-cardiac 2.36%, cardiac 1.29%), while exercise stress had the lowest mortality (all-cause 0.42%, non-cardiac 0.37%, cardiac 0.05%) and AdenoEx had an intermediate mortality (all-cause 1.3%, non-cardiac 0.91%, cardiac 0.39%); all P values <0.001. The majority of non-cardiac deaths were attributed to cancer. Using exercise stress as a reference standard, multivariable Cox regression analyses demonstrated that adenosine stress was independently predictive of all-cause mortality [HR 3.23 (CI 1.77-5.88); P < 0.001], non-cardiac death [HR 2.67 (CI 1.34-5.31); P = 0.005], and cardiac death [HR 6.30 (CI 1.55-25.56); P = 0.010] after adjusting for univariate predictors of mortality. These findings were consistent in the subgroups of patients with normal and abnormal MPI. AdenoEx was predictive of all-cause, non-cardiac, and cardiac deaths in univariate analysis, but it was not predictive by multivariate analysis. Propensity score matched cohort analysis showed that the adenosine stress group had the highest all-cause (P < 0.001), non-cardiac (P = 0.013), and cardiac deaths (P < 0.001), while the exercise stress group had the lowest mortality of any cause. ConclusionsThe inability to perform any level of exercise during a SPECT-MPI stress is associated with high mortality risk, which is derived from both cardiac and non-cardiac deaths.

A new mechanism of post-transfer editing by aminoacyl-tRNA synthetases: catalysis of hydrolytic reaction by bacterial-type prolyl-tRNA synthetase

Aminoacyl tRNA synthetases are enzymes that specifically attach amino acids to cognate tRNAs for use in the ribosomal stage of translation. For many aminoacyl tRNA synthetases, the required level of amino acid specificity is achieved either by specific hydrolysis of misactivated aminoacyl-adenylate intermediate (pre-transfer editing) or by hydrolysis of the mischarged aminoacyl-tRNA (post-transfer editing). To investigate the mechanism of post-transfer editing of alanine by prolyl-tRNA synthetase from the pathogenic bacteria Enterococcus faecalis, we used molecular modeling, molecular dynamic simulations, quantum mechanical (QM) calculations, site-directed mutagenesis of the enzyme, and tRNA modification. The results support a new tRNA-assisted mechanism of hydrolysis of misacylated Ala-tRNAPro. The most important functional element of this catalytic mechanism is the 2′-OH group of the terminal adenosine 76 of Ala-tRNAPro, which forms an intramolecular hydrogen bond with the carbonyl group of the alanine residue, strongly facilitating hydrolysis. Hydrolysis was shown by QM methods to proceed via a general acid-base catalysis mechanism involving two functionally distinct water molecules. The transition state of the reaction was identified. Amino acid residues of the editing active site participate in the coordination of substrate and both attacking and assisting water molecules, performing the proton transfer to the 3′-O atom of A76.

Adenosine Increases Hepatic Artery Flow in Liver Transplant Recipients: A Pilot Study

BackgroundThe aim of this study was to assess the effect of low-dose adenosine on hepatic artery flow (HAF) when administered intraoperatively by continuous infusion. Materials and MethodsBetween January 2009 and August 2009, 74 patients underwent orthotopic liver transplantation (OLT). Ten patients were enrolled for adenosine treatment, and 64 non-study patients served as controls. After arterial reperfusion, a 16-G central venous catheter was placed in the gastroduodenal artery, and adenosine was continuously infused at doses ranging from 0.7 to 2.8 μg/kg/min for 30 min. HAF and portal vein flow were measured using a transit time flow meter before adenosine infusion, during infusion, and 10 min after infusion. Liver function tests were monitored routinely, duplex ultrasonography was performed on postoperative day 1, and the hepatic artery resistive index measured. The patients were followed for 1 year. ResultsAdenosine significantly increased HAF at doses from 0.7 to 2.8 μg/kg/min. The smallest increase in HAF was 24% above the baseline; in 80% of patients, the increase in HAF was >50% of the baseline values. In 2 patients, HAF was increased by >300%. The dosing started at 0.7 μg/kg/min, and 6 of 10 patients responded. Three patients required an increase to 1.4 μg/kg/min. Doses >2.8 μg/kg/min did not further increase HAF. One patient showed a minimal response regardless of the dose. There were no differences between the adenosine group and control group with respect to liver function (aspartate aminotransferase, alanine aminotransferase, total bilirubin, and International Normalized Ratio), platelet count on POD2, hepatic artery resistive index, and post-transplant length of stay, intensive care days, or 1-year patient survival rates. ConclusionsThis pilot study established that adenosine administered directly into the hepatic artery produces a similar effect on HAF in cadaveric liver transplant recipients to that found in the laboratory without producing systemic side effects.

