Background: Elimination of a drug during renal replacement therapy is not only dependent on flow rates, molecular size and protein binding, but is often influenced by difficult to predict drug membrane interactions. In vitro models allow for extensive profiling of drug clearance using a wide array of hemofilters and flow rates. We present a bovine blood based in vitro pharmacokinetic model for intermittent renal replacement therapy. Methods: Four different drugs were analyzed: gentamicin, doripenem, vancomicin and teicoplanin. The investigated drug was added to a bovine blood reservoir connected to a hemodialysis circuit. In total seven hemofilter models were analyzed using commonly employed flow rates. Pre-filter, post-filter and dialysate samples were drawn, plasmaseparated and analyzed using turbidimetric assays or HPLC. Protein binding of doripenem and vancomycin was measured in bovine plasma and compared to previously published values for human plasma. Results: Clearance values were heavily impacted by choice of membrane material and surface as well as by dialysis parameters such as blood flow rate. Gentamicin clearance ranged from a minimum of 90.12 ml/min in a Baxter CAHP-170 diacetate hemofilter up to a maximum of 187.90 ml/min in a Fresenius medical company Fx80 polysulfone model (blood flow rate 400 ml/min, dialysate flow rate 800 ml/min). Clearance of Gentamicin vs Vancomicin over the F80s hemofilter model using the same flow rates was 137.62 mL vs 103.25 ml/min. Doripenem clearance with the Fx80 was 141.25 ml/min. Conclusion: Clearance values corresponded very well to previously published data from clinical pharmacokinetic trials. In conjunction with in silico pharmacometric models. This model will allow precise dosing recommendations without the need of large scale clinical trials.

Ceftaroline fosamil, a fifth-generation cephalosporin antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA), is currently approved for the treatment of pneumonia and complicated skin and soft tissue infections. However, pharmacokinetics data on free lung tissue concentrations in critical patient populations are lacking.

Turmeric is a yellowish orange spice, widely used in Asian cuisine and obtained from the rhizome of Curcuma longa. It is a mixture of three curcuminoids namely, curcumin, demethoxycurcumin and bisdemethoxycurcumin. Turmeric has been used as a medicinal substance since ancient times for respiratory and gastrointestinal problems. The aim of the present study was to investigate which curcuminoid contributes to the observed pharmacological activities, all three curcuminoids, the major curcumin metabolite tetrahydrocurcumin, and the non-enzymatic curcumin hydrolysis products ferulic acid, feruloyl methane and vanillin were analyzed for spasmolytic, inotropic and chronotropic activity. Furthermore, their uptake in respective tissue samples was also investigated and correlated with activity. Spasmolytic activity was determined in guinea pig ileum, aorta and pulmonary artery. Inotropic and chronotropic activity was determined on guinea pig papillary muscles and right atrium respectively, while tissue uptake was quantified by using high-performance liquid chromatography (HPLC). All the curcuminoids exhibited significant spasmolytic activity with highest EC50 values for bisdemethoxycurcumin (5.8 ± 0.6 μM) followed by curcumin (12.9 ± 0.7 μM), demethoxycurcumin (16.8 ± 3 μM) and tetrahydrocurcumin (22.9 ± 1.5 μM). While only demethoxycurcumin was able to significantly relax the pulmonary artery with EC50 value of 15.78 ± 0.85 μM. All three curcuminoids showed mild negative chronotropic effects in the isolated right atrium; tetrahydrocurcumin demonstrated no activity. Curcumin and bisdemethoxycurcumin also showed mild positive inotropic effect whereas demethoxycurcumin and tetrahydrocurcumin exhibited weak negative inotropic one. Interestingly, ferulic acid, feruloyl methane and vanillin demonstrated no pharmacologicical activity at all in the various isolated organs. All three curcuminoids and tetrahydrocurcumin showed high uptake into the various tissues where concentrations correlated with pharmacological activity. The results indicate pronounced differences in the in vitro pharmacological activities of curcumin, demethoxycurcumin, bisdemethoxycurcumin and tetrahydrocurcumin which have to be considered in humans after per-oral intake of turmeric powder.

