La amiodarona como causa de parálisis periódica hipopotasémica tirotóxica (réplica) / Amiodarone as cause of thyrotoxic hypokalaemic periodic paralysis (response)

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Novel bis(indolyl)maleimide pyridinophanes that are potent, selective inhibitors of glycogen synthase kinase-3.

Novel bis(indolyl)maleimide pyridinophanes 3, 9a, 9b, 10a, 10b, and 11 were prepared by cobalt-mediated [2+2+2] cycloaddition of an appropriate alpha,omega-diyne with an N,N-dialkylcyanamide. These macrocyclic heterophanes were found to be potent, selective inhibitors of glycogen synthase kinase-3beta. An X-ray structure of a co-crystal of GSK-3beta and 3 (IC(50)=3nM) depicts the hydrogen bonding and hydrophobic interactions in the ATP-binding pocket of this serine/threonine protein kinase.

Synthesis of macrocycles via cobalt-mediated [2 + 2 + 2] cycloadditions.

We investigated the formation of macrocycles from alpha,omega-diynes in cobalt-mediated co-cyclotrimerization reactions. Long-chain alpha,omega-diynes underwent metal-mediated [2 + 2 + 2] cycloadditions with nitriles, cyanamides, or isocyanates in the presence of CpCo(CO)2 (Cp = cyclopentadienide) to yield pyridine-containing macrocycles, i.e., meta- and para-pyridinophanes, such as 5m/5p, 35m/35p, and 41m/41p. The regioselectivity of these reactions was affected by the length and type of linker unit between the alkyne groups, as well as by certain stereoelectronic factors. An analogous alpha,omega-cyano-alkyne, 28, combined with an alkyne to yield two isomeric meta-pyridinophanes, such as 5m and 29m, and an ortho cycloadduct (benzannulation product), such as 29o. We developed a reaction protocol for these cobalt-based [2 + 2 + 2] cycloadditions that involves markedly improved conditions such that this process offers a convenient, flexible synthetic approach to macrocyclic pyridine-containing compounds. For example, diyne 6 reacted with p-tolunitrile in 1,4-dioxane to give 7p and 7m (7:1 ratio) in 87% yield at a moderate temperature of ca. 100 degrees C in 24 h without photoirradiation or syringe-pump addition. Isocyanates were also effective reactants, as exemplified by the formation of 44p almost exclusively (44p:44m > 50:1) in 64% yield from diyne 8 and 2-phenylethylisocyanate. By using this improved protocol we were able to co-cyclotrimerize long-chain alpha,omega-diynes with alkynes in certain cases to demonstrate a successful macrocyclic variant of the Vollhardt reaction. For instance, diyne 6 reacted with dipropylacetylene to give paracyclophane 57p and benzannulene 57o (2:1 ratio) in 29% yield.

Cobalt-mediated cyclotrimerisation of bis-alkynes and cyanamides.

CpCo(CO)2-mediated cyclotrimerisation of bis-alkynes and cyanamides provides multisubstituted 2-aminopyridines, including macrocyclic products, such as 22 (50% yield).

Catalytic activity of dodecacarbonyltetracobalt in aqueous media: a "greening" of the Pauson-Khand reaction.

The unprecedented reactivity of Co(4)(CO)(12) with enynes under aqueous conditions, representing the development of a mild and simple aqueous-phase cobalt-catalyzed PK reaction protocol, is described herein.

Cobalt-mediated macrocyclizations. Facile synthesis of 2-oxo pyridinophanes via [2 + 2 + 2] cycloaddition of alpha, omega-diynes and isocyanates.

[reaction: see text] Cobalt-mediated [2 + 2 + 2] cycloaddition of alpha,omega-diynes and isocyanates provides a direct approach to macrocyclic 2-oxopyridinophanes. This macrocyclization process, which proceeded most efficiently with aliphatic isocyanates, was conveniently performed at a moderate temperature (85 degrees C) without irradiation or syringe-pump addition.

A sterically-encumbered, C2-symmetric chiral acetal for enhanced asymmetric induction in the Pauson-Khand reaction.

High levels of diastereoselection were achieved in the PKR of 1,6- and 1,7-cyclopropylidenynes bearing a bulky propargylic C(2)-symmetric acetal.

Pathogenesis of the acute coronary syndromes and therapeutic implications.

