Phase I/IIa study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of lucitanib in advanced solid tumors.

Background: Lucitanib is a potent, oral inhibitor fibroblast growth factor receptor types 1 and 2 (FGFR), vascular endothelial growth factor receptor types 1, 2, and 3 (VEGFR), platelet-derived growth factor receptor types α and β (PGFRα/β), which are essential kinases for tumor growth, survival, migration, and angiogenesis. Several tumor types, including breast carcinoma, demonstrate amplification of fibroblast growth factor (FGF)-related genes. There are no approved drugs for molecularly defined FGF-aberrant (FGFR1- or FGF3/4/19-amplified) tumors.

HPLC-MS/MS method for quantitative determination of the novel dual inhibitor of FGF and VEGF receptors E-3810 in tumor tissues from xenograft mice and human biopsies.

We developed and validated a high-performance liquid chromatography-tandem mass spectrometry analytical method to measure E-3810, a novel dual inhibitor of fibroblast growth factor receptor 1 and vascular endothelial growth factor receptor 1-3 in tissues and determined the drug concentration in a biopsy of human breast cancer for the first time. The method is a modification of our previous one in plasma to study the clinical pharmacokinetics of the drug during the phase I/II trial. In view of the changes in matrix, we applied a partial validation protocol to determine recovery, sensitivity, range of linearity, precision, accuracy and stability of the method over three runs in a mouse tumor tissue and liver.

A first in human phase I study of the proteasome inhibitor CEP-18770 in patients with advanced solid tumours and multiple myeloma.

Background: The safety, pharmacokinetics (PK) and pharmacodynamics of CEP-18770, a new peptide boronic acid proteasome inhibitor, have been investigated after intravenous administration on days 1, 4, 8 and 11 of every 21d cycle in patients with solid tumours and multiple myeloma (MM).

Patients And Methods: Thirty-eight patients were treated with CEP-18770 at escalating doses from 0.1 to 1.

Antimicrobial activity of doripenem against Gram-negative pathogens: results from INVITA-A-DORI Brazilian study.

In vitro activity of doripenem and comparator antimicrobial agents was evaluated against Gram-negative bacilli recently isolated from Brazilian private hospitals that were enrolled in the INVITA-A-DORI Brazilian Study. A total of 805 unique Gram-negative bacilli were collected from patients hospitalized at 18 medical centers between May/08 and March/09. Each hospital was asked to submit 50 single Gram-negative bacilli isolated from blood, lower respiratory tract or intraabdominal secretions.

Development and validation of a high-performance liquid chromatography-tandem mass spectrometry method for the determination of the novel inhibitor of angiogenesis E-3810 in human plasma and its application in a clinical pharmacokinetic study.

E-3810, 6-[[7-[(1-aminocyclopropyl)methoxy]-6-methoxy-4-quinolyl]oxy]-N-methyl-naphthalene-1-carboxamide, is a novel, potent, dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors with antiangiogenic properties, now under early clinical evaluation as an anticancer agent. To investigate its clinical pharmacokinetics, a high-performance liquid chromatography-tandem mass spectrometry method was developed and validated to measure the drug in human plasma on the basis of simple protein precipitation with methanol after addition of deuterated E-3810 as internal standard. The method requires a small volume of sample (100 µl) and is rapid and selective, allowing good resolution of peaks in 5 min.

Antimicrobial activity of ceftobiprole against gram-negative and gram-positive pathogens: results from INVITA-A-CEFTO Brazilian study.

Ceftobiprole is a broad-spectrum cephalosporin with potent activity against staphylococci, including those resistant to oxacillin, as well as against most gram-negative bacilli including Pseudomonas aeruginosa. In this study, the in vitro activity of ceftobiprole and comparator agents was tested against bacterial isolates recently collected from Brazilian private hospitals. A total of 336 unique bacterial isolates were collected from hospitalized patients between February 2008 and August 2009.

Development and validation of a high-performance liquid chromatography-tandem mass spectrometry method for the determination of the novel proteasome inhibitor CEP-18770 in human plasma and its application in a clinical pharmacokinetic study.

CEP-18770, [(1R)-1-{[(2S,3R)-3-hydroxy-2-{[(6-phenyl-2-pyridinyl)carbonyl]amino}butanoyl]amino}-3-methylbutyl]boronic acid, is a novel proteasome inhibitor, now under early clinical evaluation as an anticancer agent. To investigate its clinical pharmacokinetics, a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed and validated to measure the drug in human plasma, based on simple protein precipitation with acetonitrile after the addition of irbesartan as internal standard. The method requires a small volume of sample (100 µl) and is rapid and selective, allowing good resolution of peaks in 5 min.

