Oxidation of human red blood cells by a free radical initiator: effects on rheological properties.

The main aim of this study was the investigation of the rheological properties of Red Blood Cells (RBCs) obtained from subjects admitted to blood donors, associated with the lipid profile of High-Density Lipoprotein Cholesterol (HDL-C), Low-Density Lipoprotein Cholesterol (LDL-C), Triglyceride (TG) and Total Cholesterol (TOT-C). The deformability index of RBCs was determined by using a Dynamic Stress Rheometer (DSR-500) under oxidative injury induced by 2.2'-azo-bis (2-amidinopropane) dihydrochloride (AAPH). An increased rigidity of RBCs in subjects with borderline level of hyperlipidemia was found, compared with the control group. In order to explain the reason for the reduced deformability, a borderline group was studied for the evaluation of anionic permeability on membrane, haemolysis and morphological changes induced by AAPH, as well as ThioBarbituric Acid Reactive Substances (TBARs) generation. Haemolysis by AAPH indicated a decrease of globular resistance in the borderline group, furthermore, the elevated values of TBARs suggested lipid peroxidative damage to the RBCs membrane associated with morphological changes and anion permeability alterations. Our study shows the correlation between biochemical and morphological parameters of RBCs and their rheological behavior during oxidative injury. Rheological studies might be useful as a clinical and diagnostic monitoring technique and provide support for further research.

Sunitinib: bridging present and future cancer treatment.

Tyrosine kinase receptors (RTKs) are a heterogeneous group of transmembrane proteins involved in signal transduction. These receptors are expressed in many different cells and regulate cellular growth, differentiation and angiogenesis. Overexpression and/or the structural alteration of different RTKs classes are generally associated to cancer and, when RTKs-mediated signal transduction pathways are abnormally activated, generate cancer growth, angiogenesis and metastatization. Therapeutic intervention targeting RTKs concerns antagonist drugs as little molecules or monoclonal antibodies. Sunitinib malate is a little molecule able to block intracellular tyrosine kinase domain of RTKs, which has both direct anticancer and antiangiogenetic activity. Sunitinib targets selectively vascular endothelial growth factor, KIT, Flt3 and platelet-derived growth factor receptors and the receptor encoded by the ret proto-oncogene. This drug is used in the treatment of gastrointestinal stromal cancer (GIST) resistant to imatinib and metastatic renal cell carcinoma (RCC). In this review, we report preclinical data of sunitinib, even about synergism with chemotherapy and radiotherapy, data relative to phase III trials of sunitinib in the treatment of GIST and RCC, and we try to plan what will be future applications of sunitinib in different types of cancer, even in association to chemotherapy, radiotherapy and monoclonal antibodies.

Antiproliferative effect of millimeter radiation on human erythromyeloid leukemia cell line K562 in culture: ultrastructural- and metabolic-induced changes.

In the present study we compared the proliferation behavior, the ultrastructural morphology and the glycolitic metabolism of K562 cells irradiated by low-power wide-band millimeter waves, with those of sham-exposed K562 cells (control), maintained in the same culture conditions. The gigaHertz radiation treatments, performed between 53-78 10(9) Hz, induced a noticeable inhibition of the cell proliferation that could be related to relevant ultrastructural changes. Such effects brought the irradiated cell system to lose the homeostasis and to trigger defense/reparatory mechanisms in order to reestablish a new steady state. (13)C-Nuclear magnetic resonance data on the kinetic of glucose metabolism demonstrated that the irradiated cells enhanced the glycolitic aerobic pathway, indicating that such system need to produce an extra-bioenergy. Most of the ATP synthesized served probably to perform the above processes resulting in a significant decrease of the proliferation rate without significant cell death increment.

2,6-Diketopiperazines from amino acids, from solution-phase to solid-phase organic synthesis.

A method to prepare 1,3-disubstituted 2,6-diketopiperazines (2,6-DKP) as useful heterocyclic library scaffolds in the search of new leads for drug discovery is described. The method can be used in solution-phase and solid-phase conditions. In the key step of the synthesis, the imido portion of the new molecule is formed in solution through intramolecular cyclization, under basic conditions, of a secondary amide nitrogen on a benzyl ester. A Wang resin carboxylic ester is used as the acylating agent under solid-phase conditions, allowing the cyclization to take place with simultaneous cleavage of the product from the resin ("cyclocleavage"). The synthetic method worked well with several couples of amino acids, independently from their configuration, and was used for the parallel synthesis of a series of fully characterized compounds. The use of iterative conditions in the solid phase (repeated addition of fresh solvent and potassium carbonate to the resin after filtering out the product-containing solution) allowed us to keep diastereoisomer content below the detection limit by HPLC and (1)H NMR (200 MHz).

