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La profilaxis con arándano americano de la infección de orina recurrente infantil se ha mostrado eficaz en el modelo experimental del adulto. Existen pocos datos sobre su eficacia, seguridad y dosis recomendadas en la población pediátrica.

There are limited data on the prognostic role of biomarkers in anticoagulated patients with atrial fibrillation (AF). We evaluated the prognostic value of high sensitivity TnT (hsTnT) and high‐sensitivity interleukin‐6 (hsIL6) in a large cohort of AF patients taking oral anticoagulant therapy (OAC) as both biomarkers have been associated with adverse cardiovascular events. Methods: We studied 930 patients (51% male; median age 76) with permanent/ paroxysmal AF who were stabilized (for at least 6 months) on OAC (INRs 2.0–3.0). Plasma hsTnT and hsIL6 levels were quantified by electrochemiluminescense immunoassay at baseline. Patients were followed‐up for up to 2 years, and adverse events (thrombotic and vascular events, mortality and major bleeding) were recorded. Results: At follow‐up, 96 patients (3.97%/year) died whilst 107 had an adverse cardiovascular event (3.14%/year). On multivariate analysis, high hsTnT and high hsIL6 remained significantly associated with prognosis even after adjusting for CHADS2score: HR 2.21 (1.46–3.35, P<0.001) for high hsTnT and 1.97 (1.29–3.02, P = 0.002) for high hsIL6, for adverse cardiovascular events. For all‐cause mortality, the HRs were 1.79 (1.13–2.83, P = 0.013) and 2.48 (1.60–3.85, P<0.001), respectively. The integrated discrimination index (IDI) values of clinical scores (CHADS2and CHA2DS2‐VASc) were improved by the addition of hsTnT and/or hsIL6 (all P<0.05). Conclusion: In a large ‘real world’ cohort of anticoagulated AF patients, both hsTnT and hsIL6 levels provided prognostic information that was complementary to clinical risk scores for prediction of long‐term cardiovascular events and death, suggesting that these biomarkers may potentially be used to refine clinical risk stratification in AF.

Platelet activation is a complex mechanism of response to vascular injury and atherothrombotic disease, leading to thrombus formation. A wide variety of surface receptors -integrins, leucine-rich family receptors, G protein coupled receptors, tyrosine kinase receptors- and intraplatelet molecules support and regulate platelet activation. They are potential targets of antiplatelet therapy for the prevention and treatment of arterial thrombosis. Despite the overall clinical benefit of established antiplatelet drugs targeting cyclooxigenase-1 (COX-1), glycoprotein integrin IIb3, and the purinergic P2Y12 receptor of adenosine diphosphate, a significant proportion of treated patients continue to experience recurrent ischaemic events. This may be in partly attributed to insufficient inhibition of platelet activation. In addition, it should not be underestimated that these drugs are not immune from bleeding complications The substantial progress in understating the regulation of platelet activation has played a key role in the development of novel antiplatelet agents. Current examples of drug under development and evaluation include: novel P2Y12 receptor inhibitors (prasugrel, ticagrelor, cangrelor, and elinogrel), thrombin receptor PAR-1 antagonists (vorapaxar, atopaxar), new integrin glycoprotein IIb/IIIa inhibitors, and inhibitors targeting the thromboxane receptor (TP), phosphodiesterases, the collagen receptor glycoprotein VI, and intraplatelet signalling molecules. This review summarizes the mechanisms of action and current clinical evaluation of these novel antiplatelet agents

