Cortrak® duodenal tube placements: A solution for more patients? A preliminary survey to the introduction of electromagnetic-guided placement of naso-duodenal feeding tubes.

RATIONALE: The Cortrak® feeding tube, an electromagnetic (EM) guided feeding tube which is placed by a trained nurse at the patient's bedside, is reported to be a safe, patient friendly and cost effective answer to the disadvantages of endoscopic placement of naso-duodenal feeding tubes. However, this procedure requires a learning curve and regular practice. This study aims to evaluate whether introducing Cortrak® feeding tube placement would be profitable in a tertiary referral academic hospital. METHODS: We re-evaluated all endoscopically placed post-pyloric feeding tubes in the years 2012-2013. Taking into consideration training for nurses to learn how to place Cortrak® feeding tubes, strict inclusion criteria were formulated for the initial retrospective analysis: age 18 years or older, normal GI anatomy and non-ICU admitted patients. As a secondary analysis we also evaluated ICU patients (age >18 and normal upper GI tract). RESULTS: Patient records of 487 duodenal feeding tube placements in 331 patients were evaluated; 125 non-ICU placements (in 90 patients) and 84 ICU placements (in 75 ICU patients) fulfilled the inclusion criteria. Main reasons for exclusion were: abnormalities of the upper GI tract (n = 176) and endoscopy for diagnostic reasons (n = 74). Main indications for placements were gastroparesis (37%) or insufficient food intake (20%). For secondary analysis, 84 placements in 75 ICU patients were re-evaluated, with main indication gastroparesis (62%). CONCLUSION: In our hospital, at least one quarter of the duodenal tube placements would qualify for Cortrak® placement in the initial phase. Once routine has been built up and also ICU patients could be considered, half or more patients requiring a naso-duodenal feeding tube would qualify for Cortrak® placement, adding up to 3 placements per week. The findings of this study may help to decide on the profitability of introducing this method in our own hospital. The next step will be to perform a cost-benefit analysis to study whether implementing Cortrak® in practice is cost-effective and feasible.

Investigating unexpected INRs: in search of the culprit--adherence, interactions, genetics, and superwarfarin.

Treatment with coumarin derivatives is highly individualised due to high intra- and inter-individual variation in dose response and risks of severe bleeding or thromboembolic complications. Treatment focuses on reaching and maintaining a stable target international normalised ratio (INR). However, unexpected INRs that are not explained by noncompliance or vitamin K intake may occur. Here we describe seven cases of unexpected INRs, and provide clues that clarify the underlying mechanism.

A simple and sensitive assay for the quantitative analysis of paclitaxel in human and mouse plasma and brain tumor tissue using coupled liquid chromatography and tandem mass spectrometry.

The development and validation of an assay for the determination of paclitaxel in human plasma, human brain tumor tissue, mouse plasma and mouse brain tumor tissue is described. Paclitaxel was extracted from the matrices using liquid-liquid extraction with tert-butyl methyl ether, followed by chromatographic analysis using an alkaline eluent. Positive ionization electrospray tandem mass spectrometry was performed for selective and sensitive detection. The method was validated according to the FDA guidelines on bioanalytical method validation. Validation results indicate that calibration standards in human plasma can be used to quantify paclitaxel in all tested matrices. In human samples, the validated range for paclitaxel was from 0.25-1000 ng ml(-1) using 200 microl plasma aliquots and from 5 to 5000 ng g(-1) using 50 microl tumor homogenate aliquots (0.2 g tissue ml(-1) control human plasma). In mice, the ranges were 1-1000 ng ml(-1) and 5-5000 ng g(-1) using 50 microl of mouse plasma and 50 microl of tumor homogenate aliquots (0.2 g tissue ml(-1) control human plasma), respectively. The method can be applied to studies generating only small sample volumes (e.g. mouse plasma and tumor tissue), but also to studies in human plasma requiring a lower limit of quantitation. The assay was applied successfully to several studies with both human and mouse samples.

Bioanalysis of zosuquidar trihydrochloride (LY335979) in small volumes of human and murine plasma by ion-pairing reversed-phase high-performance liquid chromatography.

