The Leptospermum scoparium (Manuka)-Specific Nectar and Honey Compound 3,6,7-Trimethyllumazine (LepteridineTM) That Inhibits Matrix Metalloproteinase 9 (MMP-9) Activity.

3,6,7-trimethyllumazine (Lepteridine™) is a newly discovered natural pteridine derivative unique to Manuka (Leptospermum scoparium) nectar and honey, with no previously reported biological activity. Pteridine derivative-based medicines, such as methotrexate, are used to treat auto-immune and inflammatory diseases, and Manuka honey reportedly possesses anti-inflammatory properties and is used topically as a wound dressing. MMP-9 is a potential candidate protein target as it is upregulated in recalcitrant wounds and intestinal inflammation. Using gelatin zymography, 40 µg/mL LepteridineTM inhibited the gelatinase activities of both pro- (22%, p < 0.0001) and activated (59%, p < 0.01) MMP-9 forms. By comparison, LepteridineTM exerted modest (~10%) inhibition against a chromogenic peptide substrate and no effect against a fluorogenic peptide substrate. These findings suggest that LepteridineTM may not interact within the catalytic domain of MMP-9 and exerts a negligible effect on the active site hydrolysis of small soluble peptide substrates. Instead, the findings implicate fibronectin II domain interactions by LepteridineTM which impair gelatinase activity, possibly through perturbed tethering of MMP-9 to the gelatin matrix. Molecular modelling analyses were equivocal over interactions at the S1' pocket versus the fibronectin II domain, while molecular dynamic calculations indicated rapid exchange kinetics. No significant degradation of synthetic or natural LepteridineTM in Manuka honey occurred during simulated gastrointestinal digestion. MMP-9 regulates skin and gastrointestinal inflammatory responses and extracellular matrix remodelling. These results potentially implicate LepteridineTM bioactivity in Manuka honey's reported beneficial effects on wound healing via topical application and anti-inflammatory actions in gastrointestinal disorder models via oral consumption.

Mind the gap: An analysis of foregone health gains from unfunded cancer medicines in New Zealand.

Publicly funded cancer medicines listed on the New Zealand Pharmaceutical Schedule were compared with those listed on the Australian Pharmaceutical Benefits Scheme. To quantify the health gains offered by the cancer medicines funded in Australia but not in New Zealand, clinical trial data reporting median progression-free survival (PFS) and overall survival (OS) were sought. The differences in the median PFS and OS for the unfunded medicines, relative to the comparator medicine funded in NZ, were then assessed against the American Society of Clinical Oncology Cancer Research Committee (ASCO-CRC) recommended targets for clinically meaningful health gains. Our analysis confirms that, whilst New Zealand funds fewer cancer medicines than Australia, most of the additional medicines funded in Australia do not deliver clinically meaningful health gains as defined by the ASCO-CRC guidance. This suggests that New Zealand is not missing substantive opportunities for improvements to New Zealand's cancer survival rates through additional medicines funding. A policy of funding more new cancer medicines in order to achieve numerical parity with Australia or other countries would not result in substantive health improvement and would cost significantly more, and investing the millions of dollars needed to achieve funding parity with other countries would not represent good value for money in terms of delivering the best health outcomes for all New Zealanders, rather selective funding of new medicines that demonstrate clear clinical benefit and that are cost-effective and affordable is the sensible approach.

Prospective controlled pilot study of arteriovenous fistula placement using the novel Optiflow device.

OBJECTIVE: Arteriovenous fistula (AVF) maturation failure remains a significant problem with reported early failure rates around 50%. Suboptimal hemodynamics, variable surgical skills, and technique dependency are widely believed to contribute to AVF nonmaturation. The Optiflow (Bioconnect Systems, Ambler, Pa) is a novel anastomotic device placed in situ that has potential for improving hemodynamics and standardizing AVF placement. We report results from a prospective nonrandomized controlled pilot study designed to investigate the safety and performance of the Optiflow. METHODS: Forty-one participants underwent AVF formation using either a 3-mm or 4-mm Optiflow and 39 matched control participants underwent AVF formation using the standard technique at two sites. Patients were observed for 90 days after AVF placement. The primary end point was unassisted maturation, which was defined as an outflow vein with a diameter ≥5 mm and blood flow ≥500 mL/min measured by Doppler ultrasound. The secondary performance end point was unassisted patency, and the primary safety end point was freedom from device-related serious adverse events. RESULTS: Unassisted maturation rates at 14, 42, and 90 days were 76%, 72%, and 68%, respectively, for the Optiflow group and 67%, 68%, and 76%, respectively, in the control group (P = .38, .69, and .47 at 14, 42, and 90 days). There was a trend to earlier maturation (assessed at 14 days) in the 4-mm Optiflow group compared with the control group (P = .059). There were no device-related serious adverse events. CONCLUSIONS: Maturation results for both the Optiflow and control groups were highly favorable compared with historical assisted maturation rates of approximately 50%. The Optiflow appears to be safe and effective in the placement of AVFs, with high maturation rates.

