Vascular damage and anti-angiogenic effects of tumor vessel-targeted liposomal chemotherapy

The poor selective toxicity of chemotherapeutic anticancer drugs leads to dose-limiting side effects that compromise clinical outcome. Solid tumors recruit new blood vessels to support tumor growth, and unique epitopes expressed on tumor endothelial cells can function as targets for the anti-angiogenic therapy of cancer. An NGR peptide that targets aminopeptidase N, a marker of angiogenic endothelial cells, was coupled to the surface of liposomal doxorubicin (NGR-SL[DXR]) and was used to treat orthotopic neuroblastoma (NB) xenografts in SCID mice. Pharmacokinetic studies indicated that liposomes coupled to NGR peptide had long-circulating profiles in blood. Their uptake into NB tumor was time dependent, being at least 10 times higher than that of nontargeted liposomes (SL[DXR]) after 24 h, with DXR spreading outside the blood vessels and into the tumors. No uptake was observed into tumors of mice treated with the mismatched peptide ARA-targeted SL[DXR]. Tumor-specific DXR uptake was completely blocked when mice were coinjected with a 50-fold molar excess of the soluble NGR peptide. Adrenal tumor-bearing mice treated with 2 mg/kg/week/x3 of NGR-SL[DXR] partly outlived the control mice (P < 0.001), whereas doses > 3 mg/kg/week/x3 were toxic. Histopathological analysis of cryosections taken from treated mice revealed pronounced destruction of the tumor vasculature with a marked decreased in vessel density. Double staining of tumors with terminal deoxynucleotidyl transferase-mediated nick end labeling and antifactor VIII antibody or antihuman NB demonstrated endothelial cell apoptosis in the vasculature, as well as increased tumor cell apoptosis. Moreover, mice injected with 3 mg/kg/week/x3 of NGR-SL[DXR] displayed rapid tumor regression, as well as inhibition of metastases growth (P = 0.0002). One day after the third treatment, four of six mice showed no evidence of tumors, and the two others showed a >80% reduction in tumor mass and a >90% suppression of blood vessel density (P < 0.01). In contrast, mice treated with ARA-SL[DXR] formed large well-vascularized tumors. Finally, a metronomic administration of NGR-SL[DXR] (1 mg/kg/every other 2 days x 9) induced complete tumor eradication in all animals (P < 0.0001). Our strategy markedly enhanced the therapeutic index of DXR and enabled metronomic administration of therapeutic doses. A dual mechanism of action is proposed: indirect tumor cell kill via the destruction of tumor endothelium by NGR-targeted liposomes and direct tumor cell kill via localization of liposomal DXR to the tumor interstitial space. This combined strategy has the potential to overcome some major limitations of conventional chemotherapy.     

Cross-national comparisons of the Cambridge Cognitive Examination-revised: the CAMCOG-R: results from the European Harmonization Project for Instruments in Dementia

BACKGROUND: Transnational and psychometrically appropriate versions of instruments used in the diagnosis of dementia are essential for comparing information between different countries. The Cambridge Examination for Mental Disorders of the Elderly incorporates a brief neuropsychological test battery, Cambridge Cognitive Examination (recently revised version), which provides objective data on performance across a number of cognitive domains. OBJECTIVE: To harmonise the Cambridge Cognitive Examination between seven European countries. METHOD: 40 patients with probable or possible Alzheimer's disease of each of the seven countries were administered the Cambridge Cognitive Examination. The Nurse Observation Scale for Geriatrics was used to assess concordance between cognitive and behavioural measures. RESULTS: Only small differences between the various Cambridge Cognitive Examination versions were found, and patterns of correlation between Cambridge Cognitive Examination and the Nurse Observation Scale for Geriatrics were consistent. CONCLUSION: These findings indicate that the harmonisation of the Cambridge Cognitive Examination was successful.     

The effect of CYP3A5 polymorphisms on the pharmacokinetics of tacrolimus in adolescent kidney transplant recipients.

