A novel angiopoietin-derived peptide displays anti-angiogenic activity and inhibits tumour-induced and retinal neovascularization.

BACKGROUND AND PURPOSE: Pathological angiogenesis is associated with various human diseases, such as cancer, autoimmune diseases and retinopathy. The angiopoietin (Ang)-Tie2 system plays critical roles in several steps of angiogenic remodelling. Here, we have investigated the anti-angiogenic effect of a novel angiopoietin-derived peptide. EXPERIMENTAL APPROACH: Using computational methods, we identified peptides from helical segments within angiopoietins, which were predicted to inhibit their activity. These peptides were tested using biochemical methods and models of angiogenesis. The peptide with best efficacy, A11, was selected for further characterization as an anti-angiogenic compound. KEY RESULTS: The potent anti-angiogenic activity of A11 was demonstrated in a multicellular assay of angiogenesis and in the chorioallantoic membrane model. A11 bound to angiopoietins and reduced the binding of Ang-2 to Tie2. A11 was also significantly reduced vascular density in a model of tumour-induced angiogenesis. Its ability to inhibit Ang-2 but not Ang-1-induced endothelial cell migration, and to down-regulate Tie2 levels in tumour microvessels, suggests that A11 targets the Ang-Tie2 pathway. In a rat model of oxygen-induced retinopathy, A11 strongly inhibited retinal angiogenesis. Moreover, combination of A11 with an anti-VEGF antibody showed a trend for further inhibition of angiogenesis, suggesting an additive effect. CONCLUSIONS AND IMPLICATIONS: Our results indicate that A11 is a potent anti-angiogenic compound, through modulation of the Ang-Tie2 system, underlining its potential as a therapeutic agent for the treatment of ocular and tumour neovascularization, as well as other pathological conditions that are dependent on angiogenesis.

Audit of initial use of the ultrasound-guided transversus abdominis plane block in children.

The extent of dermatomal block post transversus abdominis plane block is described in adults as T7-L1; other authors argue extent above T10 is infrequent (supra-iliac 20 ml injection). A paediatric guideline recommends this block for upper and lower abdominal surgery using 0.2 ml/kg. We aimed (through prospective audit) to document the multi-level block achieved with ultrasound-guided transversus abdominis plane block in children having abdominal surgery, during a departmental training period. Data included patient, anaesthetic and surgical details, transversus abdominis plane block characteristics (anterior supra-iliac injections) and dermatomal blockade to ice. Twenty-seven children received 38 blocks performed by 58% consultant and 42% trainee operators (90% novices): 16 unilateral/11 bilateral for umbilical (1), inguinal (13), laparoscopic (8) and laparotomy (5) surgery. Dermatomal assessment for 35 blocks (mean local anaesthetic volume 0.4 ml/kg [SD 0.2]) revealed the median blockade achieved was 3 dermatomes (interquartile range 3 to 4) involving T10 to L1 in 75% of patients. Eight blocks (six patients) also involved T8 and T9, following 0.31 to 0.81 ml/kg. One patient (3% of assessed blocks) had no block to ice at 60 minutes, but required no postoperative analgesia. Ultrasound-guided transversus abdominis plane blocks performed by supra-iliac approach and novice operators produced lower abdominal sensory blockade in children of usually 3 to 4 dermatomes, and should be offered for lower abdominal surgery only, as only 25% had upper abdominal block extension. The optimal local anaesthetic dose/volume, duration of effect and utility for these blocks in relation to peripheral and neuraxial blockade needs clarification.

Post-craniotomy pain in a paediatric population.

There is little information about analgesia use or pain experienced in children after neurosurgery. The aims of this study were to assess the degree of pain experienced by children after neurosurgery and the analgesic regimens used, and to identify factors associated with significant pain. Data for 52 children who underwent craniotomy were collected contemporaneously over 72 hours. Data included demographics, intraoperative surgical and anaesthetic details, postoperative medications and postoperative pain scores as routinely collected by nursing staff Pain was also assessed by an independent observer (auditor) using an age and developmentally appropriate tool, on a scale from zero to 10. For most of the time the children had little or no pain. Over the 72 hours the median pain score recorded by nursing staff was 0.7 and by the auditor was 1.3. However in spite of the low median scores, 42% of children had at least one episode of a pain score > or = 3. Postoperatively, 71% of children received parenteral morphine, 92% of children received paracetamol, 35% oxycodone, 19% oral codeine, 4% tramadol and 2% ibuprofen. Using multivariate regression, duration of procedure was the only factor associated with parenteral morphine use for > 24 hours, and older age was the only factor associated with having an episode of pain scoring > 3. No episodes of significant respiratory depression were noted. At our institution, children receive multimodal analgesia after neurosurgery, commonly parenteral morphine, and this is usually associated with low pain scores.