Carbapenem-resistant Pseudomonas aeruginosa outbreak in an intensive care unit of a teaching hospital.

The genetic similarity of carbapenem-resistant Pseudomonas aeruginosa strains isolated in the Hospital Universitário São Francisco, Bragança Paulista, São Paulo, Brasil, was evaluated by pulsed field gel electrophoresis (PFGE). A unique clone was detected among 5 of 7 isolates, suggesting that cross-contamination might have played a role in the spread of carbapenem-resistant P. aeruginosa strains.

A pseudo-outbreak of vancomycin-resistant Enterococcus faecium.

Five VRE isolates were reported from sterile samples. No infections were diagnosed among the patients, who were on different wards. PFGE showed that all five isolates were clonal.

Antibody response to Haemophilus influenzae type b tetanus conjugate vaccine with two doses given at 3 and 5 months of age.

Background: In developed countries, the use of Hib conjugate vaccines has led to the near disappearance of invasive Hib disease, but costs have limited its use in developing countries. In order to identify more economical vaccination schedules, we carried out a trial to evaluate the immunogenicity of an alternative two-dose PRP-T regimen, based on a previous report in which carrier priming could be obtained with prior diphtheria-tetanus-pertussis (DTP) vaccination.

Methods: Healthy infants were enrolled to receive the PRP-T given at 3 and 5 months of age, with DTP vaccination given at 2, 4 and 6 months of age.

Molecular typing and antimicrobial susceptibility of vancomycin-resistant Enterococcus faecium in Brazil.

Objectives: To characterize vancomycin-resistant enterococci (VRE) isolates and to evaluate the mode of dissemination of this pathogen in Brazil.

Design: We collected 22 vancomycin-resistant Enterococcus faecium isolates from 6 medical centers in Sao Paulo, Brazil, and 1 isolate from a medical center in Curitiba, Brazil.

Participants: All Brazilian hospitals that had identified vancomycin-resistant E.

Enterococcus faecalis resistant to vancomycin and teicoplanin (VanA phenotype) isolated from a bone marrow transplanted patient in Brazil.

We report for the first time in Brazil, a patient from whom an Enterococcus faecalis VanA phenotype was isolated. Glycopeptide resistance is not commonly observed in Enterococcus faecalis, so this finding is of great concern since this species is responsible for 90% of enterococcal infections in Brazil. The isolate was recovered from a surveillance rectal swab culture from a patient with acute lymphocytic leukemia (ALL).

Evaluation of the in vitro Activity of Cefprozil Relative to Other Oral Antimicrobial Agents Against Bacteria in Clinical Specimens from Patients in São Paulo With Respiratory Tract Infections.

Cefprozil is a new oral second generation cephalosporin. Its in vitro antimicrobial activity was evaluated against 371 recent clinical isolates from patients with respiratory infections. We tested the susceptibility of 244 streptococci (96 Streptococcus pneumoniae, 105 group viridans streptococci, 32 Streptococcus agalactiae, and 11 group A beta-hemolitic streptococci) 107 Haemophilus influenzae, and 20 oxacillin-susceptible S.

Evaluation of the in vitro Activity of Two Fourth-Generation Cephalosporins Against Bacterial Samples Isolated From Patients in Several Brazilian Hospitals.

Cefpirome and cefepime are two fourth-generation cephalosporins recently introduced in Brazil. They have a very similar range of in vitro antimicrobial activity, but some differences have been noticed. The goal of this study was to compare the in vitro activity of cefpirome and cefepime against bacterial samples isolated in Brazilian hospitals.

Antimicrobial susceptibility of coagulase-negative staphylococci and characterization of isolates with reduced susceptibility to glycopeptides.

The antimicrobial susceptibility of 239 coagulase-negative staphylococci (CNS) isolates consecutively collected from blood culture in patients admitted in a 600-bed teaching hospital was evaluated. The isolates were identified to the species level by conventional methods and the MicroScan Positive Combo Panel type 6 system, and their susceptibility to vancomycin, teicoplanin, and oxacillin were tested by agar dilution, disk diffusion, and MicroScan-WalkAway system. The species distribution was as follows: Staphylococcus epidermidis 120 (50.

In Vitro Antimicrobial Activity Against Enterococci Isolated in a University Hospital in São Paulo, Brazil.

The prevalence of multiresistant enterococci (MRE) is rapidly increasing and becoming an important problem in several countries. São Paulo Hospital is a 600-bed tertiary hospital located in São Paulo, Brazil. The use of vancomycin is very high in the hospital due to the high prevalence of multi-resistant S.