Atherosclerosis is characterized by the thickening and obstruction of the arterial lumen and thrombosis associated with vulnerable disrupted plaques seems to be responsible for the accelerated process of clinical syndrome presentation. Strategies to promote plaque stabilization and reduce thrombus burden have been one of the major targets of recent times. Modification of diet and lifestyle has important benefit in reducing coronary risk. Several pharmacological strategies for reducing cardiovascular morbidity and mortality have demonstrated effectiveness. Statins and angiotensin converting enzyme, fibrinolytics, inhibitors of the intrinsic coagulation cascade and anti-platelet agents have been developed to reduce the impact of atherosclerosis and inhibit thrombogenesis.

[Cellular and molecular bases of cholesterol accumulation in the vascular wall and its contribution to the progression of atherosclerotic lesion]. / Bases celulares y moleculares de la acumulación de colesterol en la pared vascular y su contribución a la progresión de la lesión aterosclerótica.

The rupture of atherosclerotic plaques depends mainly on their composition. Vulnerable plaques are those that contain a large lipidic core, which derives either from the retention and modification of LDL and/or from necrosis of foam cells. Most foam cells derive from monocyte/macrophages. Although some of them, especially in advanced plaques, derive from smooth muscle cells. Different receptors involved in the process of foam cell formation have been identified: e.g., scavenger receptors, VLDL receptors and alpha 2-macroglobulin/low density lipoprotein receptor-related proteins. The LDL derived cholesterol collected by these receptors is transformed through the enzyme acyl CoA cholesterol acyl transferase (ACAT) in esterified cholesterol, the hallmark of foam cell formation. High density lipoprotein (HDL) allows the release of free cholesterol from the plasmatic membrane inducing the regression of atherosclerotic lesions.

Prevention of cholesteryl ester accumulation in P388D1 macrophage-like cells by increased cellular vitamin E depends on species of extracellular cholesterol. Conventional heterologous non-human cell cultures are poor models of human atherosclerotic foam cell formation.

Since the cellular role of the antioxidative vitamins in the formation of foam cells has not yet been studied in detail, we investigated the effect of alpha-tocopherol and ascorbic acid loading of P388D1 macrophage-like cells on their cholesterol and cholesteryl ester levels and their response to the exposure to different lipoproteins. alpha-Tocopherol loading, but not ascorbic acid loading, of P388D1 cells strongly reduced their cellular cholesteryl ester/cholesterol ratio (the crucial indicator of foam cell formation) when fetal calf serum was the only extracellular source of cholesterol. Balance studies suggest that this effect of alpha-tocopherol was mainly due to a reduced uptake of fetal-calf-serum-derived cholesterol. alpha-Tocopherol loading, however, did not reduce the cholesteryl ester/cholesterol ratio when human unmodified low-density lipoprotein (LDL) was added to culture medium containing fetal calf serum. Thus, the uptake of fetal-calf-serum-derived cholesterol was competitively reduced by human LDL, the uptake of which remained unaffected by alpha-tocopherol. Similarly, alpha-tocopherol loading did not prevent cholesteryl ester formation induced by human LDL either oxidized with Cu2+, ultraviolet light or HOCl, or modified by acetylation, aggregation or by malondialdehyde treatment. The present experimental conditions lacked any pro-oxidative burden, since (a) ascorbic acid, either alone or combined with alpha-tocopherol, did not affect cellular cholesteryl ester levels, (b) foam cell formation was not a linear function of the degree of oxidative LDL modification, and (c) alpha-tocopherol lacked specific effects on oxidatively modified LDL. Thus, the reduction of cellular cholesteryl esters by alpha-tocopherol in the absence of human unmodified LDL was hardly due to common antioxidative properties of vitamin E. In conclusion, the present observation that a desirable alpha-tocopherol effect on the cholesteryl ester balance in mouse-tumor-derived P388D1 cells strongly depended on the species of extracellular cholesterol carrier, cautions against premature generalizations of conventional non-human cell culture data.

[Haemophilus influenzae systemic infections in a children's hospital]. / Infecciones sistémicas a Haemophilus influenzae en un hospital infantil.

Thirty seven infections due to "Haemophilus influenzae" b were registered from January 1979 to December 1983. The organism was isolated from blood and/or CSF in all cases. Relation with sex or season predominance was not observed. Children's age was 1 day to 9 years, 83% were below 2 years. They were 16 meningitis (43.2%); 10 pneumonias (27.0%); 4 epiglottitis (10.8%); 4 bacteremias; 2 perinatal infections and 1 case of arthritis. Six cases (16.2%) were hospital infections. Age for meningitis and pneumonias was significantly lower than for epiglottitis. Eight strains were ampicillin resistant (21.6%). In meningitis 31.1% and in pneumonias 30.0% of the strains were resistant. There were no resistances in other localizations. One strain resistant to both, ampicillin and chloramphenicol was treated with cefotaxim.