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The racemic alpha-trifluoromethyl-alpha-amino-beta-sulfone hydroxamates 1 were synthesized by means of a nucleophilic addition of sulfur-stabilized carbanions to a N-Cbz imine of trifluoropyruvate (4). The free amino derivative 1a was the most potent inhibitor of both MMP-3 (stromelysin-1) and MMP-9 (gelatinase-B), showing an IC50 = 14 nM and 1 nM, respectively, and excellent selectivity versus MMP- 1 (>5000-fold difference in inhibitory capacity). The N-Me derivative 1b was the most selective for MMP-3 with respect to MMP-9 (62-fold difference).

El tabaquismo es uno de los principales problemas de salud pública de los países desarrollados. A pesar de la extensa evidencia clínica y epidemiológica de sus efectos adversos sobre la salud oral y general, el abandono del tabaco no sigue una progresión nada alentadora. Durante los últimos años ha crecido el reconocimiento del importante papel del equipo odontológico en el cese del hábito tabáquico de sus pacientes. El objetivo de este trabajo es realizar una revisión de la evidencia existente sobre la efectividad de los programas de cese del hábito tabáquico desarrollados en la práctica odontológica, presentando estrategias y protocolos de actuación propuestos en los últimos años, para poder establecer una sistemática de actuación sobre los pacientes aplicable a la clínica diaria, que resulte factible y efectiva. Para ello se ha llevado a cabo una búsqueda bibliográfica sobre programas de cese del hábito tabáquico a nivel odontológico, así como de protocolos de actuación propuestos en los últimos años para estas intervenciones. Este trabajo concluye que existe una considerable evidencia científica que respalda la eficacia de los programas para el cese del hábito tabáquico aplicados en odontología. Se trata de intervenciones conductuales breves, que pueden complementarse con terapias farmacológicas, y de las que debe ser partícipe,todo el equipo odontológico.

Rupture of the atherosclerotic plaque: does a good animal model exist?Cullen P, Baetta R, Bellosta S, Bernini F, Chinetti G, Cignarella A, von Eckardstein A, Exley A, Goddard M, Hofker M, Hurt-Camejo E, Kanters E, Kovanen P, Lorkowski S, McPheat W, Pentikainen M, Rauterberg J, Ritchie A, Staels B, Weitkamp B, de Winther M; MAFAPS Consortium.Institute of Arteriosclerosis Research, Domagkstrasse 3, D-48149 Muenster, Germany. cullen@uni-muenster.deBy its very nature, rupture of the atherosclerotic plaque is difficult to study directly in humans. A good animal model would help us not only to understand how rupture occurs but also to design and test treatments to prevent it from happening. However, several difficulties surround existing models of plaque rupture, including the need for radical interventions to produce the rupture, lack of direct evidence of rupture per se, and absence of convincing evidence of platelet- and fibrin-rich thrombus at the rupture site. At the present time, attention should therefore focus on the processes of plaque breakdown and thrombus formation in humans, whereas the use of animal models should probably be reserved for studying the function of particular genes and for investigating isolated features of plaques, such as the relationship between cap thickness and plaque stability.

To investigate the direct anti-atherosclerotic properties of statins.Using in vitro and ex vivo models, the effect of different statins on key events involved in atherogenesis has been investigated. We studied the ability of statins to modulate modified LDL-induced cholesterol esterification, metalloproteinase secretion by macrophages, and arterial myocyte migration and proliferation. The mechanisms underlying the inhibitory effect of statins have also been explored. Finally, the antiproliferative effect of sera from statin-treated patients has been confirmed in a cell culture system.Fluvastatin, simvastatin, lovastatin, atorvastatin, and cerivastatin, but not pravastatin, dose-dependently decrease smooth muscle cell (SMC) migration and proliferation. Moreover, statins are able to reduce cholesterol accumulation in macrophages in vitro by blocking cholesterol esterification and endocytosis of modified lipoproteins and matrix-degrading enzyme secretion. This in vitro inhibition was completely prevented by mevalonate and partially by all-trans farnesol and all-trans geranylgeraniol, confirming the specific role of isoprenoid metabolites (probably through prenylated protein[s]) in regulating these cellular events. The inhibitory effect of statins on SMC proliferation has been shown in different models of proliferating cells, such as cultured arterial myocytes and rapidly proliferating carotid and femoral intimal lesions in rabbits, independently of their ability to reduce plasma cholesterol. Finally, ex vivo studies showed that sera from fluvastatin-treated patients interfere with SMC proliferation.These results suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors exert a direct anti-atherosclerotic effect in the arterial wall, beyond their effects on plasma lipids that could translate into a more significant prevention of cardiovascular disease. These findings provide a basis for the beneficial effect of statins in clinical trials also involving diabetic patients--a population with a higher absolute risk of recurrent cardiovascular events.