Clopidogrel is a thienopyridine, which inhibits the platelet P2Y adenosine diphosphate (ADP) receptor termed P2Y12. It is taken as a prodrug that requires biotransformation to an active metabolite by cytochrome P450 (CYP) isoenzymes. In addition, esterases shunt the majority of clopidogrel to an inactive pathway, whilst the remaining prodrug requires two separate CYP-dependent oxidative steps. PPIs might diminish the antiplatelet effects and the clinical effectiveness of clopidogrel possibly through inhibition of CYP2C19 and CYP3A4 isoenzymes. Treatment with clopidogrel and aspirin decreases recurrent cardiovascular events after an acute coronary syndrome. However, an inherent increment of major bleeding is also associated with antiplatelet therapy, as well as dyspepsia with aspirin. Also, major bleeding has been associated with high risk for ischemic events and mortality. For this reason, a proton pump inhibitor (PPI) is often co-prescribed to reduce the risk of gastrointestinal tract bleeding, but its concomitant use might reduce the inhibitory effect of clopidogrel on platelet aggregation. Nevertheless, doubts exist about the possible interaction of concomitant PPI use that may reduce the inhibitory effect of clopidogrel on platelet aggregation. Indeed, there is some controversy with regard to the true risk of cardiovascular adverse events arising from a potential drug-drug interaction between clopidogrel and PPI. In this article, we will review the current status and controversies in relation to a possible interaction between clopidogrel and PPIs.

Abstract: Extraction selectivity of whole wool wax from raw wool by using ethanol-modified carbon dioxide at constant pressure (100 bar) and temperature (60°C) was studied. A kinetic study was carried out to optimize the percentage of ethanol and the extraction time. The modified carbon dioxide was decompressed in ethanol as a collection solvent, leading to the formation of two different fractions as a function of their solubility. Qualitative and quantitative analyses of the lipid classes present in the collected fractions were performed by TLC coupled to an automated FID system (TLC-FID). Moreover, a detailed structural comparison was carried out between the aliphatic high-molecular-mass esters and the steryl ester patterns by means of subambient pressure GC-MS in both the EI and the ammonia positive Cl modes. Considerable differences in the lipid composition of the two wool wax fractions collected were observed by TLC-FID and GC-MS.

Extraction selectivity of whole wool wax from raw wool by using ethanol-modified carbon dioxide at constant pressure (100 bar) and temperature (60°C) was studied. A kinetic study was carried out to optimize the percentage of ethanol and the extraction time. The modified carbon dioxide was decompressed in ethanol as a collection solvent, leading to the formation of two different fractions as a function of their solubility. Qualitative and quantitative analyses of the lipid classes present in the collected fractions were performed by TLC coupled to an automated FID system (TLC-FID). Moreover, a detailed structural comparison was carried out between the aliphatic high-molecular-mass esters and the steryl ester patterns by means of subambient pressure GC-MS in both the EI and the ammonia positive Cl modes. Considerable differences in the lipid composition of the two wool wax fractions collected were observed by TLC-FID and GC-MS.

Summary Voltage-dependent sodium channels (Na+ channels) were localized by autoradiography on mouse skeletal muscle using both light and electron microscopy.125I-scorpion toxins (ScTx) of both the a and ß type were used as probes. The specificity of labelling was verified by competitive inhibition with unlabelled toxin and by inhibition of aScTx labelling in depolarizing conditions. Under light microscopy, the labelling of the myocyte surface appeared randomly distributed with both the a and ß toxins. No difference in the labelling density obtained with ßScTx was observed between a 2 mm central segment of the fibre containing the endplate and an adjacent segment not containing the endplate. At the endplate, however, the ßScTx binding site density was about seven fold higher at the edge of the synaptic primary clefts. This density decreased with distance from the synaptic cleft reaching the extrasynaptic value at 30–40 µm. An analysis of myocyte labelling using electron microscopy provided evidence for a specific, but very low labelling of the myocyte interior which can be attributed to the T-tubules. These results confirm a relatively high density of Na+ channels in a perijunctional zone about 50 µm in width, which could ensure the initial spread of the surface depolarization with a high safety factor, and a homogeneous distribution over the remaining surface with a low density evaluated at 5–10 per µm2. However, the very low labelling of T-tubules could be attributed mainly to a low density of tubular Na+ channels.

