Chemical Proteomics-Based Analysis of Off-target Binding Profiles for Rosiglitazone and Pioglitazone: Clues for Assessing Potential for Cardiotoxicity

Drugs exert desired and undesired effects based on their binding interactions with protein target(s) and off-target(s), providing evidence for drug efficacy and toxicity. Pioglitazone and rosiglitazone possess a common functional core, glitazone, which is considered a privileged scaffold upon which to build a drug selective for a given target—in this case, PPARγ. Herein, we report a retrospective analysis of two variants of the glitazone scaffold, pioglitazone and rosiglitazone, in an effort to identify off-target binding events in the rat heart to explain recently reported cardiovascular risk associated with these drugs. Our results suggest that glitazone has affinity for dehydrogenases, consistent with known binding preferences for related rhodanine cores. Both drugs bound ion channels and modulators, with implications in congestive heart failure, arrhythmia, and peripheral edema. Additional proteins involved in glucose homeostasis, synaptic transduction, and mitochondrial energy production were detected and potentially contribute to drug efficacy and cardiotoxicity

Urinary adrenomedullin levels are increased and correlated with plasma concentrations in patients with Behcet's syndrome

Background: The objective was to measure urinary adrenomedullin (AM) levels in patients with active or inactive Behcet's syndrome and compare them to levels in healthy control subjects

Adrenomedullin and nitrite levels in children with primary nocturnal enuresis

PubMedID: 12185469Primary nocturnal enuresis (PNE) is the most common type of nocturnal enuresis in children, but its etiology remains unclear. Recent studies indicated the differences in urinary electrolytes in enuretic children, and stressed the existence of a renal tubular maturation defect. In this study, 30 children (aged 6-12 years) with PNE were investigated in comparison with 18 healthy controls. We evaluated plasma antidiuretic hormone, electrolytes, 24-h urine volume, osmolarity, and urinary electrolytes. Unlike other studies, we firstly assessed the plasma and urinary adrenomedullin (AM) and total nitrite levels, a stable product of nitric oxide (N0), and investigated their relationship with urinary electrolytes. The plasma AM and total nitrite levels were significantly lower than controls. Urine volume (24-h) and potassium excretion were higher than in controls. However, 24-h urinary osmolarity and excretion of AM were significantly lower than in controls. Our results indicate that there may be a problem in renal regulation of potassium in children with PNE. Although decreased levels of AM and total nitrite may be a compensatory response to abnormal potassium and water excretion, further investigations are required to exclude whether the renal synthesis of AM and NO are also deficient in these children

Increased nitric oxide production in patients with Behcet's disease: Is it a new activity marker?

Background. The origin of Behcet's disease (BD) is unclear. One of the prominent features of BD is vasculitis and thrombosis as a result of endothelial dysfunction. Because nitric oxide (NO) is synthesized by endothelium, we considered it as an interesting target of investigation in BD

Increased plasma adrenomedullin levels in patients with Behcet's disease

Background: Behcet's disease (BD) is a chronic systemic inflammatory disorder affecting multiple organs with a generalized vasculitis of arteries and veins. Endothelial dysfunction is one of the prominent features of ED. Adrenomedullin (AM) is a peptide produced not only in normal adrenal medulla but also in the vascular smooth muscle cells and endothelial cells, and its role in the course of ED has not been previously described. Objective: To detect changes of plasma AM concentrations in patients with ED compared with age- and sex-matched healthy subjects by using high-performance liquid chromatography (HPCL). We also investigated if disease activity or the duration of ED correlates with ANT levels. Methods: Forty-two consecutive patients with ED (38.5 +/- 11.1 years, 19 male and 23 female) and 20 healthy age- and sex-matched control subjects (39.5 +/- 10.9 years, 8 male and 12 female) were included in this study. We measured plasma AM levels by HPCL, and acute-phase reactants including alpha (1)-antitrypsin and alpha (2)-macroglobulin, neutrophil count and the erythrocyte sedimentation rate. Results: Mean +/- SD plasma AM levels in patients with ED (73.22 +/- 25.55 pmol/l) were significantly higher (p 12.37 pmol/l). Patients with active ED had similar plasma AM concentrations (79.32 +/- 21.89 pmol/l) with patients with inactive disease (67.44 +/- 29.92 pmol/l). On the other hand, patients with longer duration of the disease (mean duration, 13.9 +/- 3.8 years) had significantly higher plasma AM levels (83.99 +/- 19.71 pmol/l; p = 0.005) than patients (62.45 +/- 26.57 pmol/l) with shorter duration of the disease (mean duration, 5.5 +/- 2.3 years). All acute-phase reaction parameters were found to be significantly increased in the active disease. Conclusion: Considering its endothelial cell implications, AM may be involved in reparatory vessel endothelium mechanisms, especially in the chronic disease. Copyright (C) 2000 S. Karger G, Basel

Serum leptin concentrations are decreased and correlated with disease severity in age-related macular degeneration: a preliminary study

Background Age-related maculopathy (ARM) or degeneration (ARMD) is the leading cause of irreversible blindness in developed countries. Despite several studies on the morphology of ARMD, the aetiology is unknown and factor(s) contributing to the pathogenesis remain to be characterised. More recent studies have demonstrated that cholesterol esters and lipids are present within Bruch's membrane deposits and drusen, and dietary fat intake is associated with ARMD. The product of Ob gene, leptin, is a recently discovered peptide participating in human metabolism. There is a direct relationship between serum leptin and diet, and lipoprotein metabolism, but the role of leptin in the course of ARMD has not previously been investigated