Morphological and functional variations of Leydig cells in testis of the domestic pig during the different biological stages of development.

The relationship of morphometrical and androgen receptor evaluations of the main testicular interstitium cellular element (Leydig cells) in the domestic pig provided interesting numerical and morphological features during the different aging stages. As early as 25 days (a period in which the pig is sexually immature) there was a low number of Leydig cells (1.46 x 10(8)) with respect to a 78% and 35% increase in the adult (2.48 x 108) and aged (1.78 x 10(8)) animal, respectively. Interestingly, when the volume density of Leydig cells was considered, the average volume of these cells seemed to be high (75%) in the aged pig with respect to the young immature animal whereas a lower increase (27%) was observed for the adult animal. Moreover, the evaluation of testosterone receptor binding sites in the testis at the various stages of development also displayed a differentiated pattern since elevated testosterone receptor binding levels of the high dissociation affinity type were obtained for the adult pig. Thus, from the combined morphological variations of Leydig cells and testosterone receptor binding activity, it appears that this androgenic receptor component exerts distinct autocrine effects on the different functional features of some testicular tissue constituents at the different aging stages of the domestic pig.

Synthesis and biological activity of the penem antibiotic MEN 10700 and its orally absorbed ester MEN 11505.

The synthesis and biological properties of the new penem antibiotic MEN 10700 (6) and of its selected oral prodrug MEN 11505 (8f) are described. MEN 10700 showed a broad spectrum of activity, with high potency both on Gram-positive and Gram-negative strains. It also exhibited good antibacterial activity toward anaerobes and on strains selected for their resistance to other antibacterial agents (cefotaxime- or ceftazidime-resistant Gram-negative strains, ciprofloxacin-resistant E. coli, extended spectrum beta-lactamase producing and cephalosporinase inducible enterobacteria). MEN 10700 showed a very high stability to enzymatic degradation by renal dehydropeptidase DHP-I. After oral administration in rats of the pivaloyloxymethyl ester prodrug MEN 11505, the relative bioavailability of MEN 10700 was calculated as F=43%.

[Electrocardiographic changes during at term labor]. / Modificazioni elettrocardiografiche durante travaglio di parto a termine.

BACKGROUND: Electrocardiographic ST-changes are known to occur during pregnancy, puerperium and cesarean section or spontaneous labor under oxytocic, tocolytic and anesthetic treatment. The aim of the study was to detect ST-changes during spontaneous labor in healthy women, without anesthetic or oxytocic therapy, and to verify their relation to plasmatic electrolyte variations and other pathophysiologic factors. METHODS: Electrocardiograms were performed in 46 healthy women (age 30.4 +/- 6) at term pregnancy, during labor, 12-24 hours after delivery and then again three months after delivery. Hemochrome and sideremia were tested before labor and electrolytes (Na, K, Cl, Mg, Ca) were tested during each electrocardiogram. The patients were divided in two groups, patients with (group A) and without (group B) ST-changes. RESULTS: Before labor, three patients (7%) were in group A with nonspecific ST-changes (flat ST and/or fluctuating T wave) in precordial leads V2-V3-V4; group B had 43 patients (93%). During labor, group A included 27 patients (59%): 16 (59%) showed T inversion, 23 (85%) nonspecific changes, and eight (30%) had ST shift < or = 0.5 mm, in precordial and inferior leads. The three patients in group A before labor showed increased changes during labor. Group B had 19 patients (41%). Heart rate and blood pressure were within normal range in all patients. Early after delivery, seven patients out of 27 in labor were still in group A (15% of total) with nonspecific ST-changes; group B had 39 patients (85%). Three months after delivery, all patients were in group B. A drop in plasmatic K, detected during labor in all patients and returning to normal soon after delivery, was higher in group A than in group B (p < 0.01). CONCLUSIONS: ST-changes detectable during labor, similar to the ones described during pregnancy and puerperium but greater and more frequent, are independent of anesthetic and/or oxytocic treatment; they are not ischemic and disappear after delivery. They are related to the drop in plasmatic K, hyperventilation, hormonal changes, uterine contractions, O2-consumption and pain.

[Native valve infective endocarditis caused by Streptococcus bovis. Efficacy of short-term antibiotic therapy and usefulness of serial echocardiographic evaluation]. / Endocardite infettiva da Streptococcus bovis su valvola nativa. Efficacia dell'antibioticoterapia a breve termine ed utilità della valutazione ecocardiografica seriata.