A multi-centre multi-national survey of anaesthetists regarding the range of anaesthetic and surgical practices for paediatric scoliosis surgery.

Institutional responses to a detailed multi-national survey were used to characterise the range of current anaesthetic and surgical practices for paediatric scoliosis surgery. Questions addressed surgical practice, anaesthetic agents, blood-sparing techniques, neurophysiological monitoring used and recalled major complications. Twenty-seven (87%) institutions responded. The median number of cases of these institutions was 40 per year (range 5 to 700). Common practices included inhaled volatile anaesthetic maintenance (80%), omission of nitrous oxide (81%), intravenous remifentanil (88% [range 0.05 to 2.00 microg x kg(-1) x min(-1)]), and double intravenous antiemetic agent prophylaxis (59%); multimodal analgesia with paracetamol and parenteral opioids, non-steroidal anti-inflammartory drugs and epidural local anaesthetic or opioid infusion (UK) and intrathecal opioids and sub-anaesthetic doses of intravenous ketamine by infusion (Australia); use of cell-saver (81%), controlled hypotension (77%) and antifibrinolytic agents (74%) (intravenous aprotinin [59%] or tranexamic acid [44%]); and epidural somatosensory (92%), neurogenic motor-evoked (32%), compound motor action (31%) and transcranial motor-evoked potential monitoring (54%), with routine wake-up test used infrequently (19%). Fifty-four neurological or cardiac adverse events or deaths were recalled. While institutional practices varied, common themes were identified. The information obtained may suggest new strategies to various centres and could be useful for planning multi-centre audits and trials.

I.V. acetaminophen pharmacokinetics in neonates after multiple doses.

BACKGROUND: Pharmacokinetics of an i.v. prodrug of acetaminophen (propacetamol) in neonates after repeat dosing are reported, with scant data for i.v. acetaminophen formulation. METHODS: Neonates from an intensive care unit received 6-hourly prn i.v. acetaminophen dosed according to postmenstrual age (PMA): 28-32 weeks, 10 mg kg(-1); 32-36 weeks, 12.5 mg kg(-1); and > or =36 weeks, 15 mg kg(-1). A maximum of five blood samples for assay and liver function tests (LFTs) were collected. A one-compartment linear disposition model (zero-order input; first-order elimination) was used to describe time-concentration profiles using population modelling (NONMEM). RESULTS: Fifty neonates, median (range) PMA 38.6 (32-45) weeks, mean (SD) weight 2.9 (0.7) kg, received a mean of 15 doses over a median 4 days with 189 serum acetaminophen and 231 LFT measurements. Standardized population parameter estimates for a term neonate were clearance (CL) 5.24 (CV 30.5%) litre h(-1) 70 kg(-1) and volume of distribution (V) 76 (29.6%) litre 70 kg(-1). CL increased with PMA from 4.4 litre h(-1) 70 kg(-1) at 34 weeks to 6.3 litre h(-1) 70 kg(-1) at 46 weeks. The presence of unconjugated hyperbilirubinaemia was associated with reduced CL: 150 micromol litre(-1) associated with 40% CL reduction. Acetaminophen concentrations between 10 and 23 mg litre(-1) at steady state are predicted after 15 mg kg(-1) 6-hourly for a neonate of PMA 40 weeks. Hepatic enzyme analysis of daily samples changed significantly for one patient whose alanine aminotransferase concentration tripled. CONCLUSIONS: The parameter estimates are similar to those described for propacetamol. There was no evidence of hepatotoxicity. Unconjugated hyperbilirubinaemia impacts upon CL, dictating dose reduction.

Introduction and audit of intravenous paracetamol at a tertiary paediatric teaching hospital.

Although intravenous (i.v.) paracetamol is an attractive analgesic, there is little information on its paediatric use. During an introduction phase with limited prescribing rights, an audit was performed to assess its use and cost impact at a tertiary paediatric centre. Patients receiving IV paracetamol prescribed by two pain specialists for restricted indications had their medical records retrospectively reviewed for age, weight, diagnosis, indications/dose for IV (and other route) paracetamol/other analgesics/antiemetics, vomiting/oral intake and liver function tests if performed. One-hundred-and-twenty-one children and five neonates received 1216 (median 8 each) doses of paracetamol IV Audited expenditure for IV paracetamol was 3.9 times the rectal alternative ($3435 vs. $875). Indications were appropriate, with 97% of patients nil oral, 41% vomiting, 17% having rectal route replaced and 3% avoiding parenteral morphine. Only five patients received incorrect dosing: three through prescription errors and two as guideline deviations; none were considered dangerous. No liver function test derangements could be directly attributed to paracetamol. This data facilitated our application to extend prescribing rights for IVparacetamol within our institution. As there is limited information or local experience with the use of IVparacetamol in paediatric settings in Australia, our data may be of use to other centres considering the introduction of the IV form of this agent.

