Adenosine Di Research Articles

Antiplatelet effects and pharmacokinetics of crushed ticagrelor in resuscitated patients after cardiac arrest

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Based on the PLATO-trial and its sub-studies, ticagrelor can be used for patients with an acute coronary syndrome (ACS). Some of these patients are not awake or not able to swallow tablets. Alternatively the tablets can be crushed and given through a nasogastric tube. An extra obstacle for adequate intake is medication-induced gastroparesis caused by sedatives. Purpose The first aim of the study was to evaluate the platelet function analyser closure time (CT) in patients treated with crushed ticagrelor, after successful being resuscitated after cardiac arrest of acute ischaemic origin. Either they underwent PCI or urgent CABG, either they were treated conservatively. The second aim of the study was to determine plasma concentrations of ticagrelor and its main active metabolite AR-C124910XX. Methods We included 20 patients after successful resuscitation for cardiac arrest of acute ischaemic origin (16 STEMI + 4 NSTEMI). Only 1 patient was treated conservatively, 2 patients underwent an urgent CABG, the remainder were treated with PCI. All patients received a loading dose of ticagrelor before starting daily therapy. As patients were not able to swallow, tablets were crushed and given through a nasogastric tube. Measurements for Platelet Function Analysis were done at 0h, 2h, 4h, 8h, 12h, 24h and at day 4 + 4h. Platelet inhibition was tested with Platelet Function Analyser (PFA) activated by Adenosine Di Phosphate (ADP). A closure time (CT) longer than 113 seconds indicates full platelet inhibition by ticagrelor. Plasma concentration were determined at 30min, 1h, 2h, 4h, 8h, 24h and day 4 + 4h. Plasma concentrations were measured after protein precipitation, by using liquid chromatography with mass spectrometry detection. Results Out of 20 resuscitated patients enlisted in this study, 13 were still alive at day 4. At 24h, more than 80% of the survivors showed platelet inhibition as proven by a CT >113s. In 92% of the survivors, the PFA showed platelet inhibition at day 4 with a median CT of > 300s. For ticagrelor, the median time to peak plasma concentration (Tmax) was 100h [8; 100] for a median Cmax of 615.5 ng/ml [217.5; 1385.0]. The geometric mean was 467 ng/ml (248.5; 877.4). For the metabolite of ticagrelor, AR-C124910XX, median Tmax was 100h [8; 100] for a Cmax of 131.0 ng/ml [52.1; 177.7]. The geometric mean for the metabolite was 69.5 ng/ml (32.4; 149.0). Conclusions At day 4 of therapy, 92% of the survivors showed a CT longer than 113s, meaning full platelet inhibition by ticagrelor. In more than 80%, this was even the case at 24h. The median time to reach peak concentrations was 4 days, which is comparable to pharmacokinetic studies with ticagrelor in healthy volunteers. It should be noted that the dispersion in achieving Cmax is wide and can be reached earlier than at 4 days.

Strong antibiotic production is correlated with highly active oxidative metabolism in Streptomyces coelicolor M145

The Streptomyces genus is well known for its ability to produce bio-active secondary metabolites of great medical interest. However, the metabolic features accompanying these bio-productions remain to be defined. In this study, the comparison of related model strains producing differing levels of actinorhoddin (ACT), showed that S. lividans, a weak producer, had high TriAcylGlycerol (TAG) content indicative of a glycolytic metabolism. In contrast, the strong producer, S. coelicolor, was characterized by low TAG content, active consumption of its polyphosphate (PolyP) stores and extremely high ATP/ADP ratios. This indicated highly active oxidative metabolism that was correlated with induction of ACT biosynthesis. Interestingly, in conditions of phosphate limitation, the ppk mutant had TAG content and ACT production levels intermediary between those of S. lividans and S. coelicolor. This strain was characterized by high ADP levels indicating that Ppk was acting as an Adenosine Di Phosphate Kinase. Its absence resulted in energetic stress that is proposed to trigger an activation of oxidative metabolism to restore its energetic balance. This process, which is correlated with ACT biosynthesis, requires acetylCoA to fuel the Krebs cycle and phosphate for ATP generation by the ATP synthase coupled to the respiratory chain, resulting in low TAG and polyP content of the ACT producing strains.

