BINOL-amino acid conjugates as triggerable carriers of DNA-targeted potent photocytotoxic agents

Mild photoactivation of new BINOL-amino acid and -amino ester conjugates (BINOLAMs) yielded alkylating and DNA cross-linking agents with high photoefficiency and superior cytotoxicity. Detection of the transient electrophile, by laser flash photolysis (LFP), suggests that BINOL-quinone methides (QMs) are key intermediates in the process. QMs trapping by water, monitored in a time-dependent product distribution analysis, demonstrated that the phototriggered reactivity of BINOLAMs as bis-alkylating agents is the result of a two-step process involving sequential photogeneration of monoalkylating QMs. Light activation of the BINOL-L-amino esters produced cytotoxic QMs very effective against human tumor LoVo cells with EC50 in the 130-230 nM range. Trimethylpsoralen (PS) is about 4 times less potent than our newly tested compounds. BINOL-L-proline methyl ester showed notable photoselectivity because it displayed cytotoxic effects upon irradiation only and was able to efficiently reach the target DNA inside the cells, where it forms both alkylated and cross-linked species

Bacterial infection in patients with advanced cirrhosis : a multicentre prospective study

AIMS: To evaluate the prevalence, incidence and clinical relevance of bacterial infection in predominantly non-alcoholic cirrhotic patients hospitalised for decompensation. PATIENTS/METHODS: A total of 405 consecutive admissions in 361 patients (249 males and 112 females; 66 Child-Pugh class B and 295 class C) were analysed. Blood, urine, ascitic and pleural fluid cultures were performed within the first 24 hours, during hospitalisation whenever infection was suspected, and again before discharge. RESULTS: Over a one year period, 150 (34%) bacterial infections (89 community- and 61 hospital-acquired) involving urinary tract (41%), ascites (23%), blood (21%) and respiratory tract (17%) were diagnosed. The prevalence of bacterial peritonitis was 12%. Infections were asymptomatic in 69 cases (46%) and 130 (87%) involved a single site. Enteric flora accounted for 62% of infections, Escherichia Coli being the most frequent pathogen (25%). Community-acquired infections were associated with more advanced liver disease (Child-Pugh mean score 10.2+/-2.1 versus 9.5+/-1.9, p<0.05), renal failure (p<0.05), and high white blood cell count (p<0.01). Hospital-acquired infections occurred more frequently in patients admitted for gastrointestinal bleeding (p<0.05). The in-hospital mortality was significantly higher in infected than in non-infected patients (15% versus 7%, p<0.05), and infection emerged as an independent variable affecting survival. Moreover bacterial infection accounted for a significantly prolonged hospital stay. CONCLUSIONS: Bacterial infection, regardless of the aetiology, is a severe complication of decompensated cirrhosis, and, although frequently asymptomatic, accounts for both longer hospital stay and increased mortality