Photoreactive derivatives of alpha- and beta-scorpion toxins have been used to analyze the subunit composition of Na+ channels in rat brain. In synaptosomes, both types of toxins preferentially labeled (greater than 85%) a component of 34,000 Da and, at a lower level, another component of 300,000 Da. Reduction of disulfide bridges shifted this latter band from 300,000 Da to 272,000 Da but did not modify the migration of the 34,000-Da component. Similarly, two bands were labeled in cultured brain neurons, one at 259,000 Da by alpha-scorpion toxins and the other at 34,000 Da by both alpha- and beta-scorpion toxins. Contrary to what was observed in synaptosomes, in cultured brain neurons reduction of disulfide bridges had no effect on the migration of the labeled high molecular weight component. Labeling of the smaller polypeptide was obtained even when cells were solubilized with sodium dodecyl sulfate immediately after cross-linking which proves that the 34,000-Da component is not a product of proteolysis. Binding sites for alpha- and beta-scorpion toxins, respectively, did not develop in parallel during neuronal maturation in culture: the increase in beta-scorpion toxin-binding site density was lower and later than that for alpha-scorpion toxin. When related to morphological development, the increase in alpha-scorpion toxin-binding sites was correlated to neurite growth, whereas the increase in beta-scorpion toxin-binding sites was associated with the development of chemical synapses. Finally, in cultured neurons, but not in synaptosomes, both the binding of beta-scorpion toxin and the labeling of the 34,000-Da component by beta-scorpion toxin were enhanced by depolarization of the cell membrane.

Seven polypeptides highly toxic to mice were isolated from the venom of the scorpion, Centruroides suffusus suffusus (Css), and their chemical and toxic properties were characterized. It was shown that the most active toxins by intracerebroventricular injection are less active when injected subcutaneously. The complete amino acid sequence (66 residues) of toxin II (Css II) has been determined. The C-terminal end is amidated as found for most other scorpion toxins. Css II is a beta-type toxin, previously used to define the binding site for activation of the sodium channel. Using rat brain synaptosomes, we demonstrated that all Css toxins compete with 125I-Css II to bind to site 4 and should be considered as beta-scorpion toxins. Specific binding parameters for Css VI, one of the most active toxins, were determined: KD = 100 pM; capacity in binding sites, 2.2 pmol of toxin/mg of synaptosomal protein. Css VI was shown to inhibit gamma-aminobutyric acid uptake by synaptosomes: K 0.5 = 100 pM, which agrees with its KD. Competition experiments between the seven Css toxins and 125I-Css II for antiserum raised against Css II demonstrated that all these toxins have common antigenic properties.

The effects of Ptychodiscus brevis toxin 2 (PbTx-2) on the binding of neurotoxins at four different neurotoxin receptor sites on voltage-sensitive sodium channels in rat brain synaptosomes were examined. Binding of saxitoxin at neurotoxin receptor site 1 and Leiurus quinquestriatus alpha-scorpion toxin (LqTx) at neurotoxin receptor site 3 was unaffected. PbTx-2 enhanced binding of batrachotoxinin A 20-alpha-benzoate (BTX-B) to neurotoxin receptor site 2 and Centruroides suffusus suffusus beta-scorpion toxin (CsTx II) to site 4 on sodium channels. These results support the proposal that PbTx-2 and related toxins act at a new receptor site (site 5) that has not been previously analyzed in binding experiments. Half-maximal effects of PbTx-2 were observed in the range of 20-50 nM PbTx-2. The enhancement of BTX-B binding was reduced by depolarization. Saturating concentrations of PbTx-2 reduced KD values for binding of BTX-B and CsTx-II 2.9-fold and 2.6-fold, respectively. The effects of PbTx-2 and LqTx in enhancing BTX-B binding were synergistic. A model involving both preferential binding of BTX-B, PbTx-2, LqTx, and CsTx II to active states of sodium channels and allosteric interactions among the four receptor sites at which these toxins act accommodates these and previous results.