Comparison of the blood-brain barrier and liver penetration of acridine antitumor drugs

Summary The blood-brain barrier penetration of amsacrine and its analogs 9-({2-methoxy-4-[(methylsulfonyl)-amino]phenyl}amino)-,5-dimethyl-4-acridine carboxamide (CI-921) and M-[2-(dimethylamino)ethyl]-acridine-4-carboxamide (AC) was measured in the barbiturate-anesthetized mouse. After intracarotid administration, AC was almost completery extracted (90%) in a single transit through the brain capillaries, whereas CI-921 (20%) and amsacrine (15%) were moderately extracted. AC is retained in the brain; no loss of AC from the brain was apparent at 1, 2, 4, or 8 min after injection. In contrast, after intraportal administration, 75% of the AC, 94% of the CI-921, and 57% of the amsacrine was extracted in a single transit through the hepatic vasculature. Rather than being retained in the mouse liver, these acridine antitumor agents show time-dependent loss (t _1/2=10 min for amsacrine and AC, 24 min for CI-921). We conclude that unlike most antitumor agents, these acridine drugs appear to penetrate the blood-brain barrier readily.This study was supported by the Auckland Medical Research Foundation (New Zealand), by the Medical Research Foundation (New Zealand), by the National Science Foundation (United States/New Zealand Cooperative Science Program), by the United States Veterans Administration, and by NIH grant NS 25554     

Adeno-associated virus vector-mediated systemic delivery of IFN-beta combined with low-dose cyclophosphamide affects tumor regression in murine neuroblastoma models.

PURPOSE: Type I IFNs (IFN-alpha/beta) have shown significant antitumor activity in preclinical models but limited efficacy and significant toxicity in clinical trials. We hypothesized that the antitumor activity of type I IFNs could be enhanced by chronic, low-dose systemic delivery and sought to test this in murine neuroblastoma models. EXPERIMENTAL DESIGN: Continuous liver-generated expression of human IFN-beta (hINF-beta) was achieved through a gene therapy-mediated approach using adeno-associated virus vectors encoding hIFN-beta (AAV hINF-beta). Orthotopic localized retroperitoneal and disseminated models of neuroblastoma were established using three different xenografts. Immunohistochemical analysis and ELISA were used to evaluate the antiangiogenic effect of therapy. RESULTS: The development of both localized orthotopic (retroperitoneal) and disseminated neuroblastoma was prevented in all mice expressing hINF-beta. Continued growth of established retroperitoneal tumors, treated with AAV hINF-beta as monotherapy, was significantly restricted, and survival for mice with established, disseminated disease was significantly prolonged following administration of AAV hINF-beta. Analysis of treated tumors revealed a significant antiangiogenic effect. Mean intratumoral vessel density was diminished and expression of the angiogenic factors vascular endothelial growth factor and basic fibroblast growth factor were both decreased. Finally, combination therapy in which AAV hIFN-beta was used together with low-dose cyclophosphamide resulted in regression of both established retroperitoneal and disseminated disease. CONCLUSIONS: AAV-mediated delivery of hIFN-beta when used as monotherapy was able to restrict neuroblastoma growth due in part to inhibition of angiogenesis. When used in combination with conventional chemotherapy, AAV hIFN-beta was able to effect complete tumor regression.     

The binding of amsacrine to human plasma proteins

Determination of amsacrine plasma protein binding by both equilibrium dialysis and ultracentrifugation gave similar results and indicated that amsacrine is highly bound (approximately 97%) in human plasma. This binding is independent of amsacrine concentration over the range 1-100 mumol litre-1, but is very sensitive to plasma pH and, to a lesser extent, to temperature. Approximately 20% of the drug appeared to be covalently bound to plasma proteins. Amsacrine was bound by all plasma proteins investigated including albumin, alpha 1-acid glycoprotein and various gamma-globulins. The binding to albumin appeared to occur by two processes, a saturable process at a single site with a KD of 13.9 mumol litre-1 and a non-saturable process. Despite differences in individual protein concentrations, no significant difference was observed in the unbound amsacrine fraction in plasma from patients receiving this drug for treatment of acute myelogenous leukaemia and plasma from healthy individuals.     

Self-help materials for anxiety: a randomized controlled trial in general practice.

The efficacy of a self-help package in treating chronic anxiety was evaluated in a randomized controlled trial in which the intervention group received self-help materials in the form of an audiotape and booklet, in addition to their current treatment. The intervention was successful in terms of mean depression scores (P = 0.01), anxiety scores (P = 0.04) and general health questionnaire scores (P = 0.02) which were significantly lower for the intervention group than for the controls. In addition, the depression scores fell faster for the intervention group than for the controls. The overall mean reduction in three months in adjusted depression scores was approximately two points greater for the intervention group than for the controls (P = 0.02). Clinicians welcomed the package as a valuable addition to the therapies available for managing chronic anxiety problems. Further studies should include larger sample sizes, taking into account the non-response to postal questionnaires over time.     

Body dissatisfaction prospectively predicts depressive mood and low self-esteem in adolescent girls and boys.

This research examined whether body dissatisfaction prospectively predicted depressive mood and low self-esteem in adolescent girls and boys 5 years later. Participants were early-adolescent girls (n = 440, Time 1 M age = 12.7 years) and boys (n = 366, Time 1 M age = 12.8 years) and midadolescent girls (n = 946, Time 1 M age = 15.8 years) and boys (n = 764, Time 1 M age = 15.9 years). After controlling for Time 1 of the relevant dependent variable, ethnicity, socioeconomic status, and body mass index, Time 1 body dissatisfaction was a unique predictor of Time 2 depressive mood and low self-esteem in early-adolescent girls (depressive mood: F = 4.80, p < .05; self-esteem: F = 9.64, p < .01) and midadolescent boys (depressive mood: F = 12.27, p < .001; self-esteem: F = 9.38, p < .01) but not in early-adolescent boys or midadolescent girls. These findings are consistent with the hypothesis that body dissatisfaction is a risk factor for depressive mood and low self-esteem in both girls and boys but in different phases of adolescence.     

Working conditions and health behavior as causes of educational inequalities in self-rated health: an inverse odds weighting approach

Objective:Using a novel mediation method that presents unbiased results even in the presence of exposure–mediator interactions, this study estimated the extent to which working conditions and health behaviors contribute to educational inequalities in self-rated health in the workforce.Methods:Respondents of the longitudinal Survey of Health, Ageing, and Retirement in Europe (SHARE) in 16 countries were selected, aged 50–64 years, in paid employment at baseline and with information on education and self-rated health (N=15 028). Education, health behaviors [including body mass index (BMI)] and working conditions were measured at baseline and self-rated health at baseline and two-year follow-up. Causal mediation analysis with inverse odds weighting was used to estimate the total effect of education on self-rated health, decomposed into a natural direct effect (NDE) and natural indirect effect (NIE).Results:Lower educated workers were more likely to perceive their health as poor than higher educated workers [relative risk (RR) 1.48, 95% confidence interval (CI) 1.37–1.60]. They were also more likely to have unfavorable working conditions and unhealthy behaviors, except for alcohol consumption. When all working conditions were included, the remaining NDE was RR 1.30 (95% CI 1.15–1.44). When BMI and health behaviors were included, the remaining NDE was RR 1.40 (95% CI 1.27–1.54). Working conditions explained 38% and health behaviors and BMI explained 16% of educational inequalities in health. Including all mediators explained 64% of educational inequalities in self-rated health.Conclusions:Working conditions and health behaviors explain over half of the educational inequalities in self-rated health. To reduce health inequalities, improving working conditions seems to be more important than introducing health promotion programs in the workforce.