PubMed · 14664277
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Sidney Goldstein. 2003. A COMET lost.. https://pubmed.ncbi.nlm.nih.gov/14664277/
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Hypertension and lipid disorders in type II diabetes contribute to increased coronary risk, but optimal drug therapy has not been defined. We investigated primary care physicians choices of antihypertensive and lipid-lowering therapy for subjects with type II diabetes diagnosed with hypertension. Subjects were registered with 105 UK general practices in the General Practice Research Database and prescribed oral hypoglycaemic drugs for the first time between January 1993 and December 2001. We evaluated prescriptions for antihypertensive drugs in subjects with secondary diagnoses of hypertension in the first year following initiation of oral hypoglycaemic therapy. Data were analysed for 4519 diabetic subjects with diagnosed hypertension. Between 1993 and 2001, the proportion prescribed thiazide diuretics increased from 20 to 30%; angiotensin-converting enzyme (ACE) inhibitors from 35 to 45% and angiotensin receptor blockers from 0 to 8%. The proportion of subjects prescribed lipid-lowering therapy increased from 8% in 1993 to 33% in 2001, with the proportion prescribed statins increasing from 1 to 30%. At different general practices, the proportion prescribed thiazide diuretics ranged from 0 to 52%, beta-blockers from 5 to 60%, ACE inhibitors from 15 to 81%, and statins from 0 to 50%. Variation between practices was not explained by adjusting for age, sex, prevalent coronary heart disease or study year. Trends in drug utilisation were consistent with the evolving evidence base but there were wide variations in drug utilisation between practices. A more consistent approach to drug selection might be associated with improved patient outcomes.
OBJECTIVES: It has been shown that sarcolemmal rupture can occur during reenergization in cardiomyocytes in which previous ischemia has induced sarcolemmal fragility by calpain-dependent hydrolysis of structural proteins. We tested the hypothesis that attenuated calpain activation contributes to the protection against reperfusion-induced cell death afforded by ischemic preconditioning (IPC), and investigated the involvement of protein kinase A (PKA) in this effect. METHODS: Calpain activity and degradation of different structural proteins were studied along with the extent of necrosis in isolated rat hearts submitted to 60 min of ischemia and 30 min of reperfusion with or without previous IPC (two cycles of 5 min ischemia-5 min reperfusion), and the ability of different treatments to mimic or blunt the effects of IPC were analyzed. RESULTS: IPC accelerated ATP depletion and rigor onset during ischemia but reduced LDH release during reperfusion by 69% (P<0.001). At the end off reperfusion, calpain activity was reduced by 66% (P<0.001) in IPC, and calpain-dependent degradation of sarcolemmal proteins was attenuated. Addition of the calpain inhibitor MDL-28170 mimicked the effects of IPC on protein degradation and reduced LDH release by 48% (P<0.001). The effects of IPC on calpain, alpha-fodrin, and LDH release were blunted by the application of the PKA inhibitor H89 or alprenolol during IPC, while transient stimulation of PKA with CPT-cAMP or isoproterenol before ischemia attenuated calpain activation, alpha-fodrin degradation, and markedly reduced LDH release (P<0.001). In hearts exposed to Na(+)-free perfusion, IPC attenuated calpain activation by 67% (P<0.001) and reduced by 56% (P<0.001) LDH release associated to massive edema occurring during Na(+) readmission without modifying its magnitude. CONCLUSION: These results are consistent with PKA-dependent attenuation of calpain-mediated degradation of structural proteins being an end-effector mechanism of the protection afforded by IPC.
Metoprolol and its metabolites alpha-hydroxymetoprolol, O-desmethylmetoprolol, metoprolol acid and deaminated metoprolol were quantified in dog plasma using an isocratic high-performance liquid chromatographic method (with a BetaBasic Cyano column) with fluorescence detection. A solid phase extraction technique (Oasis HLB, Waters) was used to extract metoprolol and its four metabolites from dog plasma with high recovery rates. The method was shown to be sensitive and reproducible and was used to determine the pharmacokinetic profile of metoprolol in dog. To the best of our knowledge, this is the only method that can extract and analyze metoprolol and its four metabolites in a single assay.