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

Low serum Insulin Like Growth Factor - 1 in patients with Stress Urinary Incontinence

ABSTRACT Objective: SUI, involuntary loss of urine, occurs when intra abdominal pressure exceeds urethral pressure in women. Recent animal study has shown that there are therapeutic effects of Insulin-like growth factors (IGF-1) on stress urinary incontinence in rats with simulated childbirth trauma. IGF-1 is an important mediator of cell growth, differentiation and transformation in various tissues and stimulates fibroblast proliferation and enhances collagen synthesis. The purpose of the current study was to determine the association between IGF-1 levels and SUI. Materials and Methods: All patients were evaluated for SUI and divided into two groups: 116 women with SUI and 76 women without SUI. Diagnosis of SUI was based on the International Consultation on Incontinence Questionnaire-Short Form (ICIQSF). Levels of IGF-1 were measured in serum by enzyme-linked immunosorbent assay. The relationship between IGF-1 levels and SUI in patients was evaluated statisticaly. Results: The mean age of patients wiyh SUI was 49.9±8.6 and 48.7±7.8 in control group. Plasma IGF-1 levels were significantly lower in SUI than in control group (106.5±26.4 and 133.3±37.1ng/mL, respectively, P <0.001). Body mass indexes were higher in women with SUI than women without SUI. Conclusion: In this study lower serum IGF-1 levels were found to be associated with SUI. Serum IGF-1 level appears to be a specific predictor of SUI, and it may be used in early prediction of SUI in female population

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

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

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