Differential and Simultaneous Adenosine Di- and Triphosphate Binding by MutS

The roles of ATP binding and hydrolysis in the function of MutS in mismatch repair are poorly understood. As one means of addressing this question, we have determined the affinities and number of adenosine di- and triphosphate binding sites within MutS. Nitrocellulose filter binding assay and equilibrium fluorescence anisotropy measurements have demonstrated that MutS has one high affinity binding site for ADP and one high affinity site for nonhydrolyzable ATP analogues per dimer equivalent. Low concentrations of 5'-adenylylimidodiphosphate (AMPPNP) promote ADP binding and a large excess of AMPPNP is required to displace ADP from the protein. Fluorescence energy transfer and filter binding assays indicate that ADP and nonhydrolyzable ATP analogues can bind simultaneously to adjacent subunits within the MutS oligomer with affinities in the low micromolar range. These findings suggest that the protein exists primarily as the ATP.MutS.ADP ternary complex in solution and that this may be the form of the protein that is involved in DNA encounters in vivo.

Affinity labeling of the two species of Escherichia coli lysyl-tRNA synthetase with adenosine di- and triphosphopyridoxals.

Lysyl-tRNA synthetase (LysRS), a representative of the class 2 aminoacyl-tRNA synthetases, occurs as two species in Escherichia coli: LysRSs and LysRSu. To identify the ATP-binding site in this enzyme, we have applied affinity labeling with reactive adenine nucleotide analogs. Incubation of either enzyme species with adenosine di- or triphosphopyridoxal, followed by borohydride reduction, resulted in a time-dependent incorporation of the reagent, accompanied with the loss of both tRNA(Lys) aminoacylation, and lysine-dependent isotopic ATP-PPi exchange activities. LysRSu appeared less sensitive to adenosine triphosphopyridoxal than LysRSs. Complete inactivation with either reagent corresponded to the incorporation of about 2 mol of reagent per mol of dimeric enzyme. MgATP and ATP protected both enzyme species against the inactivation, suggesting that the modification occurs at the ATP-binding site. Sequence analysis of the labeled peptide isolated from the inactivated LysRSs and LysRSu revealed that bulk of the label was distributed among six lysyl residues at positions 25, 82, 114, 156, 364, and 505, with preference for Lys-114 and Lys-156. In LysRSs, Lys-132 and Lys-185 were also modified by both reagents, although these residues are not conserved in LysRSu. It is concluded that the folding of the LysRSs and LysRSu polypeptides and the relative locations of the identified lysyl residues with respect to the binding site for the two labels are very similar.

An NMR study of 1H, 31P, and 23Na relaxation and molecular dynamics in the polycrystalline sodium salts of adenosine Di- and triphosphate

Proton spin-lattice relaxation times in the laboratory frame, T 1(H),have been measured as a function of frequency and temperature (333K> T > 80 K). The spin-lattice relaxation times in the rotating frame, T 1 ϱ (H), have been measured at two different rotating fields while M 2(H), the proton second moment, has been extracted from the shape of the FID. In addition, T 1( 31P) and T 1( 23 Na) have been measured as functions of temperature at 81 and 50 MHz, respectively. The results demonstrate clearly that the water content of the compounds influences the results to a large extent. It seems that water molecules at some of the lattice sites can be removed from the structure by evacuation, while others are more tightly bound to the ADP and ATP molecules. The more loosely bound water molecules are very mobile and dominate the relaxation results in the high-temperature region via the spin-rotation and dipolar mechanisms. The more tightly bound water molecules rotate about their twofold axes and this motion, characterized by a distribution of correlation times, results in a T 1(H) minimum in the low-temperature region. The results have been interpreted in terms of a Fuoss-Kirkwood distribution function. The 23Na spin-lattice relaxation rates are dominated by the quadrupolar interactions, which provide a dominating relaxation mechanism for the proton spins in the rotating frame. In the case of Na 2ATP, T 1(P) is independent of the degree of hydration of the sample, but the NaADP T 1(H), values are influenced strongly by a change in the water content. An X-ray determination of the lengths of the a axes of the unit cells has provided supporting evidence for the interpretation of the NMR results.

