Improving the quality of palliative and terminal care in the hospital by a network of palliative care nurse champions: the study protocol of the PalTeC-H project

BACKGROUND: The quality of care of patients dying in the hospital is often judged as insufficient. This article describes the protocol of a study to assess the quality of care of the dying patient and the contribution of an intervention targeted on staff nurses of inpatient wards of a large university hospital in the Netherlands. METHODS/DESIGN: We designed a controlled before and after study. The intervention is the establishment of a network for palliative care nurse champions, aiming to improve the quality of hospital end-of-life care. Assessments are performed among bereaved relatives, nurses and physicians on seven wards before and after introduction of the intervention and on 11 control wards where the intervention is not applied. We focus on care provided during the last three days of life, covered in global ratings of the quality of life in the last three days of life and the quality of dying, and various secondary endpoints of treatment and care affecting quality of life and dying. DISCUSSION: With this study we aim to improve the understanding of and attention for patients’ needs, and the quality of care in the dying phase in the hospital and measure the impact of a quality improvement intervention targeted at nurses

Cluster Editing: Kernelization based on Edge Cuts

Kernelization algorithms for the {\sc cluster editing} problem have been a popular topic in the recent research in parameterized computation. Thus far most kernelization algorithms for this problem are based on the concept of {\it critical cliques}. In this paper, we present new observations and new techniques for the study of kernelization algorithms for the {\sc cluster editing} problem. Our techniques are based on the study of the relationship between {\sc cluster editing} and graph edge-cuts. As an application, we present an ${\cal O}(n^2)$-time algorithm that constructs a $2k$ kernel for the {\it weighted} version of the {\sc cluster editing} problem. Our result meets the best kernel size for the unweighted version for the {\sc cluster editing} problem, and significantly improves the previous best kernel of quadratic size for the weighted version of the problem

Role of intestinal P-glycoprotein in the plasma and fecal disposition of docetaxel in humans

Multidrug resistance (MDR)-1-P-glycoprotein (P-gp) is a drug-transporting protein that is abundantly present in biliary ductal cells and epithelial cells lining the gastrointestinal tract. Here, we have determined the role of P-gp in the metabolic disposition of the antineoplastic agent docetaxel (Taxotere) in humans. Pharmacokinetic profiles were evaluated in five cancer patients receiving treatment cycles with docetaxel alone (100 mg/m2 i.v. over a 1-h period) and in combination with a new potent inhibitor of P-gp activity, R101933 (200-300 mg b.i.d.). The terminal disposition half-life and total plasma clearance of docetaxel were not altered by treatment with oral R101933 (P > or = 0.27). The cumulative fecal excretion of docetaxel, however, was markedly reduced from 8.47 +/- 2.14% (mean +/- SD) of the dose with the single agent to less than 0.5% in the presence of R101933 (P = 0.0016). Levels of the major cytochrome P450 3A4-mediated metabolites of docetaxel in feces were significantly increased after combination treatment with R101933 (P = 0.010), indicating very prominent and efficient detoxification of reabsorbed docetaxel into hydroxylated compounds before reaching the systemic circulation. It is concluded that intestinal P-gp plays a principal role in the fecal elimination of docetaxel by modulating reabsorption of the drug after hepatobiliary secretion. In addition, the results indicate that inhibition of P-gp activity in normal tissues by effective modulators, and the physiological and pharmacological consequences of this treatment, cannot be predicted based on plasma drug monitoring alone

On the (non-)existence of polynomial kernels for Pl-free edge modification problems