BACKGROUND: CYP3A5 gene polymorphism has been shown to influence tacrolimus (TAC) blood concentration and dose requirement in adult kidney transplant patients. The aim was to analyze retrospectively the modification induced by CYP3A5 gene polymorphism on TAC's pharmacokinetic parameters obtained from 26 adolescents receiving TAC as their main immunosuppressive drug. MATERIAL/METHODS: The adolescent kidney transplant patients were genotyped for CYP3A5*3 and grouped accordingly. TAC dose, blood levels, and dose-normalized TAC blood concentration and volume of distribution obtained at different post-transplant periods during the first post-transplant year were correlated with the corresponding genotype. RESULTS: During the first three months post-transplant, heterozygotes (CYP3A5*1/*3) displayed a lower TAC blood concentration than homozygotes (CYP3A5*3/*3) (at 1 month: 7.8+/-2.1 vs. 13.4+/-6 ng/ml, p=0.007) despite a therapeutic monitoring strategy. Between 3-12 months post-transplant, TAC blood concentration was comparable between the two groups, but a two-fold increase in the daily drug dose was necessary for the heterozygotes (at 6 months: 0.23+/-0.1 vs. 0.13+/-0.06 mg/kg, p=0.04). The dose-normalized TAC concentration [(ng/ml)/(mg/kg)] was significantly lower in patients displaying the CYP3A5*1/*3 polymorphism (at 2 weeks: 33+/-2.16 vs. 71.1+/-37.8, p=0.01; 6 months: 35.4+/-12.9 vs. 85.2+/-58.9, p=0.01). At the same time, the volume of distribution of the drug in the latter group was distinctly increased for the entire post-transplant year (at 6 months: 1.79+/-0.42 vs. 0.73+/-0.5 l/kg, p=0.001). CONCLUSIONS: The great influence of CYP3A5 on the pharmacokinetics and pharmacodynamics of TAC in young transplant recipients suggests the need for pre-transplant screening of this polymorphism to improve TAC therapy.     

Rat mast cells synthesize a nitric oxide like-factor which modulates the release of histamine

Rat serosal mast cells were evaluated for their capacity to generate a nitric oxide-like factor by two bioassays: inhibition of platelet aggregation and stimulation of mast cell guanylate cyclase. Incubation of mast cells with human washed platelets, both treated with indomethacin, inhibited thrombin-induced platelet aggregation which was potentiated by superoxide dismutase and reversed by oxyhaemoglobin. When mast cells alone were stirred at 1000 rpm, a time dependent increase in the levels of their cGMP but not cAMP was observed. Preincubation of mast cells with N^G-monomethyl-l-arginine significantly enhanced E. coli lipopolysaccharide-evoked histamine release. Our results show that mast cell histamine release can be modulated by an intrinsically generated nitric oxide-like factor.     

Closed system endotracheal suctioning maintains lung volume during volume-controlled mechanical ventilation

OBJECTIVE: A closed suction system (CS) maintains connection with the mechanical ventilator during tracheal suctioning and is claimed to limit loss in lung volume and oxygenation. We compared changes in lung volume, oxygenation, airway pressure and hemodynamics during endotracheal suctioning performed with CS and with an open suction system (OS). DESIGN: Prospective, randomized study. SETTING: Intensive care unit in a university hospital. PATIENTS: We enrolled ten patients, volume-controlled (VC) ventilated with a Siemens Servo 900 ventilator (PaO2/FIO2 192 +/- 70, PEEP 10.7 +/- 3.9 cmH2O). INTERVENTIONS: We performed four consecutive tracheal suction maneuvers, two with CS and two with OS, at 20-min intervals. During the suction maneuvers continuous suction was applied for 20 s. MEASUREMENTS AND MAIN RESULTS: We measured end-expiratory lung volume changes (delta VL), tidal volume (VTrt), respiratory rate (RR) and minute volume (VErt) by respiratory inductive plethysmography; arterial oxygen saturation (SpO2), airway pressure and arterial pressure (PA). Loss in lung volume during OS (delta VL 1.2 +/- 0.7 l) was significantly higher than during CS (delta VL 0.14 +/- 0.1 l). During OS we observed a marked drop in SpO2, while during CS the change was only minor. During CS ventilation was not interrupted and we observed an immediate increase in RR (due to the activation of the ventilator's trigger), while VTrt decreased, VErt was maintained. CONCLUSIONS: Avoiding suction-related lung volume loss can be helpful in patients with an increased tendency to alveolar collapse; CS allows suctioning while avoiding dramatic drops in lung volumes and seems to be safe during the VC ventilation setting that we used.     

Effects of a Systemic Pesticide Along an Aquatic Tri-Trophic Food Chain

Bulletin of Environmental Contamination and Toxicology - Systemic pesticides, such as the neonicotinoid imidacloprid, can be introduced into aquatic ecosystems through contaminated plant material,...     