We report a case of infective endocarditis on native valve, due to Streptococcus bovis, treated successfully with short time antibiotic therapy (10 days versus minimum suggested treatment of two weeks) by using penicillin G together with streptomycin (six days), followed, by treatment with imipenem (four days) because of allergic reactions. Diagnosis was simpler thanks to Durack's new criteria that include positive echocardiographic findings (valvular vegetations) within major clinical criteria for definite diagnosis of infective endocarditis, different from preceding Von Reyn's criteria which did not provide diagnostic weight for echocardiographic data. Serial echocardiograms have also been useful to evaluate the early response to the treatment and its persistent efficacy in the follow-up.

2-Substituted penems with amino acid-related side chains: synthesis and antibacterial activity of a new series of beta-lactam antibiotics.

A new series of 6-(hydroxyethyl)penems 2-substituted with amino acid-related side chains was synthesized. The nature of the amino acyl derivative proved to be crucial both from a synthetic point of view, as beta-lactam ring opening can compete with C-2 nucleophilic substitution, and for antibacterial activity. Primary amino acid amides emerged as the most suitable side chains for enhancing permeability through a Gram-negative outer membrane. In vitro activity of the new 2-[(aminoamido)methyl]penems 3a-u was influenced by the nature and position of the amide moiety, the ring size for cyclic amides, and the configuration of the amino acid. Compounds bearing amides derived from small N-methyl amino acids (such as 3a) or from cyclic amino acids (such as prolinamide 3p and 4-hydroxyprolinamide 3r) showed broad spectrum in vitro activity against both Gram-positive and Gram-negative microorganisms.

[Early echocardiographic identification of viable myocardium after acute myocardial infarct using inotropic agents: comparison of dobutamine and enoximone]. / Ricerca ecocardiografica precoce del miocardio vitale dopo infarto miocardico acuto con agenti inotropi: confronto tra dobutamina ed enoximone.

BACKGROUND: The reversibility of regional dysfunction early after acute myocardial infarction may be obtained with inotropic adrenergic stimulation, in particular during low dose dobutamine infusion, suggesting the presence of viable myocardium. The aim of this study was to determine whether viable myocardium can be identified by two-dimensional echocardiography after an i.v. bolus of enoximone-positive inotropic non-adrenergic drug, phosphodiesterase III inhibitor as well as during dobutamine infusion, in patients with acute myocardial infarction. METHODS: Twelve male patients, aged 57 +/- 10 years and treated with rtPA (100 mg i.v. in 180 minutes) within the first 6 hours of a first anterior myocardial infarction were studied. All patients underwent a dobutamine infusion (5 and 10 mcg/kg/min, 5 minutes per dose) 4 +/- 1 days after entrance, followed by an enoximone bolus (1 mg/kg over 5 minutes) 1 hour later. Echocardiography was performed before dobutamine and enoximone, during dobutamine, 10 minutes after enoximone and at 6 +/- 2 months follow-up. A Wall Motion Score Index (WMSI) was calculated as recommended by the American Society of Echocardiography. All patients underwent coronarography on days 9-11 post-infarction. RESULTS: Improvement in regional function of basally asynergic segments occurred in 8 patients during dobutamine infusion, as well as after enoximone i.v. bolus, and in 1 patient only during dobutamine infusion. Both dobutamine and enoximone tests were found to be negative in the other 3 patients. A decrease of WMSI was observed with both dobutamine and enoximone tests (from 1.84 +/- 0.32 to 1.73 +/- 0.31; p = .002 with dobutamine; from 1.84 +/- 0.32 to 1.70 +/- 0.27; p = .0132 with enoximone) with concordant wall motion changes between two tests in 73/84 (87%; K = 0.61) basally asynergic segments. There were no complications occurred during the study. Of 8 patients with positive response for viable myocardium to both tests, 6 had a patent and 2 an occluded infarct-related artery. However, in the latter a collateral circulation toward necrotic area was present. At follow-up improvement in regional function of basally asynergic segments, with a decrease of WMSI (from 1.74 +/- 0.23 to 1.59 +/- 0.24; p < .05), was observed in 4 of 8 patients with viable myocardium detected by either dobutamine or enoximone. CONCLUSIONS: 1) Viable asynergic myocardium may be identified early after acute myocardial infarction by enoximone bolus, as carefully and safely as by dobutamine infusion; 2) transient recovery of post-ischemic myocardial dysfunction may be obtained independently of beta-receptor stimulation.