Given a graph G = (V,E) and an integer k, an edge modification problem for a graph property P consists in deciding whether there exists a set of edges F of size at most k such that the graph H = (V,E \vartriangle F) satisfies the property P. In the P edge-completion problem, the set F of edges is constrained to be disjoint from E; in the P edge-deletion problem, F is a subset of E; no constraint is imposed on F in the P edge-edition problem. A number of optimization problems can be expressed in terms of graph modification problems which have been extensively studied in the context of parameterized complexity. When parameterized by the size k of the edge set F, it has been proved that if P is an hereditary property characterized by a finite set of forbidden induced subgraphs, then the three P edge-modification problems are FPT. It was then natural to ask whether these problems also admit a polynomial size kernel. Using recent lower bound techniques, Kratsch and Wahlstrom answered this question negatively. However, the problem remains open on many natural graph classes characterized by forbidden induced subgraphs. Kratsch and Wahlstrom asked whether the result holds when the forbidden subgraphs are paths or cycles and pointed out that the problem is already open in the case of P4-free graphs (i.e. cographs). This paper provides positive and negative results in that line of research. We prove that parameterized cograph edge modification problems have cubic vertex kernels whereas polynomial kernels are unlikely to exist for the Pl-free and Cl-free edge-deletion problems for large enough l

The orally administered P-glycoprotein inhibitor R101933 does not alter the plasma pharmacokinetics of docetaxel

This Phase I study was performed to assess the feasibility of combining docetaxel with the new P-glycoprotein inhibitor R101933 and to determine the dose limiting toxicity of this combination. Fifteen patients received oral R101933 alone at a dose escalated from 200 to 300 mg twice daily (b.i.d.; cycle 0), an escalating i.v. dose of docetaxel (60, 75, and 100 mg/m2) as a 1-h infusion (cycle 1), and the combination (cycle 2 and further). Dose limiting toxicity consisting of mucositis and neutropenic fever was reached at the combination of docetaxel, 100 mg/m2, and R101933, 300 mg b.i.d., and the maximum tolerated dose was established at docetaxel, 100 mg/m2, and R101933, 200 mg b.i.d. Plasma concentrations of R101933 achieved in patients were in the same range as required in preclinical rodent models to overcome paclitaxel resistance. The plasma pharmacokinetics of docetaxel were not influenced by the R101933 regimen at any dose level tested, as indicated by plasma clearance values of 26.5 +/- 7.78 liters/h/m2 and 23.4 +/- 4.52 liters/h/m2 (P = 0.15) in cycles 1 and 2, respectively. These findings indicate that the contribution of a P-glycoprotein inhibitor to the activity of anticancer chemotherapy can now be assessed in patients for the first time independent of its effect on drug pharmacokinetics

Pharmacokinetic considerations and recommendations in palliative care, with focus on morphine, midazolam and haloperidol

Introduction: A variety of medications are used for symptom control in palliative care, such as morphine, midazolam and haloperidol. The pharmacokinetics of these drugs may be altered in these patients as a result of physiological changes that occur at the end stage of life. Areas covered: This review gives an overview of how the pharmacokinetics in terminally ill patients may differ from the average population and discusses the effect of terminal illness on each of the four pharmacokinetic processes absorption, distribution, metabolism, and elimination. Specific considerations are also given for three commonly prescribed drugs in palliative care: morphine, midazolam and haloperidol). Expert opinion: The pharmacokinetics of drugs in terminally ill patients can be complex and limited evidence exists on guided drug use in this population. To improve the quality of life of these patients, more knowledge and more pharmacokinetic/pharmacodynamics studies in terminally ill patients are needed to develop individualised dosin

Phase I and pharmacokinetic study of the polyamine synthesis inhibitor SAM486A in combination with 5-fluorouracil/leucovorin in metastatic colorectal cancer