[In vitro susceptibility testing of 446 clinical isolates of gram-positive bacteria to new quinolones, carbapenems and cephalosporins].

Objective: To assess the in vitro susceptibility of gram-positive bacteria isolated in the São Paulo Hospital against five fluoroquinolones, three carbapenems and three cephalosporins.

Materials And Method: Susceptibility was tested in 77 isolates of streptococci, 38 enterococci, 25 S. aureus and 91 S.

New antianginal nitro esters with reduced hypotensive activity. Synthesis and pharmacological evaluation of 3-[(nitrooxy)alkyl]-2H-1,3-benzoxazin-4(3H)-ones.

New nitro ester 3-[(nitrooxy)alkyl]-2H-1,3-benzoxazin-4(3H)-ones show marked inhibitory activity against ischemia-induced electrocardiographic changes, with only limited systemic hemodynamic effects, and are reported in the present study. These new nitro vasodilators are potent inhibitors of the electrocardiographic T-wave and S-T segment elevation induced by intravenous or intracoronary administration of Arg-vasopressin or methacholine in the anesthetized rat. The most active compounds are up to 300- and 600-fold more potent than glyceryl trinitrate or Nicorandil, respectively.

Protective effects of ITF 296 in the isolated rabbit heart subjected to global ischemia.

The anti-ischemic action of ITF 296 was evaluated in isovolumic, electrically driven rabbit heart preparations subjected to temporary ischemia and reperfusion. Reduction of perfusion rate from 20 to 0.2 ml/min produced a sharp decrease of peak systolic pressure, left ventricular (LV)-developed pressure, and LV dP/dt, which culminated in complete ventricular arrest within 3-4 min.

Protective effect of the nitrate ester ITF 296 against methacholine-induced myocardial ischemia in the anesthetized rat.

The activity of ITF 296 against methacholine-induced myocardial ischemia was investigated in anesthetized rats in comparison with the organic nitrates nitroglycerin (NTG) and isosorbide dinitrate (ISDN), the K(+)-channel openers nicorandil and cromakalim, the Ca(2+)-channel blocker amlodipine, and the vasodilator dipyridamole. Given as i.v.

The new nitroderivative ITF 296 improves collateral blood flow in a canine model of coronary thrombosis.

The actions of ITF 296 and isosorbide dinitrate (ISDN), 20, 70, and 200 g/kg/min, on myocardial transmural blood flow distribution during acute thrombotic occlusion of the left circumflex coronary artery (LCX) have been evaluated in seven and three anesthetized open-chest dogs, respectively, and compared with four animals receiving vehicle. Occlusion of LCX was achieved in 14 +/- 2 min by the insertion of a copper coil. This caused transmural myocardial ischemia in the LCX area, while leaving blood flow in the left anterior descending coronary artery (control area) unaffected.

Effects of ITF 296 on epicardial coronary artery diameter during acute and long-term treatment in the conscious dog.

The action of the newly developed organic nitrate ITF 296 on large coronary arteries was investigated during acute and long-term treatment in the conscious dog, chronically instrumented for recording of large coronary artery diameter (CD), mean arterial blood pressure (MBP), and heart rate (HR). Short-term steady-state infusion of ITF 296 at doses of 0.1-30 micrograms/kg/min induced a dose-dependent increase in CD.

Effect of ITF 296 on total effective vascular compliance in the anesthetized dog under autonomic blockade.

The effects of ITF 296 on venous tone, estimated as changes in total effective vascular compliance (TEVC), were investigated in the anesthetized, spontaneously breathing dog under autonomic blockade. TEVC was calculated from the correlation between the observed changes in central venous pressure (CVP) and the experimentally induced changes in blood volume during an 11-min cycle of whole blood infusion (2 ml/kg/min), withdrawal, and reinfusion. Stepwise increasing doses (short steady-state infusions) of ITF 296 (3, 10, and 30 micrograms/kg/min) resulted in a dose-dependent increase in TEVC (+27, +54, and +67%), whereas mean blood pressure (MBP) was reduced (-12, -23, and -33%, respectively).

Antireactive properties of glucosamine sulfate.

Glucosamine (CAS 3416-24-8) is an aminomonosaccharide naturally occurring in the human body. It was tested for antiinflammatory activities and it showed to protect against the edema provoked in the rat paw by carrageenin, dextran, formalin, but not against the edema provoked by specific inflammation mediators, such as bradykinin, serotonin, histamine. Glucosamine protected against pleurities provoked in the rat by carrageenin, but not against that provoked by bradykinin.