Formation of thin luminescent Eu3+-LB films by in situ coordination with 2,3,5,6-tetra(2 '-pyridyl)pyrazine and 1-octadecanol in pure and mixed Langmuir monolayers

The in situ complexation between 2,3,5,6-tetra(2-pyridyl)pyrazine (tppz) molecules and europium ions at the air-liquid interface by means of mixed 1-octadecanol Langmuir films is reported. These films were transferred to solid supports by means of the Langmuir-Blodgett (LB) technique. The EDS maps attested the homogeneity of the LB films as well as the presence of the europium ions. The mixed alcohol/tppz LB film contained a larger amount of europium ions as compared to the pure octadecanol LB film. This work reports the production of a thin luminescent Eu3+ film containing europium ions using only alcohol molecules as ligands an unexpected result, since it is well known that there is an occurrence of non-radiative deactivation of excited europium by hydroxyl groups. Europium ion multiple binding sites were detected from lifetime decay measurements of these films in the presence of tppz molecules. (C) 2012 Elsevier B.V. All rights reserved.

A Phase I clinical trial of lodenafil carbonate, a new phosphodiesterase Type 5 (PDE5) inhibitor, in healthy male volunteers

Lodenafil carbonate is a new phosphodiesterase Type 5 (PDE5) inhibitor used in treatment of erectile dysfunction. Objective: The present study was conducted to evaluate the safety, tolerability, and pharmacokinetics of lodenafil carbonate after administering ascending (1 - 100 mg) single oral doses to healthy male volunteers (n = 33). Methods: The study was an open-label, dose-escalation, Phase I clinical trial involving the administration of single oral doses of lodenafil carbonate. Lodenafil carbonate was administered sequentially, escalating in single doses of 1 mg - 100 mg with a washout period of at least 1 week between each dose. The progression to the next dose was allowed after clinical and laboratory exams, Ambulatory Monitoring of Arterial Pressure (AMAP) without relevant clinical modifications and adverse events without clinical relevancy. Blood samples were collected at pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 14, 16, 20 and 24 h post-dosing. Plasma samples for measurement of lodenafil carbonate and lodenafil were analyzed by liquid chromatography coupled to tandem mass spectrometry. Results: No serious adverse events were observed, and none of the subjects discontinued the study due to intolerance. The AMAP measurements, clinical and laboratory exams and ECG revealed no significant changes even at higher doses. Lodenafil carbonate was not detected in any samples, indicating that it acts as a prodrug. The mean lodenafil pharmacokinetic parameters for t(max) and t(1/2) were 1.6 (+/- 0.4) h and 3.3 (+/- 1.1) h, respectively. This study demonstrated that lodenafil carbonate was well tolerated and showed a good safety profile in healthy male volunteers.

Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial

Background: Bevacizumab improves the efficacy of oxaliplatin-based chemotherapy in metastatic colorectal cancer. Our aim was to assess the use of bevacizumab in combination with oxaliplatin-based chemotherapy in the adjuvant treatment of patients with resected stage III or high-risk stage II colon carcinoma. Methods: Patients from 330 centres in 34 countries were enrolled into this phase 3, open-label randomised trial. Patients with curatively resected stage III or high-risk stage II colon carcinoma were randomly assigned (1: 1: 1) to receive FOLFOX4 (oxaliplatin 85 mg/m(2), leucovorin 200 mg/m(2), and fluorouracil 400 mg/m(2) bolus plus 600 mg/m(2) 22-h continuous infusion on day 1; leucovorin 200 mg/m(2) plus fluorouracil 400 mg/m(2) bolus plus 600 mg/m(2) 22-h continuous infusion on day 2) every 2 weeks for 12 cycles; bevacizumab 5 mg/kg plus FOLFOX4 (every 2 weeks for 12 cycles) followed by bevacizumab monotherapy 7.5 mg/kg every 3 weeks (eight cycles over 24 weeks); or bevacizumab 7.5 mg/kg plus XELOX (oxaliplatin 130 mg/m(2) on day 1 every 2 weeks plus oral capecitabine 1000 mg/m(2) twice daily on days 1-15) every 3 weeks for eight cycles followed by bevacizumab monotherapy 7.5 mg/kg every 3 weeks (eight cycles over 24 weeks). Block randomisation was done with a central interactive computerised system, stratified by geographic region and disease stage. Surgery with curative intent occurred 4-8 weeks before randomisation. The primary endpoint was disease-free survival, analysed for all randomised patients with stage III disease. This study is registered with ClinicalTrials.gov, number NCT00112918. Findings: Of the total intention-to-treat population (n=3451), 2867 patients had stage III disease, of whom 955 were randomly assigned to receive FOLFOX4, 960 to receive bevacizumab-FOLFOX4, and 952 to receive bevacizumab-XELOX. After a median follow-up of 48 months (range 0-66 months), 237 patients (25%) in the FOLFOX4 group, 280 (29%) in the bevacizumab-FOLFOX4 group, and 253 (27%) in the bevacizumab-XELOX group had relapsed, developed a new colon cancer, or died. The disease-free survival hazard ratio for bevacizumab-FOLFOX4 versus FOLFOX4 was 1.17 (95% CI 0.98-1.39; p=0.07), and for bevacizumab-XELOX versus FOLFOX4 was 1.07 (0.90-1.28; p=0.44). After a minimum follow-up of 60 months, the overall survival hazard ratio for bevacizumab-FOLFOX4 versus FOLFOX4 was 1.27 (1.03-1.57; p=0.02), and for bevacizumab-XELOX versus FOLFOX4 was 1.15 (0.93-1.42; p=0.21). The 573 patients with high-risk stage II cancer were included in the safety analysis. The most common grade 3-5 adverse events were neutropenia (FOLFOX4: 477 [42%] of 1126 patients, bevacizumab-FOLFOX4: 416 [36%] of 1145 patients, and bevacizumab-XELOX: 74 [7%] of 1135 patients), diarrhoea (110 [10%], 135 [12%], and 181 [16%], respectively), and hypertension (12 [1%], 122 [11%], and 116 [10%], respectively). Serious adverse events were more common in the bevacizumab groups (bevacizumab-FOLFOX4: 297 [26%]; bevacizumab-XELOX: 284 [25%]) than in the FOLFOX4 group (226 [20%]). Treatment-related deaths were reported in one patient receiving FOLFOX4, two receiving bevacizumab-FOLFOX4, and five receiving bevacizumab-XELOX. Interpretation: Bevacizumab does not prolong disease-free survival when added to adjuvant chemotherapy in resected stage III colon cancer. Overall survival data suggest a potential detrimental effect with bevacizumab plus oxaliplatin-based adjuvant therapy in these patients. On the basis of these and other data, we do not recommend the use of bevacizumab in the adjuvant treatment of patients with curatively resected stage III colon cancer.