Binding of Adenosine Di- and Triphosphates to Myosin during the Hydrolysis of Adenosine Triphosphate<xref ref-type="fn" rid="fn1"><sup>*</sup></xref>

Binding of Adenosine Di- and Triphosphates to Myosin during the Hydrolysis of Adenosine Triphosphate<xref ref-type="fn" rid="fn1"><sup>*</sup></xref>

Transphosphorylation of Adenosine Di- and Tri-phosphates in the Presence of Calcium Phosphate Precipitates

IT has been discovered by Lowenstein1,2 that in dilute aqueous solution in the presence of certain divalent cations there is a tendency for the terminal phosphate group of the adenosine triphosphate ion (ATP) to be transferred to inorganic phosphate or other suitable acceptor. For example: where ADP represents the adenosine diphosphate ion. Krane and Glimcher3 have recently shown that a similar non-enzymatic transphosphorylation occurs on the surface of calcium phosphate crystals with hydroxyapatite structure when they are in contact with aqueous solutions of ATP. In this reaction the acceptor is phosphate belonging to the crystal. The rate of reaction is faster and less dependent on pH than that of Lowenstein.

Nuclear Magnetic Resonance Spectra of Adenosine Di- and Triphosphate: II. EFFECT OF COMPLEXING WITH DIVALENT METAL IONS

Nuclear Magnetic Resonance Spectra of Adenosine Di- and Triphosphate: II. EFFECT OF COMPLEXING WITH DIVALENT METAL IONS

Phosphorus Magnetic Resonance Spectra of Adenosine Di- and Triphosphate: I. EFFECT OF pH

Phosphorus Magnetic Resonance Spectra of Adenosine Di- and Triphosphate: I. EFFECT OF pH

Changes in Adenosine Di- and Tri-phosphate Concentrations in the Early Stages of the Action of of Yeast on Glucose

IN a previous communication1 we reported attempts to measure the concentrations of adenosine diphosphate and triphosphate in yeast fermenting or respiring in the presence of glucose, in the steady state of these processes. We concluded that there was little difference in the concentration of adenosine diphosphate under anaerobic or aerobic conditions, while the concentration of adenosine triphosphate was slightly higher aerobically. Propionitrile at a concentration sufficient to inhibit the Pasteur effect had no effect aerobically on the concentration of either substance.

Studies on isolated tumour mitochondria; phosphate release from adenosine di- and triphosphates.

Studies on isolated tumour mitochondria; phosphate release from adenosine di- and triphosphates.

Improved method for isolation of adenosine di- and triphosphates.

Improved method for isolation of adenosine di- and triphosphates.

Improved Method for Isolation of Adenosine Di- and Triphosphates

Improved Method for Isolation of Adenosine Di- and Triphosphates

Carbodiimides. Part V.1 A Novel Synthesis of Adenosine Di- and Triphosphate and P1,P2-Diadenosine-5'-pyrophosphate

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCarbodiimides. Part V.1 A Novel Synthesis of Adenosine Di- and Triphosphate and P1,P2-Diadenosine-5'-pyrophosphateH. G. KhoranaCite this: J. Am. Chem. Soc. 1954, 76, 13, 3517–3522Publication Date (Print):July 1, 1954Publication History Published online1 May 2002Published inissue 1 July 1954https://doi.org/10.1021/ja01642a048RIGHTS & PERMISSIONSArticle Views286Altmetric-Citations69LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (825 KB) Get e-Alerts Get e-Alerts

Structure of Adenosine Di- and Tri-Phosphate

DEFINITE proof of the constitution of adenosine diphosphate and adenosine triphosphate, desirable because of its significance both for the structure of the co-dehydrogenases and of the intrinsic interest of the adenosine polyphosphates, has not hitherto been presented. The usual formulation of adenosine triphosphate as adenosine 5′-triphosphate (I) (Lohmann1) is in doubt only as regards the mode of attachment of the labile phosphoryl groups to the 5′-phosphoribofuranoside residue; the formation of muscle adenylic acid (adenosine 5′-phosphate) on hydrolysis of adenosine triphosphate and of inosine triphosphate by deamination virtually excludes the location of these phosphoryl groups elsewhere in the molecule.