We have developed and validated a sensitive and selective method for the quantitative determination of the P-glycoprotein inhibitor zosuquidar (LY335979) in human and murine plasma using only 50 microl sample volumes. Sample pretreatment involved liquid-liquid extraction with tert-butyl methyl ether. Zosuquidar and the internal standard chlorpromazine were separated using a narrow bore column (2.1 mm x 150 mm) packed with 3.5 microm symmetry C(18) material. The mobile phase consisted of 38% (v/v) acetonitrile in 50mM ammonium acetate buffer pH 3.8 containing 0.005 M 1-octyl sulfonic acid and was delivered at 0.2 ml/min. Detection was performed with a fluorescence detector set at an excitation wavelength of 260 nm and an emission wavelength of 460 nm. The calibration curve was prepared in blank human plasma and was linear over the dynamic range (10-1000 ng/ml). The lower limit of quantitation was 20 ng/ml. The validation results showed that the assay was selective and reproducible. Within the range of the calibration curve the accuracy was close to 100% and within-day and between-day precision were within the generally accepted 15% range. This method was applied to study the pharmacokinetics of i.v. administered zosuquidar in mice. The sensitivity of the assay was sufficient to determine the drug concentration in plasma samples obtained up to 24 h after administration.

Cannulation of the jugular vein in mice: a method for serial withdrawal of blood samples.

We have developed and validated a method that allows serial drawing of blood samples in freely moving mice using a cannula that is inserted via the jugular vein into the right atrium of the heart. The cannula was tunnelled subcutaneously to the head of the animal and attached to the skin by sutures, together with a metal spring, which was covered with PVC tubing for protection of the outer part of the cannula. Samples of blood up to 250 micro l could be taken at serial time points. The blood volume in the circulation was maintained by replacement with an equal volume of blood obtained from donor animals. The applicability of this method of blood sampling for pharmacokinetic purposes was validated by comparing plasma concentrations-time curves in six cannulated animals after receiving an intravenous bolus dose of 10 mg/kg of the anti-cancer agent docetaxel versus the results in plasma samples obtained by cardiac puncture of non-cannulated mice. The presented method may lead to improved pharmacokinetic data produced from a reduced number of mice.

Determination of cyclosporin A in human and mouse plasma by reversed-phase high-performance liquid chromatography.

An isocratic reversed-phase high-performance liquid chromatographic method with ultraviolet detection at 227 nm has been validated for the determination of cyclosporin A in human and mouse plasma. The cyclosporin D analog PSC 833 was used as internal standard. Plasma samples were pretreated by liquid-liquid extraction with diethyl ether. A good chromatographic separation between cyclosporin A, the internal standard and two potentially interfering endogenous peaks was achieved using a stainless steel column packed with 5 microm Nova-Pak phenyl material operated at 72 degrees C, and a mobile phase consisting of acetonitrile-methanol-water (20:52:28, v/v/v). The calibration curve for cyclosporin A in human plasma was linear over the tested concentration range of 0.11 to 5.34 microM. Murine plasma samples (200 microl) were diluted up to a total volume of 500 microl with blank human plasma and the concentrations were read from the calibration curve prepared in human plasma. The lower limit of quantitation was 0.11 microM using 500 microl of human plasma and 0.28 microM using 200 microl of mouse plasma. The validation data showed that the assay is sensitive, selective and reproducible for determination of cyclosporin A. The applicability was demonstrated in a pharmacokinetic experiment where mice received oral cyclosporin A.

The co-solvent Cremophor EL limits absorption of orally administered paclitaxel in cancer patients.

