[Liposomial iron: a new proposal for the treatment of anaemia in chronic kidney disease]. / Il ferro liposomiale: una nuova proposta per il trattamento dell'anemia nei pazienti affetti da insufficenza renale cronica.

Iron supplementation is essential for the treatment of anemia in the chronic kidney disease (CKD) population. Liposomial iron is a preparation of ferric pyrophosphate carried within a phospholipidic membrane. Compared to other oral formulations, it is well absorbed from the gut and demonstrates high bioavailability together with a lower incidence of side effects. The aim of our study was to evaluate the effectiveness of treatment with liposomial iron compared to intravenous iron in a CKD population with anemia and iron deficiency. Our study is a single-center, prospective, randomized, fourth-phase study. Enrollment for the study began in October 2011 and CKD 3, 4 and 5 patients were randomized to receive either intravenous iron or liposomial iron in a 1:2 ratio. The primary outcome was set as the increase of hemoglobin from baseline. The secondary outcomes were the reduction of erythropoietin dosage by at least 25% in patients treated with erythropoiesis-stimulating agents and an increase in serum ferritin of 100 ng/ml from baseline values. In the preliminary study, 21 patients were analyzed, 14 of whom were treated with oral liposomial iron and 7 with intravenous iron. The observed increase of hemoglobin at 8 weeks compared to baseline was similar in both groups but was significant in the liposomial group only.

Discovery of glycine hydrazide pore-occluding CFTR inhibitors: mechanism, structure-activity analysis, and in vivo efficacy.

The cystic fibrosis transmembrane conductance regulator (CFTR) protein is a cAMP-regulated epithelial Cl- channel that, when defective, causes cystic fibrosis. Screening of a collection of 100,000 diverse small molecules revealed four novel chemical classes of CFTR inhibitors with Ki < 10 microM, one of which (glycine hydrazides) had many active structural analogues. Analysis of a series of synthesized glycine hydrazide analogues revealed maximal inhibitory potency for N-(2-naphthalenyl) and 3,5-dibromo-2,4-dihydroxyphenyl substituents. The compound N-(2-naphthalenyl)-[(3,5-dibromo-2,4-dihydroxyphenyl)methylene]glycine hydrazide (GlyH-101) reversibly inhibited CFTR Cl- conductance in <1 min. Whole-cell current measurements revealed voltage-dependent CFTR block by GlyH-101 with strong inward rectification, producing an increase in apparent inhibitory constant Ki from 1.4 microM at +60 mV to 5.6 microM at -60 mV. Apparent potency was reduced by lowering extracellular Cl- concentration. Patch-clamp experiments indicated fast channel closures within bursts of channel openings, reducing mean channel open time from 264 to 13 ms (-60 mV holding potential, 5 microM GlyH-101). GlyH-101 inhibitory potency was independent of pH from 6.5-8.0, where it exists predominantly as a monovalent anion with solubility approximately 1 mM in water. Topical GlyH-101 (10 microM) in mice rapidly and reversibly inhibited forskolin-induced hyperpolarization in nasal potential differences. In a closed-loop model of cholera, intraluminal GlyH-101 (2.5 microg) reduced by approximately 80% cholera toxin-induced intestinal fluid secretion. Compared with the thiazolidinone CFTR inhibitor CFTR(inh)-172, GlyH-101 has substantially greater water solubility and rapidity of action, and a novel inhibition mechanism involving occlusion near the external pore entrance. Glycine hydrazides may be useful as probes of CFTR pore structure, in creating animal models of CF, and as antidiarrheals in enterotoxic-mediated secretory diarrheas.