Impact of Intracoronary Adenosine on Myonecrosis in Patients with Unstable Angina Pectoris Undergoing Percutaneous Coronary Intervention.

In this study, we aimed to investigate the impact of prophylactic intracoronary adenosine administered during percutaneous coronary intervention (PCI) due to unstable angina pectoris on myonecrosis by measuring post-procedural levels of cardiac troponin I (cTnI) and creatine kinase-myocardial band (CK-MB). A total of 122 patients with unstable angina undergoing PCI were included in this single-center, double-blind, randomized study. The patients were randomly allocated to adenosine and placebo groups. In the adenosine group, a single-dose of intracoronary adenosine (100μg for the right coronary artery and 150μg for the left coronary artery) was administered. Primary endpoint was post-PCI myonecrosis, which was defined as abnormal levels of periprocedural cTnI. Secondary endpoints were defined as elevated cTnI levels [5 × upper limit of normal (ULN)], abnormal CK-MB levels, angiographic coronary flow measured by Thrombolysis In Myocardial Infarction (TIMI) frame count (TFC), the cumulative incidence of in-hospital death and in-hospital urgent target vessel revascularization (TVR). Clinical and angiographic characteristics of both adenosine (61 patients, 61±9years) and placebo (61 patients, 59±10years) groups were similar (p>0.05 for all). Post-procedural abnormal cTnI levels in the adenosine group were significantly lower than the placebo group (32% vs. 55%, p: 0.011). cTnI >5 × ULN (21% vs. 31%, p: 0.217) and abnormal CK-MB levels (11% vs. 19%, p: 0.263) were similar in both groups. Post-procedural TFCs in the adenosine group were significantly lower than the placebo group (24±4 vs. 27±5, p: 0.004). In-hospital events including death and urgent TVR were not observed in either group. Intracoronary administration of single-dose adenosine in patients with unstable angina undergoing PCI is associated with decreased periprocedural myonecrosis and improved coronary blood flow.

Impact of intracoronary adenosine administration during primary PCI: A meta-analysis

BackgroundAim of the present study was to evaluate all randomized trials, comparing intracoronary adenosine versus placebo in STEMI patients undergoing primary PCI. Methods and resultsPubMed, the Cochrane Library and ISI Web of Knowledge electronic databases were scanned for eligible studies up to February 23rd 2015. The summary measure used was risk ratio (RR) with 95% confidence intervals. A total of 13 studies were eligible, including 1487 patients. Incidence of ST resolution was significantly higher in the IC adenosine group than in the placebo group (RR=1.20 [1.05–1.38]; p=0.008). At metaregression, a significant correlation was found between the magnitude of the adenosine-related effect on ST resolution and the mean ischemic time (p=0.011) or the percentage of patients with the LAD as the infarct-related artery (p=0.03). Furthermore, we found a larger increase in LVEF (p=0.02) with a parallel reduction in the incidence of heart failure (HF) (RR=0.50 [0.28–0.89]; p=0.02) in the IC adenosine group. Finally, IC adenosine administration was associated with a significantly lower incidence of major adverse cardiac events (MACE) both at short- (RR=0.62 [0.39–0.98] p=0.04) and long-term (RR=0.61 [0.39–0.95] p=0.03). ConclusionsThis is the first meta-analysis demonstrating a clinical benefit for IC adenosine in hard endpoints, such as adverse cardiovascular events, in patients undergoing primary PCI.