The purpose of this study was to investigate the effect of the co-solvents Cremophor EL and polysorbate 80 on the absorption of orally administered paclitaxel. 6 patients received in a randomized setting, one week apart oral paclitaxel 60 mg m(-2) dissolved in polysorbate 80 or Cremophor EL. For 3 patients the amount of Cremophor EL was 5 ml m(-2), for the other three 15 ml m(-2). Prior to paclitaxel administration patients received 15 mg kg(-1) oral cyclosporin A to enhance the oral absorption of the drug. Paclitaxel formulated in polysorbate 80 resulted in a significant increase in the maximal concentration (C(max)) and area under the concentration-time curve (AUC) of paclitaxel in comparison with the Cremophor EL formulations (P = 0.046 for both parameters). When formulated in Cremophor EL 15 ml m(-2), paclitaxel C(max) and AUC values were 0.10 +/- 0.06 microM and 1.29 +/- 0.99 microM h(-1), respectively, whereas these values were 0.31 +/- 0.06 microM and 2.61 +/- 1.54 microM h(-1), respectively, when formulated in polysorbate 80. Faecal data revealed a decrease in excretion of unchanged paclitaxel for the polysorbate 80 formulation compared to the Cremophor EL formulations. The amount of paclitaxel excreted in faeces was significantly correlated with the amount of Cremophor EL excreted in faeces (P = 0.019). When formulated in Cremophor EL 15 ml m(-2), paclitaxel excretion in faeces was 38.8 +/- 13.0% of the administered dose, whereas this value was 18.3 +/-15.5% for the polysorbate 80 formulation. The results show that the co-solvent Cremophor EL is an important factor limiting the absorption of orally administered paclitaxel from the intestinal lumen. They highlight the need for designing a better drug formulation in order to increase the usefulness of the oral route of paclitaxel

One-day intensified lansoprazole-quadruple therapy for cure of Helicobacter pylori infection.

BACKGROUND: Peptic ulcer patients need to be treated with antimicrobials to cure Helicobacter pylori infection. Seven-day quadruple therapy is the regimen with the highest cure rates. An ultra-short quadruple therapy was evaluated prospectively. METHODS: Forty-six consecutive H. pylori positive patients (33 had proven ulcer disease) were prescribed lansoprazole 30 mg b.d. on days 1-4, and on day 4 they received in addition tripotassium dicitrato bismuthate 120 mg, tetracycline 250 mg and metronidazole 250 mg at 09.00, 11.00, 13.00, 15.00, 17.00, 19.00, 21.00, 23.00 hours. Repeat endoscopy with biopsies for CLOtest, Giemsa stain and culture was carried out 6 weeks later. RESULTS: Follow-up was complete. Overall cure rate (all three biopsy-based tests negative) was 26/46 (57%; 95% CI: 41-71%). Antibiotic sensitivity was available in 42. Thirty-nine carried a metronidazole sensitive strain and 23/39 (59%) were cured, three carried a resistant strain and therapy failed in all. Three out of four in whom susceptibility was unknown were cured. Metronidazole resistance was induced in 8 out of 16 with a sensitive strain. Only one patient (3%) reported severe side effects. CONCLUSIONS: This convenient quadruple regimen showed that a short contact time is sufficient to kill H. pylori in vivo. Since 57% of patients are cured with a 14-h treatment, a slightly longer treatment duration may increase the cure rate to above 90%.

4-day lansoprazole quadruple therapy: a highly effective cure for Helicobacter pylori infection.

OBJECTIVES: We have advocated quadruple therapy as the optimal therapy for cure of Helicobacter pylori infection. In this study, we investigated the efficacy and tolerability of 4-day therapy with lansoprazole, bismuth, tetracycline, and metronidazole. METHODS: In a prospective open study, 51 consecutive patients, most of them with chronic peptic ulcer disease and biopsy proven H. pylori infection, received 4-day lansoprazole quadruple therapy after 3 days of lansoprazole pretreatment. Repeat endoscopy was performed 6 wk later, with antral and corpus biopsies for rapid urease test, histology, and culture. A patient was considered cured if three methodologies had negative results. RESULTS: By intention-to-treat, 48 of 51 patients (94%) (95% CI 84%-99%) were cured; per protocol, 48 of 49 (98%) (95% CI 89%-100%) were cured. In 14 patients, the bacterial isolates were tested for metronidazole susceptibility: 12/12 with a sensitive strain were cured, as were 2/2 with a resistant strain. The regimen was well tolerated. Most side effects were mild, and none caused treatment to be stopped prematurely. CONCLUSIONS: Four-day lansoprazole quadruple therapy achieves a very high cure rate in an unselected population of mainly ulcer patients. Furthermore, the regimen is short, can be used in patients allergic to penicillin, and is well tolerated, with no dropouts due to side effects. Presently, this regimen should be used only in patients with a metronidazole-sensitive pre-treatment bacterial isolate. When empiric treatment is used, 7-day quadruple therapy remains the therapy of choice, because it has well-documented efficacy against metronidazole-resistant strains. Further studies are needed to define the optimal treatment duration for quadruple therapy in patients with metronidazole-resistant strains.