PURPOSE: The purpose of our study was to determine the maximum-tolerated\n dose, dose-limiting toxicity, safety profile, and pharmacokinetics of the\n polyamine synthesis inhibitor SAM486A given in combination with\n 5-fluorouracil/leucovorin (5-FU/LV) in cancer patients. EXPERIMENTAL\n DESIGN: Patients with advanced colorectal cancer were treated with 5-FU\n [bolus (400 mg/m(2)) followed by a 22-h infusion (600 mg/m(2))] and LV\n (200 mg/m(2)) and escalating doses of SAM486A, 1-3-h infusion daily for 3\n days. Plasma sampling was performed to characterize the pharmacokinetics\n and pharmacodynamics of the combination RESULTS: Twenty-seven patients\n with metastatic colorectal cancer and 1 with pseudomyxoma peritonei were\n treated. Twenty-six patients received SAM486A in the combination at doses\n ranging from 25 to 150 mg/m(2)/day. Dose-limiting toxicity consisting of\n fatigue grade 3 was seen at 150 mg/m(2)/day. Other adverse events included\n neutropenia, hand and foot syndrome, nausea, vomiting, diarrhea, and\n constipation. Fifteen of 26 patients evaluable for best response according\n to the Southwest Oncology Group criteria achieved a partial response [8\n (30%) of 26] or stable disease [9 (35%) of 26]. SAM486A did not influence\n the pharmacokinetics of 5-FU, and SAM486A clearance was similar to that\n when used as a single agent. CONCLUSIONS: The novel molecular agent\n SAM486A is tolerable and safe in combination with a standard 5-FU regimen\n in patients with advanced colorectal cancer. The dose of SAM486A\n recommended for additional studies with this combination is 125\n mg/m(2)/day. A disease-directed evaluation of SAM486A using this regimen\n is warranted

Scopolaminebutyl given prophylactically for death rattle: Study protocol of a randomized double-blind placebo-controlled trial in a frail patient population (the SILENCE study)

Background: Death rattle (DR), caused by mucus in the respiratory tract, occurs in about half of patients who are in the dying phase. Relatives often experience DR as distressing. Anticholinergics are recommended to treat DR, although there is no evidence for the effect of these drugs. Anticholinergic drugs decrease the production of mucus but do not affect existing mucus. We therefore hypothesize that these drugs are more effective when given prophylactically. Methods: We set up a randomized double-blind, placebo-controlled, multi-center study evaluating the efficacy of prophylactically given subcutaneous scopolaminebutyl for the prevention of DR in the dying phase. The primary outcome is the occurrence of DR defined as grade ≥ 2 according to the scale of Back measured by a nurse at 2 consecutive time points with an interval of 4 h. Secondary outcomes include adverse effects, quality of dying, quality of life in the last three days and bereavement. A sub-study will explore the experience of participating in a clinical trial in the dying phase from the perspective of relatives. Four hospices will include 200 patients. Discussion: This is the first double-blind placebo-controlled study to prevent DR in patients in the hospice setting. Research in dying patients is challenging. We will apply ethical and organizational strategies as suggested in the literature

Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications

We have determined the in vitro and in vivo cellular distribution of the antineoplastic agent paclitaxel (Taxol) in human blood and the influence of Cremophor EL (CrEL), the vehicle used for i.v. drug administration. In the absence of CrEL, the blood:plasma concentration ratio was 1.07+/-0.004 (mean+/-SD). The addition of CrEL at concentrations corresponding to peak plasma levels achieved after the administration of paclitaxel (175 mg/m2 i.v. over a 3-h period; ie., 0.50%) resulted in a significant decrease in the concentration ratio (0.690+/-0.005; P < 0.05). Kinetic experiments revealed that this effect was caused by reduced erythrocyte uptake of paclitaxel by polyoxyethyleneglycerol triricinoleate, the major compound present in CrEL. Using equilibrium dialysis, it was shown that the affinity of paclitaxel for tested matrices was (in decreasing order) CrEL > plasma > human serum albumin, with CrEL present at or above the critical micellar concentration (approximately 0.01%). Our findings in the present study demonstrate a profound alteration of paclitaxel accumulation in erythrocytes caused by a trapping of the compound in CrEL micelles, thereby reducing the free drug fraction available for cellular partitioning. It is proposed that the nonlinearity of paclitaxel plasma disposition in patients reported previously should be reevaluated prospectively by measuring the free drug fractions and whole blood:plasma concentration ratios