The adenosine triphosphate-binding cassette transporters P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) are 2 efflux transporters at the blood-brain barrier (BBB) that effectively restrict brain distribution of dual ABCB1/ABCG2 substrate drugs, such as tyrosine kinase inhibitors. Pharmacologic inhibition of ABCB1/ABCG2 may improve the efficacy of dual-substrate drugs for treatment of brain tumors, but no marketed ABCB1/ABCG2 inhibitors are currently available. In the present study, we examined the potential of supratherapeutic-dose oral erlotinib to inhibit ABCB1/ABCG2 activity at the human BBB. Methods: Healthy men underwent 2 consecutive PET scans with C-11-erlotinib: a baseline scan and a second scan either with concurrent intravenous infusion of the ABCB1 inhibitor tariquidar (3.75 mg/min, n = 5) or after oral intake of single ascending doses of erlotinib (300 mg, n = 7; 650 mg, n = 8; or 1,000 mg, n = 2). Results: Although tariquidar administration had no effect on C-11-erlotinib brain distribution, oral erlotinib led, at the 650-mg dose, to significant increases in volume of distribution (23% +/- 13%, P = 0.008), influx rate constant of radioactivity from plasma into brain (58% +/- 26%, P = 0.008), and area under the brain time-activity curve (78% +/- 17%, P = 0.008), presumably because of combined partial saturation of ABCG2 and ABCB1 activity. Inclusion of further subjects into the 1,000-mg dose group was precluded by adverse skin events (rash). Conclusion: Supratherapeutic-dose erlotinib may be used to enhance brain delivery of ABCB1/ABCG2 substrate anticancer drugs, but its clinical applicability for continuous ABCB1/ABCG2 inhibition at the BBB may be limited by safety concerns.

ABSTRACT Critically ill patients often experience acute kidney injury and the need for renal replacement therapy in the course of their treatment in an intensive care unit (ICU). These patients are at an increased risk for candidiasis. Although there have been several reports of micafungin disposition during renal replacement therapy, to this date there are no data describing the elimination of micafungin during high-dose continuous venovenous hemodiafiltration with modified AN69 membranes. The aim of this prospective open-label pharmacokinetic study was to assess whether micafungin plasma levels are affected by continuous hemodiafiltration in critical ill patients using the commonly employed AN69 membrane. A total of 10 critically ill patients with micafungin treatment due to suspected or proven candidemia were included in this trial. Prefilter/postfilter micafungin clearance was measured to be 46.0 ml/min (±21.7 ml/min; n = 75 individual time points), while hemofilter clearance calculated by the sieving coefficient was 0.0038 ml/min (±0.002 ml/min; n = 75 individual time points). Total body clearance was measured to be 14.0 ml/min (±7.0 ml/min; n = 12). The population area under the curve from 0 to 24 h (AUC 0–24 ) was calculated as 158.5 mg · h/liter (±79.5 mg · h/liter; n = 13). In spite of high protein binding, no dose modification is necessary in patients receiving continuous venovenous hemodiafiltration with AN69 membranes. A dose elevation may, however, be justified in certain cases. (This study has been registered at ClinicalTrials.gov under identifier NCT02651038.)

In colorectal cancer (CRC), an increase in the stromal (S) area with the reduction of the epithelial (E) parts has been suggested as an indication of tumor progression. Therefore, an automated image method capable of discriminating E and S areas would allow an improved diagnosis. Immunofluorescence staining was performed on paraffin-embedded sections from colorectal tumors (16 samples from patients with liver metastasis and 18 without). Noncancerous tumor adjacent mucosa (n=5) and normal mucosa (n=4) were taken as controls. Epithelial cells were identified by an anti-keratin 8 (K8) antibody. Large tissue areas (5–63 mm2/slide) including tumor center, tumor front, and adjacent mucosa were scanned using an automated microscopy system (TissueFAXS). With our newly developed algorithms, we showed that there is more K8-immunoreactive E in the tumor center than in tumor adjacent and normal mucosa. Comparing patients with and without metastasis, the E/S ratio decreased by 20% in the tumor center and by 40% at tumor front in metastatic samples. The reduction of E might be due to a more aggressive phenotype in metastasis patients. The novel software allowed a detailed morphometric analysis of cancer tissue compartments as tools for objective quantitative measurements, reduced analysis time, and increased reproducibility of the data.