Longitudinal evaluation of mycophenolic acid pharmacokinetics in pediatric kidney transplant recipients. The role of post-transplant clinical and therapeutic variables

Abstract:  This longitudinal study assessed the influence of post-transplant clinical and therapeutic variables in 50 kidney transplant recipients aged 2–19 yr receiving a triple immunosuppressive regimen consisting of cyclosporine microemulsion (CsA), steroids and MMF (300–400 mg/m² body surface area twice daily), the full pharmacokinetic profile (10 points) of which was investigated on post-transplant days 6, 30, 180 and 360. Total plasma MPA was measured by Enzyme Multiplied Immunoassay Technique. CsA therapeutic drug monitoring (TDM) was performed via C2 blood monitoring, while MPA TDM via C0. MPA Cmax, tmax, AUC0-12 and AUC0-4 pharmacokinetic profile changed significantly during the first post-transplant year. C0 was a poor predictor of the total MPA exposure [as measured by the area under the concentration-time curve AUC)], while a truncated AUC was a good surrogate of the 12-h profile (r = 0.91; p < 0.001) Graft function and cyclosporine therapy influenced MPA pharmacokinetics, as shown by the univariate and multivariate analyses. We conclude that because after transplantation MPA exposure varied over time, a strict TDM is advisable in the pediatric population.     

Respiratory symptoms/diseases and environmental tobacco smoke (ETS) in never smoker Italian women

AIM: To study the relationship between respiratory/allergic disorders and chronic environmental tobacco smoke (ETS) exposure to husband or at workplace among non-smoking women of a general population in Italy. METHODS: Analyses regard 2195 married or employed women. Information was collected through a self-administered questionnaire. ETS exposure was validated by salivary cotinine. RESULTS: Exposure both to husband and at work resulted a significant risk factor for current dyspnoea (odds ratio (OR) 1.61, 95% confidence interval (CI) 1.20-2.16), any shortness of breath at rest (OR 2.81, 95% CI 1.83-4.30), recent wheeze (OR 1.71, 95% CI 1.04-2.82), recent attacks of shortness of breath with wheeze (OR 1.85, 95% CI 1.05-3.26), asthma diagnosis/symptoms (OR 1.50, 95% CI 1.09-2.08), diagnosis of asthma or bronchitis/emphysema (obstructive lung diseases (OLD)) (OR 2.24, 95% CI 1.40-3.58), current cough/phlegm (OR 1.52, 95% CI 1.07-2.15), and rhino-conjunctivitis (OR 1.48, 95% CI 1.13-1.94). Exposure only at work yielded higher adjusted odds ratios for all health conditions, except for rhino-conjunctivitis. Overall, about 24% of shortness of breath at rest, 16% of dyspnoea, 17% of rhino-conjunctivitis, 12% of OLD, and 10% of asthma diagnosis/symptoms are attributable to the effect of exposures to both husband and at work. Twelve percent of shortness of breath at rest and 10% of rhino-conjunctivitis cases might be avoided by eliminating exposure only at work and only to husband, respectively. CONCLUSIONS: Lifetime ETS exposure, especially at work, is associated with respiratory symptoms/diseases, and it accounts for a sizeable proportion of such disorders. The combined effect of both exposures is higher than the separate effects.     

Reference equations for spirometry from a general population sample in central Italy

Aim of this study was to derive new lung function reference equations and compare the predicted values with those from three sets of existing reference equations: one derived from a Northern Italy population and the two others widely used in European (ECCS) and American (NHANES III) clinical practice. Reference equations for flow-volume curve indexes and VC were derived on 497 normal subjects, aged 8-74, from the epidemiological survey in Pisa, Central Italy (1991-1993). By applying natural cubic splines, one single smooth and continuous equation for the entire age range was provided for each index, separately by gender. Along with age and height, reference values also depended on BMI. Differences among the four reference equations for FEV(1), FVC, VC were quantified for average subjects. The magnitude largely varied over the age range in both genders, reaching up to half litre of air volume at specific ages. Age-gender-specific prevalence rates of airway obstruction, as defined by the ERS criterion, largely varied by applying the considered equations, the differences ranging from -3% to 28%. The observed discrepancies confirm that reference equations should be derived from a population most similar to that for which the equations are to be used and based on measurements obtained by the same instrument and testing procedures, in order to minimize technical variability in lung function both for clinical and epidemiological purposes.