Doxorubicin concentrations in bone tumour-relevant tissues after bolus and continuous infusion: a randomized porcine microdialysis study.

PURPOSE: Doxorubicin is a widely used chemotherapeutic drug that can be administered intravenously as both a bolus infusion and a continuous infusion. The latter is believed to lower the risk of cardiotoxicity, which is a critical long-term complication of doxorubicin treatment. The local tissue concentrations of doxorubicin will be reflected in both treatment efficacy and toxicity, but very limited information is available. The aim of this study was to measure the concentration of doxorubicin after continuous and bolus infusion in tissue compartments around a typical location of a bone tumour. METHODS: Sixteen pigs (female, Danish Landrace, mean weight 77 kg) were randomized into two groups of eight. Both groups received an intravenous infusion of 150 mg doxorubicin; Group 1 received a bolus infusion (10-15 min) and Group 2 received a continuous infusion (6 h). Before infusion, microdialysis catheters were placed intravenously and in four bone tumour-relevant tissue compartments (cancellous bone, subcutaneous tissue, synovial fluid of the knee joint and muscle tissue). Sampling was done (n = 15) over 24 h, and venous blood samples were collected as a reference. RESULTS: Area under the concentration-time curve (AUC0-24 h) for plasma (total concentration) was significantly different between the two groups, while peak drug concentration (Cmax) was significantly higher in two compartments (plasma and synovial fluid of the knee joint) in Group 1 compared to Group 2. Overall, the unbound tissue concentrations were extremely low with values below 0.20 µg/mL. CONCLUSION: The pharmacokinetic profile for doxorubicin in the investigated tissues is very similar when comparing bolus and 6 h continuous infusion.

Abdominal tissue concentrations and penetration of carboplatin in a HIPEC procedure ‒ assessment in a novel porcine model.

Objectives: Peritoneal dissemination from intraabdominal cancers is associated with poor prognosis and rapid disease progression. Hyperthermic intraperitoneal chemotherapy (HIPEC) is an antineoplastic treatment, which has improved survival and recurrence-free survival, but little is known about the acquired chemotherapy concentrations in local tissues. The aim of this study was to assess concentrations of carboplatin during and after HIPEC treatment dynamically and simultaneously in various abdominal organ tissues by means of microdialysis in a novel porcine model. Methods: Eight pigs underwent imitation cytoreductive surgery followed by HIPEC (90 min) using a carboplatin dosage of 800 mg/m2. Microdialysis catheters were placed for sampling of drug concentrations in various solid tissues: peritoneum, liver, bladder wall, mesentery and in different depths of one mm and four mm in the hepatoduodenal ligament and rectum. During and after HIPEC, dialysates and blood samples were collected over 8 h. Results: No statistically significant differences in mean AUC0-last (range: 2,657-5,176 min·µg/mL), mean Cmax (range: 10.6-26.0 µg/mL) and mean Tmax (range: 105-206 min) were found between the compartments. In plasma there was a tendency towards lower measures. No difference between compartments was found for tissue penetration. At the last samples obtained (450 min) the mean carboplatin concentrations were 4.9-9.9 µg/mL across the investigated solid tissues. Conclusions: Equal carboplatin distribution in abdominal organ tissues, detectable concentrations for at least 6 h after HIPEC completion, and a carboplatin penetration depth of minimum four mm were found. The present study proposes a new HIPEC porcine model for future research.

[Intermittent claudication].

Intermittent claudication is a manifestation of peripheral arterial occlusive disease. Multiple large international guidelines state that besides cardiovascular risk management, supervised exercise therapy (SET) should be offered to all patients with intermittent claudication. As described in this review, The Netherlands have already established a systemic rehabilitation program, ClaudicatioNet, where SET has been included and have shown positive outcomes. Despite all large national guidelines and the successful experience from the Netherlands, Denmark still fails to include SET to patients with intermittent claudication.

Influence of anastomoses on intestine ischemia and cefuroxime concentrations: Evaluated in the ileum and colon in a porcine model.

BACKGROUND: Anastomotic leakage is a serious complication following gastrointestinal surgery and is associated with increased morbidity and mortality. The incidence of anastomotic leakage is determined by anatomy and is reported to be between 4%-33% for colon anastomosis and 1%-3% for small intestine anastomosis. The etiology of anastomotic leakage of the intestine has been divided into three main factors: healing disturbances, communication between intra- and extra-luminal compartments, and infection. All three factors interact, and one factor will inevitably lead to the other two factors resulting in tissue ischemia, tissue necrosis, and anastomotic leakage. AIM: To evaluate ischemic metabolites and cefuroxime concentrations in both anastomosis and non-anastomosis ileum and colon in a porcine model. METHODS: Eight healthy female pigs (Danish Landrace breed, weight 58-62 kg) were included in this study. Microdialysis catheters were placed for sampling of ischemic metabolites (glucose, lactate, glycerol, and pyruvate) and cefuroxime concentrations in both anastomosis and non-anastomosis ileum and colon. Cefuroxime 1.5 g was administered as an intravenous infusion over 15 min. Subsequently, dialysates and blood samples were collected over 8 h and the ischemic metabolites and cefuroxime concentrations were quantified in all samples. The concentrations of glucose, lactate, glycerol and pyruvate were determined using the CMA 600 Microdialysis Analyzer with Reagent Set A (M Dialysis AB, Sweden), and the concentrations of cefuroxime and meropenem were quantified using a validated ultra-high-performance liquid chromatography assay. RESULTS: Only the colon anastomosis induced mean ischemic lactate/pyruvate ratios above 25 (ischemic cut-off) throughout the entire sampling interval, and simultaneously decreased glucose concentrations. The mean time for which cefuroxime concentrations were maintained above the clinical breakpoint minimal inhibitory concentration for Escherichia coli (8 µg/mL) ranged between 116-128 min across all the investigated compartments, and was similar between the anastomosis and non-anastomosis ileum and colon. For all pigs and in all the investigated compartments, a cefuroxime concentration of 8 µg/mL was reached within 10 min after administration. When comparing the pharmacokinetic parameters between the anastomosis and non-anastomosis sites for both ileum and colon, only colon Tmax and half-life differed between anastomosis and non-anastomosis (P < 0.03). Incomplete tissue penetrations were found in all tissues except for the non-anastomosis colon. CONCLUSION: Administering 1.5 g cefuroxime 10 min prior to intestine surgery seems sufficient, and effective concentrations are sustained for approximately 2 h. Only colon anastomosis was locally vulnerable to ischemia.