Full therapeutic heparin doses ranging from 5000-10,000 units or weight based (70-100 units/kg) have been recommended during percutaneous coronary interventions. However, there are currently no data available in regards to the appropriate dosing of unfractionated heparin during intravascular ultrasound (IVUS) studies without therapeutic coronary interventions. The goal of this study was to evaluate the safety of low dose unfractionated heparin during IVUS studies, shortly after endomyocardial biopsy in cardiac transplant patients.At the University of Arizona Medical Center, transplant patients routinely undergo diagnostic IVUS studies for the detection of early cardiac allograft vasculopathy (CAV) shortly after endomyocardial biopsy. A low-dose heparin (2000 to 3000 Units) is given before coronary wire and IVUS catheter advancement without checking activated clotting time. We evaluated the occurrence of any thromboembolic event or any other adverse outcomes in this population.A total of 108 cardiac transplant patients, who had underwent routine IVUS studies between 2004-2008 were identified retrospectively. The average heparin dose used was 2528 ± 501 units. The left anterior descending artery was studied in 93% of cases. There was no thromboembolic event. Only one catheter-induced coronary dissection occurred treated with percutaneous coronary intervention. An endomyocardial biopsy was performed 10-15 minutes before the administration of low-dose heparin. There were no other major adverse cardiac events in this population during the procedure.This is the first study showing the safety of low-dose heparin use during diagnostic IVUS studies in cardiac transplant patients, even shortly after endomyocardial biopsy.
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β-adrenergic blocking agents have been in use for nearly 40 years. β-blockers have been more thoroughly studied in the past twenty years as they have become commonly prescribed to heart failure patients. The class of β-blockers has grown considerably and has many pharmaceutical applications in patients with heart failure. Carvedilol has been the most effective beta-blocker in the treatment of the systolic heart failure. Carvedilol is a non-selective β- and α-blocker enantiomer with antioxidant effects that are attributed to its carbazole moiety. Carvedilol is taken twice daily because it is extensively metabolized and therefore loses its effectiveness due to a short half-life. Recently a long acting carvedilol has become available, as Coreg CR. Coreg CR is available for once-a-day administration as controlled-release oral capsules containing 10, 20, 40, or 80 mg carvedilol phosphate. The subject of the current report is to design a new structural analog of carvedilol that incorporates a protecting group such as a fluorine atom at position 8 of the carbazole ring for the purpose of blocking a critical metabolic pathway thus increasing its half life. This will follow discussion regarding current carvedilol patents. We believe that carvedilol activity will remain unchanged. The synthesis of 8-Fluoro-1, 2, 3, 9- tetrahydro-4H-carbazol-4-one, a key synthetic intermediate of the designed carvedilol analog, was carried out and successfully characterized.
The development of peptide β-hairpins is problematic, because folding depends on the amino acid sequence and changes to the sequence can significantly decrease folding. Robust β-hairpins that can tolerate such changes are attractive tools for studying interactions involving protein β-sheets and developing inhibitors of these interactions. This paper introduces a new class of peptide models of protein β-sheets that addresses the problem of separating folding from the sequence. These model β-sheets are macrocyclic peptides that fold in water to present a pentapeptide β-strand along one edge; the other edge contains the tripeptide β-strand mimic Hao [JACS 2000, 122, 7654] and two additional amino acids. The pentapeptide and Hao-containing peptide strands are connected by two δ-linked ornithine (δOrn) turns [JACS 2003, 125, 876]. Each δOrn turn contains a free α-amino group that permits the linking of individual modules to form divalent β-sheets. These "cyclic modular β-sheets" are synthesized by standard solid-phase peptide synthesis of a linear precursor followed by solution-phase cyclization. Eight cyclic modular β-sheets 1a−1h containing sequences based on β-amyloid and macrophage inflammatory protein 2 were synthesized and characterized by 1H NMR. Linked cyclic modular β-sheet 2, which contains two modules of 1b, was also synthesized and characterized. 1H NMR studies show downfield α-proton chemical shifts, δOrn δ-proton magnetic anisotropy, and NOE cross-peaks that establish all compounds but 1c and 1g to be moderately or well folded into a conformation that resembles a β-sheet. Pulsed-field gradient NMR diffusion experiments show little or no self-association at low (≤2 mM) concentrations. Changes to the residues in the Hao-containing strands of 1c and 1g improve folding and show that folding of the structures can be enhanced without altering the sequence of the pentapeptide strand. Well-folded cyclic modular β-sheets 1a, 1b, and 1f each have a phenylalanine directly across from Hao, suggesting that cyclic modular β-sheets containing aromatic residues across from Hao are better folded.
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