ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group.

58,050 patients entering 1086 hospitals up to 24 h (median 8 h) after the onset of suspected acute myocardial infarction (MI) with no clear contraindications to the study treatments (in particular, no cardiogenic shock or persistent severe hypotension) were randomised in a "2 x 2 x 2 factorial" study. The treatment comparisons were: (i) 1 month of oral captopril (6.25 mg initial dose titrated up to 50 mg twice daily) versus matching placebo; (ii) 1 month of oral controlled-release mononitrate (30 mg initial dose titrated up to 60 mg once daily) versus matching placebo; and (iii) 24 h of intravenous magnesium sulphate (8 mmol initial bolus followed by 72 mmol) versus open control. There were no significant "interactions" between the effects of these three treatments, and the results for each are based on the randomised comparison of about 29,000 active versus 29,000 control allocated patients. Captopril There was a significant 7% (SD 3) proportional reduction in 5-week mortality (2088 [7.19%] captopril-allocated deaths vs 2231 [7.69%] placebo; 2p = 0.02), which corresponds to an absolute difference of 4.9 SD 2.2 fewer deaths per 1000 patients treated for 1 month. The absolute benefits appeared to be larger (perhaps about 10 fewer deaths per 1000) in certain higher-risk groups, such as those presenting with a history of previous MI or with heart failure. The survival advantage appeared to be maintained in the longer term (5.4 [SD 2.8] fewer deaths per 1000 at 12 months). Captopril was associated with an increase of 52 (SD 2) patients per 1000 in hypotension considered severe enough to require termination of study treatment, of 5 (SD 2) per 1000 in reported cardiogenic shock, and of 5 (SD 1) per 1000 in some degree of renal dysfunction. It produced no excess of deaths on days 0-1, even among patients with low blood pressure at entry. Mononitrate There was no significant reduction in 5-week mortality, either overall (2129 [7.34%] mononitrate-allocated deaths vs 2190 [7.54%] placebo) or in any subgroup examined (including those receiving short-term non-study intravenous or oral nitrates at entry). Further follow-up did not indicate any later survival advantage. The only significant side-effect of the mononitrate regimen studied was an increase of 15 (SD 2) per 1000 in hypotension. Those allocated active treatment had somewhat fewer deaths on days 0-1, which is reassuring a bout the safety of using nitrates early in acute MI.(ABSTRACT TRUNCATED AT 400 WORDS

Synthesis of novel Bi-, Tri-, and tetracyclic nucleosides by reaction of a common cyclic enamine derived from TSAO-T with nucleophiles

We report here the efficient regio-and stereoselective synthesis of new polycyclic nucleosides using a common cyclic enamine (7) as the starting material. In fact, the reaction of 7, easily prepared by reaction of 5¢-O-Tosyl TSAO-T under basic nonnucleophilic conditions (potassium carbonate), with different classes of nucleophiles, for example, nitrogen-, oxygen-, sulfur-, and carbon-based nucleophiles, or with amino acids afforded, with total regio-and stereoselectivity, new bi-, tri-, and tetracyclic nucleosides. This straighforward route represents an original and unambiguously regio- and stereoselective pathway to these compounds. Some of these polycyclic nucleosides may be useful intermediates for a second series of reactions that may lead to the generation of structurally new nucleosides.We thank Susana Ruiz and Marı´a Jose´ Galeote for their excellent technical as- sistance. We thank the Ministry of Education of Spain for grants to C.C. and M.-C.B. The Spanish Ministerio de Ciencia y Tecnologı´a (Project SAF2003-07219-C02- 01) and the European Commission (Projects QLK2-CT- 2000-00291 and HPAW-CT-2002-90001) are acknowl- edged for their financial support.Peer reviewe

Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Fibrinolytic Therapy Trialists' (FTT) Collaborative Group.

Large randomised trials have demonstrated that fibrinolytic therapy can reduce mortality in patients with suspected acute myocardial infarction (AMI). The indications for, and contraindications to, this treatment in some categories of patient are disputed, examples being late presentation, elderly patients, and those in cardiogenic shock. This overview aims to help resolve some of the remaining uncertainties. From all trials of fibrinolytic therapy versus control that randomised more than 1000 patients with suspected AMI, information was sought and checked on deaths during the first 5 weeks and on major adverse events occurring during hospitalisation. The nine trials included 58,600 patients, among whom 6177 (10.5%) deaths, 564 (1.0%) strokes, and 436 (0.7%) major non-cerebral bleeds were reported. Fibrinolytic therapy was associated with an excess of deaths during days 0-1 (especially among patients presenting more than 12 h after symptom onset, and in the elderly) but this was outweighed by a much larger benefit during days 2-35. This "early hazard" should not obscure the very clear overall survival advantage that is produced by fibrinolytic therapy. Benefit was observed among patients presenting with ST elevation or bundle-branch block (BBB)--irrespective of age, sex, blood pressure, heart rate, or previous history of myocardial infarction or diabetes--and was greater the earlier treatment began. Among the 45,000 patients presenting with ST elevation or BBB the relation between benefit and delay from symptom onset indicated highly significant absolute mortality reductions of about 30 per 1000 for those presenting within 0-6 h and of about 20 per 1000 for those presenting 7-12 h from onset, and a statistically uncertain benefit of about 10 per 1000 for those presenting at 13-18 h (with more randomised evidence needed in this latter group to assess reliably the net effects of treatment). Fibrinolytic therapy was associated with about 4 extra strokes per 1000 during days 0-1: of these, 2 were associated with early death and so were already accounted for in the overall mortality reduction, 1 was moderately or severely disabling, and 1 was not. This overview indicates that fibrinolytic therapy is beneficial in a much wider range of patients than is currently given such treatment routinely