Population pharmacokinetics of teicoplanin and attainment of pharmacokinetic/pharmacodynamic targets in adult patients with haematological malignancy.

OBJECTIVES: To describe the population pharmacokinetics of teicoplanin in adult patients with haematological malignancies receiving higher than standard doses, and to perform Monte Carlo simulations to determine dosing regimens associated with optimal teicoplanin concentrations. METHODS: This was a hospital-based clinical trial (EudraCT 2013-004535-72). Nine blood samples were collected on Day 3, plus single trough samples on Days 7 and 10, and 24 and 48 hours after the last dose. Teicoplanin minimum inhibitory concentrations were determined for Gram-positive isolates from study patients. Population pharmacokinetic analyses and Monte Carlo dosing simulations were undertaken using Pmetrics. RESULTS: Thirty adult haematological malignancy patients were recruited with a mean (SD) loading dose, age, total body weight, and creatinine clearance of 9.5 (1.9) mg/kg, 63 (12) years, 69.1 (15.8) kg, and 72 (41) mL/min, respectively. A three-compartment linear pharmacokinetic model best described the teicoplanin concentration data. Covariates supported for inclusion in the final model were creatinine clearance for clearance and total body weight for volume of the central compartment. The median (IQR) area under the concentration-time curve from 48 to 72 hours (AUC48-72h) was 679 (319) mg.h/L. There was a strong correlation between the AUC48-72h and trough concentration at 72 hours (Pearson correlation coefficient 0.957, p <0.001). Dosing simulations showed that administration of five loading doses at 12-hourly intervals, stratified by total body weight and creatinine clearance, increased the probability of achieving target concentrations within 72 hours. CONCLUSIONS: To increase the number of patients achieving optimal teicoplanin concentrations an individualized dosing approach, based on body weight and creatinine clearance, is recommended.

Tumour vasculature targeting agents in hybrid/conjugate drugs.

Tumour vasculature targeting has been a very active area of cancer drug discovery over the last decade. Growth of solid tumours beyond a certain point requires a sufficient blood supply in order for them to develop and metastasise. While novel anti-angiogenic and vascular disrupting agents represent an important contribution to the armoury of anti-cancer agents they nevertheless usually require combination with standard cytotoxic therapy in order to demonstrate positive clinical outcomes. In line with this consensus, a new concept has arisen, namely the design of functional hybrids where at least one component of the design targets a tumour angiogenic/vasculature pathway. This review will outline examples of such hybrid/conjugate-based approaches. Emphasis will be placed on their preclinical evaluation with particular focus on the RGD/NGR-conjugates, heparin-related hybrids and antibody-drug conjugates. In conclusion, the benefits and shortcomings of hybrids under development will be discussed in the context of future directions and applications.

Profiling harmful medication errors in an acute Irish teaching hospital.

BACKGROUND: Medication error reporting systems in hospitals are faced with the challenge of processing vast numbers of reports which identify a myriad of safety issues. With such large volumes of data and limited resources it makes sense to adopt a prioritisation approach. Several published studies have focused solely on the subset of errors which cause patient harm. The majority of such research has concerned the individual analysis of criteria associated with medication errors. However, the research described here used an alternative approach which involved linking the three criteria of medication class, patient outcome, and type of error, in order to describe the medication-related scenarios presenting greatest risk to the organisation. AIMS: To identify the highest-priority medication-related risks in an acute teaching hospital. To profile harmful medication errors submitted to a voluntary reporting system in a tertiary healthcare setting in Ireland. METHODS: A database of medication errors, reported via an internal voluntary reporting system over a 5-year period, was analysed. The criteria of medication class, patient outcome and type of error were analysed separately and then cross-tabulated. RESULTS: The medication classes, error types and adverse patient outcomes most frequently associated with harm were identified. The cross-tabulation highlighted ten priority risk areas which accounted for the majority of patient harm. CONCLUSIONS: A cross-tabulation strategy for prioritising medication-associated risks was successfully applied to a hospital database comprising medication errors. The profile developed for harmful medication errors in this acute tertiary healthcare setting was broadly in line with that published for error reporting systems internationally.

Pharmacological effects of a novel isosorbide-based butyrylcholinesterase inhibitor.