Topical drug delivery is the most widely used drug administration route for the treatment of ocular diseases. Studies investigating the intraocular in-vivo pharmacokinetics of topically administered drugs are sparse due to the technically demanding nature of the required procedures. In the present study, we set out to assess an in-vivo pharmacokinetic profile of the widely used topical antibiotic ciprofloxacin. Therefore, in-vivo microdialysis was used to assess pharmacokinetics of the anterior chamber and the vitreous in a rabbit model after topical instillation of the drug. After approval by the animal welfare and Ethics Review Committee, 8 female New Zealand White rabbits (Charles River, Germany) weighing 2.3–4.1kg were included. All experiments were performed under general anesthesia, A linear microdialysis probe (30 kDa molecular weight cut off [MWCO]) was implanted in the anterior chamber and a concentric microdialysis probe (0.5×10 mm, 20 kDa MWCO) in the vitreous of the same eye. One single drop (30 µL) of ciprofloxacin eye drops (0.09 mg in 30 µL) was administered on the ocular surface after a run-in period of 2 hours. Microdialysis samples were collected every 30min for 6h. Relative recovery was assessed by retro-dialysis to calculate absolute concentration values. Samples were analyzed using HPCL. After single administration of ciprofloxacin, the maximum free drug concentration (Cmax) was 0.373 ± 0.218 µg/mL in the anterior chamber and was reached (Tmax) after 116 ± 36 min. Calculated AUC(0-n) in the anterior chamber was 78.8 ± 47.1µg min/mL. In the vitreous, Cmax was 2.2 ± 2.5 ng/mL and maximum drug concentration was reached 106 ± 60 min after drug administration. AUC(0-n) for ciprofloxacin in the vitreous was 0.268 ± 0.370 µg min/mL. Microdialysis is a suitable method to assess in-vivo pharmacokinetics in the rabbit's eye. In the anterior chamber, the maximum concentration of ciprofloxacin was reached approximately 2h after single drug administration. In the vitreous, drug concentration was considerably lower, although the time course of drug concentration was comparable.

We assessed the pharmacokinetics (PK), tolerability and safety of tariquidar (TQD), a P-glycoprotein (Pgp) inhibitor, after intravenous administration of single ascending doses. Employed doses were up to 4-fold higher than in previous clinical trials in cancer patients and are capable of inhibiting Pgp at the blood-brain barrier. Fifteen male healthy volunteers were randomized to receive single intravenous doses of TQD at 4, 6 or 8 mg/kg body weight and underwent blood sampling for over 24 h. TQD concentrations were determined in plasma samples with high-performance liquid chromatography mass spectrometry. No dose-limiting toxicities of TQD were observed. The area under the plasma concentration-time curve from start until 24 h after the end of infusion was positively correlated with an administered TQD dose (r = 0.8981, p < 0.0001). Moreover, we found a positive correlation for volume of distribution at steady state (r = 0.7129, p = 0.0004) with TQD dose. Dose dependency of volume of distribution at steady state points to non-linear PK of TQD, which was in all likelihood caused by transporter saturation at high TQD doses. Acceptable safety and tolerability as well as dose-linear increases in plasma exposure support the future use of TQD at doses up to 8 mg/kg to inhibit Pgp at the human blood-brain barrier.

ABSTRACT The use of cardiopulmonary bypass (CPB) during cardiac surgery causes regional ventilation-perfusion mismatch, contributing to regional disturbances in antibiotic penetration into lung tissue. Ventilation-perfusion mismatch is associated with postoperative pneumonia, a frequent and devastating complication after cardiac surgery. In this prospective clinical animal study, we performed in vivo microdialysis to determine the effect of CPB on regional penetration of levofloxacin (LVX) into lung tissue. Six pigs underwent surgery with CPB (CPB group), and another six pigs underwent surgery without CPB (off-pump coronary artery bypass grafting; OPCAB group). LVX (750 mg) was administered intravenously to all pigs immediately after surgery. For regional measurements of LVX in pulmonary concentrations, microdialysis probes were inserted in both lungs of each pig. Pigs were placed in the right lateral position. Time versus concentration profiles of unbound LVX were measured in the upper and lower lung tissue and plasma in all pigs. In all pigs, maximum concentrations ( C max ) of LVX were significantly lower in the upper lung than in the lower lung (OPCAB, P = 0.035; CPB, P < 0.001). Median C max of LVX showed a significant difference in the upper versus lower lung in the CPB group ( P < 0.05). No significant difference was found in the median C max of LVX in the upper and the lower lung in the OPCAB group ( P = 0.32). Our data indicate that CPB affects perioperative regional antibiotic penetration into lung tissue. Common clinical antibiotic dosing schemes should be reevaluated in patients undergoing coronary artery bypass grafting with CPB.