Recent pharmacological advances in paediatric analgesics.

Growth and development are two linked processes that distinguish children from adults. The use of size as the primary covariate during pharmacokinetic (PK) analyses allows exploration of the effects of age. Allometric scaling models have assisted understanding of the developmental clearance changes in common analgesic drugs such as paracetamol, morphine, tramadol and local anaesthetics agents. Single nucleotide polymorphisms (pharmacogenomics [PG]) and their impact on hepatic drug metabolism for opioids, tramadol, non-steroidal anti-inflammatory drugs (NSAIDs) and drug receptor responses are increasingly reported. Altered chemical structure or formulations of common analgesics alter pharmacodynamic (PD) effects enhancing safety and efficacy for NSAIDs by stereoselectivity and the addition of nitric oxide, for intravenous paracetamol by formulation and structural difference from propacetamol and for local anaesthetics through stereoselectivity. This article focuses upon recent data for analgesics used in paediatric pain management including paracetamol, NSAIDs, morphine, tramadol, amide local anaesthetics and ketamine. It centres on PK and clinical studies in neonates, infants and children. PG studies are acknowledged as potentially allowing individual drug therapy tailoring through a decrease in between-patient population variability, although the impact of PG in the very young is less certain. There are few data describing age-related PD changes in children despite recognition that the number, affinity and type of receptors or the availability of natural ligands changes with age.

A teenager with severe asthma exacerbation following ibuprofen.

Aspirin-sensitive asthma, aspirin-intolerant asthma, aspirin- (or non-steroidal anti-inflammatory drug [NSAID]) exacerbated respiratory disease are terms for a disorder commonly described as affecting adults aged > 30y. With this perception, ibuprofen was administered for postoperative pain management to a 17-year-old boy with allergic rhinitis and previous severe asthma (at a time when well controlled), who then had a severe asthma exacerbation. Analysis of the literature in response to this case highlights four points: 1) NSAID-exacerbated asthma is not only a disorder of adults; it occurs in up to of 2% in asthmatic children, approaching probably 30% in older children with severe asthma and nasal disease. 2) The asthmatic reaction is dose-dependent and can occur with sub-therapeutic doses. Oral NSAID/aspirin challenge should be conducted in an environment where a severe asthma exacerbation can be appropriately managed. 3) The therapeutic use of non-selective [COX-1 preferential] NSAIDs should be avoided when sensitivity is known or suspected in adults and teenagers with severe asthma and chronic rhinosinusitis or nasal polyps. Use of these agents in younger children with mild episodic wheeze is probably safe. 4) Paracetamol use is probably safe, but aspirin-exacerbated respiratory disease may occur with clinical doses in a subgroup of aspirin-exacerbated respiratory disease patients. COX-2 selective inhibitors are probably safe, although this is controversial. Opioids and tramadol are suitable analgesic alternatives for patients with known or suspected susceptibility.

Use of the Bispectral Index monitor to aid titration of propofol during a drug-assisted interview.

We report two drug-assisted interviews with propofol in an 18-year-old with the diagnosis of Complex Regional Pain Syndrome type 1. We describe difficulty in titration of propofol in the first interview. Consequently, in the second interview, the Bispectral Index (BIS) monitor was applied to assist adjustment of the propofol infusion. This facilitated the achievement of a prolonged sedative-hypnotic state for a successful neuropsychological evaluation. Pertinent information was obtained from this patient. However, the role of drug-assisted interviews as a technique needs to be further elucidated.

Transient golden appendicolith.

This case report describes an accidental ingestion of a gold dental inlay prosthesis that became lodged in the appendix. A nonsurgical approach was pursued because this blunt foreign body posed a minimal perforation risk. A second opinion for an elective appendectomy was chosen by the patient until a preoperative abdominal film 20 days after ingestion documented the passage of the foreign body into the colon. The patient remained asymptomatic throughout the 3-week course. This report represents the first case to clearly document an appendiceal foreign body that spontaneously passed into the colon. We suggest that patients with blunt foreign bodies within the appendix may be treated conservatively under close medical supervision.