Blood-brain barrier (BBB) toxicity and permeability assessment after L-(4-¹°Boronophenyl)alanine, a conventional B-containing drug for boron neutron capture therapy, using an in vitro BBB model.

Since brain tumours are the primary candidates for treatment by Boron Neutron Capture Therapy, one major challenge in the selective drug delivery to CNS is the crossing of the blood-brain barrier (BBB). The present pilot study investigated (i) the transport of a conventional B-containing product (i.e., L-(4-(10)Boronophenyl)alanine, L-(10)BPA), already used in medicine but still not fully characterized regarding its CNS interactions, as well as (ii) the effects of the L-(10)BPA on the BBB integrity using an in vitro model, consisting of brain capillary endothelial cells co-cultured with glial cells, closely mimicking the in vivo conditions. The multi-step experimental strategy (i.e. Integrity test, Filter study, Transport assay) checked L-(10)BPA toxicity at 80 µg Boron equivalent/ml, and its ability to cross the BBB, additionally by characterizing the cytoskeletal and TJ's proteins by immunocytochemistry and immunoblotting. In conclusion, a lack of toxic effects of L-(10)BPA was demonstrated, nevertheless accompanied by cellular stress phenomena (e.g. vimentin expression modification), paralleled by a low permeability coefficient (0.39 ± 0.01 × 10(-3)cm min(-1)), corroborating the scarce probability that L-(10)BPA would reach therapeutically effective cerebral concentration. These findings emphasized the need for novel strategies aimed at optimizing boron delivery to brain tumours, trying to ameliorate the compound uptake or developing new targeted products suitable to safely and effectively treat head cancer. Thus, the use of in vitro BBB model for screening studies may provide a useful early safety assessment for new effective compounds.

Comparative pulmonary toxicity assessment of pristine and functionalized multi-walled carbon nanotubes intratracheally instilled in rats: morphohistochemical evaluations.

Increasing interest in safety evaluation of carbon nanotubes (CNTs) has risen in relation to their wide applications, together with the evidence of their cytotoxic effects. It has been shown that chemical functionalization extends the applications of CNTs, conferring them new functions that cannot otherwise be acquired by pristine CNTs, but also impacts on biological response to CNTs, modifying their toxicological profile. We assessed the onset of pulmonary toxic effects caused by pristine MW-CNTs and functionalized MW-NH2 or MW-COOH, 16 days after intratracheal instillation (1 mg/kg b.w.); major endpoints tested included (i) histopathology of lung (Haematoxylin/Eosin Staining), (ii) apoptotic/proliferating features examined by TUNEL and PCNA immunostaining, and (iii) presence/distribution of (1) Transforming Growth Factor-beta1 (TGFß1), (2) Interleukin-6 (IL-6) and (3) Collagen (Type I) investigated by immunochemical methods, as markers of lung toxicity, inflammation, and fibrosis, respectively. Lung histopathology from exposed animals showed dark, particulate-laden macrophages, reflecting carbon nanomaterial engulfing, both at alveolar and bronchiolar levels, after treatment with all the tested CNTs. Alteration of lung architecture was also observed in several areas showing collapsed thick-walled alveoli and the presence of micro-haemorrhagic foci. TUNEL and PCNA, indicative of apoptosis and cell proliferation respectively, showed a significant increase of immunopositive cells at bronchiolar, alveolar and macrophagic levels, as expression of an improved cellular turnover. Increased immunoreactivity for pulmonary TGFß1 and IL-6 was observed in treated rats, particularly in bronchiolar areas, collapsed alveoli and at stromal level, while evident changes for collagen were not detected. Taken together these findings demonstrated the general pulmonary toxicity coupled with inflammatory response after in vivo exposure to CNTs, without overt signs of fibrosis and granuloma formation, irrespectively of nanotube functionalization.

Cost-effectiveness of different diagnostic strategies to assess gastro-oesophageal reflux disease in patients with unexplained chronic persistent cough in Italy.

BACKGROUND: Chronic persistent cough is a common and disabling disorder and gastro-oesophageal reflux disease is considered to be the third leading cause, after asthma and postnasal drip. Therefore, patients with unexplained chronic persistent cough usually undergo a stepwise evaluation to establish the existence of a reflux disease. AIM: To identify the most cost-effective diagnostic approach to assess gastro-oesophageal reflux disease in patients with unexplained chronic persistent cough. METHODS: Direct and indirect costs associated with six diagnostic strategies using 24-h oesophageal pH-metry, oesophago-gastroduodenoscopy and the proton pump inhibitors test in different sequences, were evaluated using a decision tree model. If the first test was positive, the diagnostic work-up was stopped, if negative the patient proceeded to the second test, and so on. Clinical data from an observational prospective trial conducted in 51 patients with unexplained chronic persistent cough were used in the economic model. RESULTS: All six strategies had the same clinical effectiveness (78.4%). The diagnostic work-up with the lowest cost was the proton pump inhibitors test followed by pH-metry and then oesophago-gastroduodenoscopy with a total cost of euro 211.08 (direct euro 142.93, indirect euro 68.15). CONCLUSIONS: This study shows that the lowest cost is the strategy where proton pump inhibitors test is performed as first investigation. Implementation of this diagnostic work-up may lead to cost savings in the management of patients with chronic persistent cough.