Esomeprazole, a proton pump inhibitor, and ranitidine, a histamine-2 receptor antagonist are frequently used in intensive care patients requiring stress ulcer prophylaxis. Continuous venovenous hemodiafiltration (CVVHDF) is an important extracorporeal renal replacement therapy in critically ill patients suffering from multiple organ failure. This study investigates the pharmacokinetics and pharmacodynamics of esomeprazole and ranitidine in anuric critically ill patients undergoing CVVHDF.

Using positron emission tomography (PET) imaging we assessed, in vivo, the interaction between a microdose of (R)-[C-11] verapamil (a P-glycoprotein (Pgp) substrate) and escalating doses of the Pgp inhibitor tariquidar (3, 4, 6, and 8 mg/kg) at the blood-brain barrier (BBB) in healthy human subjects. We compared the dose-response relationship of tariquidar in humans with data obtained in rats using a similar methodology. Tariquidar was equipotent in humans and rats in its effect of increasing (R)-[C-11]verapamil brain uptake (expressed as whole-brain volume of distribution (V-T)), with very similar half-maximum-effect concentrations. Both in humans and in rats, brain V-T approached plateau levels at plasma tariquidar concentrations >1,000 ng/ml. However, Pgp inhibition in humans led to only a 2.7-fold increase in brain V-T relative to baseline scans (before administration of tariquidar) as compared with 11.0-fold in rats. The results of this translational study add to the accumulating evidence that there are marked species-dependent differences in Pgp expression and functionality at the BBB.

BACKGROUND:Arterial catheterization is painful and is associated with patient stress and anxiety. Analgesia is usually provided by subcutaneous injection of local anaesthetic. An alternative is topical anaesthesia, such as Rapydan which is a novel topical anaesthetic patch containing 70 mg each of lidocaine and tetracaine. We therefore tested the hypothesis that Rapydan patch analgesia is non-inferior to subcutaneous local anaesthetic.METHODS:Ninety patients undergoing elective major cardiac surgery were included in this prospective, double-blind clinical trial. Patients were randomly assigned to receive either a lidocaine/tetracaine patch, followed by subcutaneous injection 0.5 ml of normal saline solution, or placebo patch with subsequent subcutaneous injection of 0.5 ml of lidocaine 1%. Pain during arterial catheterization using 100-mm-long visual analogue scale (VAS) was the primary outcome. Other outcomes were pain during anaesthetic/saline injection and plasma tetracaine concentrations.RESULTS:VAS pain scores during arterial puncture were comparable in both groups and Rapydan was non-inferior to subcutaneous lidocaine. Pain scores at the time of subcutaneous injection were significantly lower (better) in patients assigned to the lidocaine/tetracaine patch than to lidocaine (P=0.001). Plasma tetracaine concentrations never exceeded the detection limit of 25 ng ml(-1) at any time in any patient.CONCLUSIONS:Both the lidocaine/tetracaine patch and subcutaneous injection of lidocaine provided comparable pain control during arterial catheter insertion. Subcutaneous lidocaine caused discomfort during injection, whereas the lidocaine/tetracaine patch required placement 20 min before the procedure. Given adequate time, the patch provided better overall analgesia by obviating the need for subcutaneous infiltration.

Methods Participating pharmacists and pharmacy technicians screened consecutive individuals picking up prescription medications about their (1) NHP use, (2) prescription medication use, (3) concurrent NHP/prescription medication use in the previous one month, and (4) the occurrence of potential AEs. If a potential AE was identified and the patient provided written consent, a research pharmacist conducted a guided telephone interview to gather additional detailed information on the AE and medical history of the patient.

Roth, G.; Sipos, W.; Hoeferl, M.; Schebesta, K.; Jaeger, W.; Krenn, C. G. Author Information