Fundamental & clinical pharmacology
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Fundam Clin Pharmacol · Jun 2007
Effects of KR-33028, a novel Na+/H+ exchanger-1 inhibitor, on ischemia and reperfusion-induced myocardial infarction in rats and dogs.
The present study was performed to evaluate the cardioprotective effects of KR-33028, a novel Na+/H+ exchanger subtype 1 (NHE-1) inhibitor, in rat and dog models of coronary artery occlusion and reperfusion. In anesthetized rats subjected to a 45-min coronary occlusion and a 90-min reperfusion, KR-33028 at 5 min before occlusion (i.v. bolus) dose-dependently reduced myocardial infarct size from 58.0% to 46.6%, 40.3%, 39.7%, 33.1%, and 27.8% for 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg respectively (P < 0.05). In anesthetized beagle dogs that underwent a 1.0-h occlusion followed by a 3.0-h reperfusion, KR-33028 (3 mg/kg, i.v. bolus) markedly decreased infarct size from 45.6% in vehicle-treated group to 16.4% (P < 0.05), and reduced the reperfusion-induced release in creatine kinase myocardial band isoenzyme (MB), lactate dehydrogenase, troponin-I, glutamic oxaloacetic transaminase, and glutamic pyruvic transaminase. ⋯ In all studies, KR-33028 caused no significant changes in any hemodynamic profiles. In an isolated rat heart model of hypothermic cardioplegia, KR-33028 (30 mum), which was added to the heart preservation solution (histidin-tryptophan-ketoglutarate) during hypothermic cardioplegic arrest, significantly improved the recovery of left ventricular developed pressure, heart rate and dP/dt(max) after reperfusion. Taken together, these results indicate that KR-33028 significantly reduced the myocardial infarction induced by ischemia and reperfusion in rats and dogs, without affecting hemodynamic profiles.
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Geriatric patients are a subset of older people with multiple comorbidities that usually have significant functional implications. Geriatric patients have impaired homeostasis and wide inter-individual variability. ⋯ This requires evaluation of evidence from clinical trials, application of the evidence to frail older people through an understanding of changes in pharmacokinetics and pharmacodynamics, and attention to medication management issues. Given that most disease occurs in older people, and that older people are the major recipients of drug therapy in the Western world, increased research and a better evidence base is essential to guide clinicians who manage geriatric patients.
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Fundam Clin Pharmacol · Jun 2007
Randomized Controlled TrialAntiplatelet drug use preceding the onset of intracerebral hemorrhage is associated with increased mortality.
Recent studies highlight the contribution of antiplatelet therapy to clinical severity and increased mortality of intracerebral hemorrhage (ICH) but results are discrepant. The aim of this report was to evaluate the association between antiplatelet drug use preceding the onset of ICH and the mortality, assessed at regular intervals, among patients with acute ICH. We analyzed data from a randomized study which enrolled consecutive patients with a documented acute ICH to evaluate the efficacy of intermittent pneumatic compression of the legs in venous thrombosis prevention. ⋯ The corresponding estimated risks for mortality related to antiplatelet drug use were 3.6 (95% CI 1.1-12), 4.5 (95% CI 1.8-11), and 3.6 (95% CI 1.5-8.6). Adjusted for age, hypertension and alcohol over use, antiplatelet therapy remained significantly associated with an increased mortality rate of acute ICH. Current antiplatelet drug use preceding the onset of ICH is associated with increased short-term ICH mortality, independently of age.