Low-dose lansoprazole and clarithromycin plus metronidazole vs. full-dose lansoprazole and clarithromycin plus amoxicillin for eradication of Helicobacter pylori infection.

AIM: To compare, in a randomized controlled trial, the efficacy and tolerability of two 1-week triple therapies for Helicobacter pylori eradication. METHODS: One hundred and thirty-four consecutive patients with non-ulcer dyspepsia and H. pylori infection were randomized to receive lansoprazole 30 mg once daily, clarithromycin 250 mg twice daily, and metronidazole 500 mg twice daily (LCM group), or lansoprazole 30 mg twice daily, clarithromycin 500 mg twice daily, and amoxicillin 1000 mg twice daily (LCA group). H. pylori status was assessed by rapid urease test, histology and 13C-urea breath test before and after therapy. RESULTS: At 3 months, H. pylori eradication (intention- to-treat/per protocol analysis) was 92.4%/93.8% in the LCM group and 83.1%/85.7% in the LCA group (P=N.S.). Side-effects were more frequently reported in the LCA group (37.9%) than in the LCM group (19.7%) (P < 0.05). CONCLUSIONS: In this open, randomized controlled trial, eradication of H. pylori by low-dose lansoprazole and clarithromycin plus metronidazole was higher with significantly less side-effects than by full-dose lansoprazole and clarithromycin plus amoxicillin. This finding may be related to the stronger synergism of clarithromycin plus metronidazole, even at lower doses, than of clarithromycin plus amoxicillin. Considering the lower cost as well, LCM should be preferred to LCA in the eradication of H. pylori.

Cancer of the esophagus--endoscopic ultrasound: selection for cure.

Several treatment options are available to treat esophageal cancer. Ideally, treatment should be individualized, based on the projected treatment outcome for that individual. Accurate staging of the extent of the disease at the time of diagnosis offers the most rational attempt at stratifying patients into categories that can be used to affect treatment choices. Endoscopic ultrasonography (EUS) is the most accurate nonoperative technique for determining the depth of tumour infiltration and thus is accurate in predicting which patients will be able to undergo complete resection. EUS is also being used for tumour staging in order to guide treatment decisions in patients with esophageal cancer.

[Alpha-interferon therapy: an echographic study of left ventricular function and a clinical assessment of cardiovascular complications]. / Terapia con alfa interferone: studio ecocardiografico della funzione ventricolare sinistra e valutazione clinica delle complicanze cardiovascolari.

Many side-effects of alpha interferon (alpha-I) therapy have occurred as a result of its widespread clinical applications. The hypothesis of alpha-I related cardiomyopathy is particularly interesting. Our study involved echocardiographic evaluation of left ventricular function and cardiovascular complications in 35 patients with chronic hepatitis treated with alpha-I at 20 MU/week for an average of 10.8 months. The results were compared with those of a control group. Of the values studied, only Max E V and the E/A ratio were statistically significant. No cardiovascular side-effects were found.

Evaluation of an oral ursodeoxycholic acid load in the assessment of bile acid malabsorption in cystic fibrosis.

Serum levels of ursodeoxycholic acid (UDCA) were measured by radioimmunoassay in 20 children with cystic fibrosis (CF) and in eight controls, who had received 300 mg of this bile acid orally. Area under the curve (AUC) after UDCA load was significantly reduced (25.24 +/- 9.54) in CF patients, as compared to controls (52.98 +/- 5.87 mean values +/- SD percent dose/liter X hr X kg body weight, P less than 0.001). AUC values were compared with daily fecal bile acids (BA) and fat excretion, and with serum fasting conjugated cholic (CCA) and chenodeoxycholic (CCDCA) acid levels. Total fecal BA were increased in CF patients (7.84 +/- 5.57 mg/kg/day) as compared to control values (2.7 +/- 1.1 mean +/- SD, P less than 00.5); they were inversely correlated with AUC values (r = 0.48) but not with steatorrhea (r = 0.32). UDCA load seems to be useful in detecting BA malabsorption in CF. Fasting CCA levels did not significantly differ in CF patients (0.87 +/- 0.61 mumol/liter) and in controls (0.60 +/- 0.26 mumol/liter) and did not correlate with fecal BA excretion. Fasting CCDCA mean levels were significantly increased (mainly in CF patients with liver damage), suggesting a lowered first-pass extraction in the liver: their determination may be useful in the follow-up of liver involvement in CF.