Development of a Tumour Growth Inhibition Model to Elucidate the Effects of Ritonavir on Intratumoural Metabolism and Anti-tumour Effect of Docetaxel in a Mouse Model for Hereditary Breast Cancer

In a mouse tumour model for hereditary breast cancer, we previously explored the anti-cancer effects of docetaxel, ritonavir and the combination of both and studied the effect of ritonavir on the intratumoural concentration of docetaxel. The objective of the current study was to apply pharmacokinetic (PK)-pharmacodynamic (PD) modelling on this previous study to further elucidate and quantify the effects of docetaxel when co-administered with ritonavir. PK models of docetaxel and ritonavir in plasma and in tumour were developed. The effect of ritonavir on docetaxel concentration in the systemic circulation of Cyp3a knock-out mice and in the implanted tumour (with inherent Cyp3a expression) was studied, respectively. Subsequently, we designed a tumour growth inhibition model that included the inhibitory effects of both docetaxel and ritonavir. Ritonavir decreased docetaxel systemic clearance with 8% (relative standard error 0.4%) in the co-treated group compared to that in the docetaxel only-treated group. The docetaxel concentration in tumour tissues was significantly increased by ritonavir with mean area under the concentration-time curve 2.5-fold higher when combined with ritonavir. Observed tumour volume profiles in mice could be properly described by the PK/PD model. In the co-treated group, the enhanced anti-tumour effect was mainly due to increased docetaxel tumour concentration; however, we demonstrated a small but significant anti-tumour effect of ritonavir addition (p value <0.001). In conclusion, we showed that the increased anti-tumour effect observed when docetaxel is combined with ritonavir is mainly caused by enhanced docetaxel tumour concentration and to a minor extent by a direct anti-tumour effect of ritonavir.

Intravenous Immunoglobulin with Enhanced Polyspecificity Improves Survival in Experimental Sepsis and Aseptic Systemic Inflammatory Response Syndromes.

Sepsis is a major cause for death worldwide. Numerous interventional trials with agents neutralizing single pro-inflammatory mediators have failed to improve survival in sepsis and aseptic systemic inflammatory response syndromes. This failure could well be explained by the widespread gene expression dysregulation known as "genomic storm" in these patients. A multifunctional polyspecific therapeutic agent might be needed to thwart the effects of this "storm". Licensed pooled intravenous immunoglobulin preparations seemed to be a promising candidate but they have also failed in their present form to prevent sepsis-related death. We report here the protective effect of a single dose of intravenous immunoglobulin preparations with additionally enhanced polyspecificity in three models of sepsis and aseptic systemic inflammation. The modification of the pooled immunoglobulin G molecules by exposure to ferrous ions resulted in their newly acquired ability to bind some pro-inflammatory molecules, complement components and endogenous "danger" signals. The improved survival in endotoxemia was associated with serum levels of pro-inflammatory cytokines, diminished complement consumption and normalization of the coagulation time. We suggest that intravenous immunoglobulin preparations with additionally enhanced polyspecificity have a clinical potential in sepsis and related systemic inflammatory syndromes.

β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis

Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain. Here we identify β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner. B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice and young heterochronic parabionts. Exogenous B2M injected systemically, or locally in the hippocampus, impairs hippocampal-dependent cognitive function and neurogenesis in young mice. The negative effects of B2M and heterochronic parabiosis are, in part, mitigated in the hippocampus of young transporter associated with antigen processing 1 (Tap1)-deficient mice with reduced cell surface expression of MHC I. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.

Retrospective evaluation of the effects of administration of tetrastarch (hydroxyethyl starch 130/0.4) on plasma creatinine concentration in dogs (2010-2013): 201 dogs

OBJECTIVE To determine changes in creatinine concentrations following the administration of 6% tetrastarch (hydroxyethyl starch [HES] 130/0.4) compared to crystalloids (CRYSs) in critically ill dogs. DESIGN Retrospective case series (2010-2013). SETTING University teaching hospital. ANIMALS Two hundred and one dogs admitted to the intensive care unit with initial plasma creatinine concentrations not exceeding laboratory reference intervals (52-117 μmol/L [0.6-1.3 mg/dL]) and receiving either CRYSs alone (CRYS group, n = 115) or HES with or without CRYSs (HES group, n = 86) for at least 24 hours. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Creatinine concentrations at admission to the intensive care unit (T0), and 2-13 days (T1) and 2-12 weeks (T2) after initiation of fluid therapy were analyzed. Creatinine concentrations were analyzed as absolute values and as the maximum percentage change from T0 to T1 (T1max%) and from T0 to T2 (T2max%), respectively. Creatinine concentrations were available for 192 dogs during T1 and 37 dogs during T2. The median cumulative dose of HES was 86 mL/kg (range, 12-336 mL/kg). No difference was detected between the groups for age, gender, body weight, and length of hospitalization. Outcome was significantly different between the HES (66% survived) and the CRYS (87% survived) groups (P = 0.014). No significant difference was detected between groups for creatinine concentrations at T0, T1, T2, T1max%, or T2max%. No significant difference was detected between the groups for T1max% creatinine in dogs subclassified as having systemic inflammatory response syndrome or sepsis. CONCLUSIONS HES administration in this canine population did not result in increased creatinine concentrations compared to administration of CRYSs. Further studies are needed to establish the safety of HES in critically ill dogs.