Isosorbide-2-benzylcarbamate-5-benzoate, a novel butyrylcholinesterase inhibitor, shows interspecies variation in its inhibitory activity (IC(50) of 4.3 nM for human plasma butyrylcholinesterase, but 1.09 microM for mouse plasma butyrylcholinesterase). Stability studies revealed that this drug is resistant to hydrolysis by human plasma (no degradation in 1 h). However, it was found to undergo rapid degradation when incubated with mouse plasma or mouse liver homogenate, yielding benzyl carbamate and benzoic acid. The addition of the carboxylesterase inhibitor bis-(4-nitrophenyl) phosphate (BNPP) inhibited the degradation of the novel drug, indicating that it may be a substrate for both butyrylcholinesterase and carboxylesterase. The absence of carboxylesterase from human plasma explains the drug's stability in this medium. In vivo, pharmacodynamic studies on single doses of 1 mg/kg to naïve male C57BL/6 mice revealed maximal plasma butyrylcholinesterase inhibition 20 min after intraperitoneal administration (approximately 60% inhibition) and 1 h after administration by gavage (approximately 45% inhibition). While this plasma butyrylcholinesterase inhibition was short-lived, the drug also penetrated the blood-brain barrier resulting in a slight (10-15%) but persistent (> or =72 h) reduction in brain butyrylcholinesterase activity.

An evaluation of the flexiguide introducer with the flexible laryngeal mask airway.

Insertion of the flexible Laryngeal Mask Airway has been achieved by a variety of techniques. We have evaluated the Flexiguide for aiding introduction of a flexible Laryngeal Mask Airway in 100 anaesthetised patients. We were successful in establishing a clear airway on the first attempt on 84 (84%) occasions and within two attempts in 97 (97%). The positioning of the laryngeal mask airway was assessed by five measures and was optimally placed in 85% of cases and good in 96%. A clear airway was achieved in 92% of cases. Insertion of the flexible Laryngeal Mask Airway with the Flexiguide was easy in 82 (82%) and slightly difficult in 15 (15%) of cases. Removal of the Flexiguide from the device was easy in 95 (95%) of cases. Airway manoeuvres were used to assist airway placement in 55% of cases with jaw thrust being most common. Minor complications occurred in three (3%) patients: two coughed and one experienced minor tissue trauma during mask insertion. There were no complications associated with use of the Flexiguide during the procedure or after anaesthesia. The Flexiguide is a useful tool to assist insertion of the flexible Laryngeal Mask Airway and is associated with few complications.

Refining the indications for surgery after proximal femoral fracture.

Many patients die shortly after surgery for proximal femoral fracture. These patients are subjected to painful operative procedures that do not improve their outcome. We attempted to identify such patients with a case-controlled study of variables associated with death in hospital after proximal femoral fracture. Bronchopneumonia, ASA grade 4, heart failure and malnutrition were significantly associated with death but the latter two variables alone were insufficiently specific to justify withholding surgical treatment. However, 90% of patients with bronchopneumonia and those deemed unfit for anaesthesia died shortly after admission and their condition was not improved by active intervention. We suggest that it is kinder to withhold early surgery in this population.

The relationship between blood flow and pulsatility index in the superior mesenteric artery at rest and during constrictor stimuli in normal subjects.

The relationships between superior mesenteric artery blood flow (SMABF) and pulsatility index (PI) measurement during rest (25 subjects) and stimuli constricting the SMA (16 subjects) have been studied in normal subjects. At rest and during constrictor stimuli, SMABF and PI were highly reproducible (r = 0.89, p < 0.01 for SMABF, and r = 0.97, p < 0.001 for PI) between two observers. There was significant correlation between changes in SMABF, PI, and SMA vascular resistance during the constrictor stimuli, except during head-up tilt when PI was unchanged. Both PI and SMABF measurements are reproducible and can be used to monitor physiological changes in suitable (18 of 25) subjects. PI measurement, although semiquantitative, by itself can also be used to monitor these changes. This may be also of importance in pathological situations such as intestinal ischemia, where measurement of volume blood flow may be less accurate due to irregularities of the vessel wall. PI measurement, however, ideally should not be used in studies involving postural change.