Modeling the 5-Fluorouracil Area Under the Curve Versus Dose Relationship to Develop a Pharmacokinetic Dosing Algorithm for Colorectal Cancer Patients Receiving FOLFOX6

5-Fluorouracil (5-FU) is administered based on standard body surface area (BSA) dosing. BSA administration results in highly variable exposure, measured as the area under the concentration-time curve (AUC). An immunoassay (OnDose®; Myriad Genetic Laboratories, Inc., Salt Lake City, UT) that measures plasma 5-FU concentration and reports an AUC in mg · h/L has been developed to optimize therapy using pharmacokinetic (PK) dosing. The results of an analysis to model the 5-FU AUC-dose relationship are presented

On the adaptive significance of stress-induced immunosuppression

We approach the field of stress immunology from an ecological point of view and ask: why should a heavy physical workload, for example as a result of a high reproductive effort, compromise immune function? We argue that immunosuppression by neuroendocrine mechanisms, such as stress hormones, during heavy physical workload is adaptive, and consider two different ultimate explanations of such immunosuppression. First, several authors have suggested that the immune system is suppressed to reallocate resources to other metabolic demands. In our view, this hypothesis assumes that considerable amounts of energy or nutrients can be saved by suppressing the immune system; however, this assumption requires further investigation. Second, we suggest an alternative explanation based on the idea that the immune system is tightly regulated by neuroendocrine mechanisms to avoid hyperactivation and ensuing autoimmune responses. We hypothesize that the risk of autoimmune responses increases during heavy physical workload and that the immune system is suppressed to counteract this

Modeling the 5‐Fluorouracil Area Under the Curve Versus Dose Relationship to Develop a Pharmacokinetic Dosing Algorithm for Colorectal Cancer Patients Receiving FOLFOX6

BACKGROUND. 5-Fluorouracil (5-FU) is administered based on standard body surface area (BSA) dosing. BSA administration results in highly variable exposure, measured as the area under the concentration-time curve (AUC). An immunoassay (OnDose®; Myriad Genetic Laboratories, Inc., Salt Lake City, UT) that measures plasma 5-FU concentration and reports an AUC in mg · h/L has been developed to optimize therapy using pharmacokinetic (PK) dosing. The results of an analysis to model the 5-FU AUC-dose relationship are presented. METHODS. A set of 589 sequential patients from a clinical database receiving 5-FU, leucovorin, and oxaliplatin (the FOLFOX6 regimen) for colorectal cancer (CRC) treatment was analyzed. A subset including only patients who had at least two consecutive cycles tested, received 1,600–3,600 mg/m(2) of continuous infusion 5-FU during the initial test cycle, and had a blood sample collected after ≥18 hours, was used to conduct regression modeling of the change in AUC versus change in dose. RESULTS. A simple regression model with R(2) = 0.51 developed over n = 307 cycle-pair observations characterizes the AUC-Dose relationship as: change in AUC = 0.02063 * dose change. The model suggests that dose changes in the range of 145–727 mg/m(2) would be sufficient to adjust the AUC to a potential therapeutic threshold of >20 mg · h/L for most patients. CONCLUSIONS. 5-FU is an ideal candidate for PK dose optimization. Because individual factors other than dose change may also affect the change in AUC, longitudinal PK monitoring in all cycles and dose adjustment to ensure AUC in the desired range of 20–30 mg · h/L are recommended

Gastrin-releasing peptide receptor (GRPR) mediates chemotaxis in neutrophils

Neutrophil migration to inflamed sites is crucial for both the initiation of inflammation and resolution of infection, yet these cells are involved in perpetuation of different chronic inflammatory diseases. Gastrin-releasing peptide (GRP) is a neuropeptide that acts through G protein coupled receptors (GPCRs) involved in signal transmission in both central and peripheral nervous systems. Its receptor, gastrin-releasing peptide receptor (GRPR), is expressed by various cell types, and it is overexpressed in cancer cells. RC-3095 is a selective GRPR antagonist, recently found to have antiinflammatory properties in arthritis and sepsis models. Here we demonstrate that i.p. injection of GRP attracts neutrophils in 4 h, and attraction is blocked by RC-3095. Macrophage depletion or neutralization of TNF abrogates GRP-induced neutrophil recruitment to the peritoneum. In vitro, GRP-induced neutrophil migration was dependent on PLC- β2, PI3K, ERK, p38 and independent of Gαi protein, and neutrophil migration toward synovial fluid of arthritis patients was inhibited by treatment with RC-3095.We propose that GRPR is an alternative chemotactic receptor that may play a role in the pathogenesis of inflammatory disorders