Arteriovenous fistula creation using the Optiflow™ vascular anastomotic connector: the OPEN (Optiflow PatEncy and MaturatioN) study.

PURPOSE: Arteriovenous fistulas (AVFs) are the preferred form of vascular access for hemodialysis. However, non-maturation and patency are major clinical problems. The Optiflow™ device is an implantable anastomotic connector used to standardize the creation of an AVF. Studies have suggested that the geometry of the anastomosis and experience of the surgeon impact patency and maturation rates. The Optiflow serves as a surgical template whereby the geometry and flow path of the anastomosis are predetermined. This prospective study was intended to evaluate maturation, patency and safety of the Optiflow. METHODS: Forty-one upper arm AVFs were created in 41 end-stage renal disease patients using the Optiflow device at two investigational sites. Patients were followed for 90 days with serial Doppler ultrasounds performed at approximately 14, 42 and 90 days to determine AVF maturation. The primary performance endpoint was unassisted maturation, defined as an outflow vein that was equal to or greater than 5 mm in diameter, and with flow equal to or greater than 500 mL/min without the need for any intervention intended to promote or maintain maturation. The primary safety endpoint was the rate of device-related serious adverse events. RESULTS: Unassisted maturation rates were 76%, 72% and 68% and unassisted patency rates were 93%, 88% and 78%, at 14, 42 and 90 days, respectively. There were no device-related serious adverse events. CONCLUSIONS: The results suggest that the Optiflow is safe for its intended use and could play an important role in enhancing AVF maturation while standardizing the anastomotic technique.

Perinatal outcome in fetuses with extremely large nuchal translucency measurement.

BACKGROUND: Studies have suggested that an entirely normal outcome is likely when the nuchal translucency (NT) measurement is very large and the karyotype, morphology and echocardiography scans are normal. Recently this has been questioned as it is based on very small numbers. AIM: Assess the outcome of pregnancies with an NT measurement of 6.5 mm or greater. METHODS: Audit of a large first trimester screening program. RESULTS: Over the ten years to 2006, 76 813 patients underwent first trimester screening, with 120 having an extremely large NT. Thirty-one cases had normal karyotypes, of which there were four sets of twins that demised. Six cases miscarried and ten were terminated, some with morphological abnormalities. Eight cases were still alive for the morphology scan, with the only abnormality being mild pyelectasis in one case. At birth, three cases were normal and another three cases had a good outcome. Two cases had coarctation of the aorta and a good outcome. One case had Noonan's syndrome, another had cerebral palsy and the case with pyelectasis had hydronephrosis, dilated ureters and some contractures. CONCLUSIONS: When the karyotype and morphology scan are normal, the outcome is often good in spite of an extremely large NT. However, even a subtle ultrasound anomaly can indicate a genetic syndrome and echocardiography cannot exclude mild cardiac abnormalities.

Spray on skin improves psychosocial functioning in pediatric burns patients: a randomized controlled trial.

PURPOSE: Microskin is a sprayed on, computer color-matched, skin camouflage which can last for up to 5 days after application. It binds to the epidermis and the patient can sweat and swim with it on. The purpose of the current study was to determine whether Microskin produces psychosocial benefit in pediatric burns patients. PROCEDURE: Twenty children with mature burn scars took part in the study and used Microskin for 5 weeks. Initially, 10 children were randomized to a treatment group while the remaining 10 became a wait-list group for 7 weeks. The wait-list group subsequently received Microskin for 5 weeks. Before and after using Microskin, children completed three psychosocial measures; the Strengths and Difficulties Questionnaire (SDQ), the Family Assessment Device-General Functioning scale (FAD-GF), and the Microskin Questionnaire (MQ-a questionnaire about their experience using Microskin developed specifically for this study). All children were followed up with the same measures 6 months after their completed use of Microskin. RESULTS: After the 5-week Microskin trial there was improvement on all scales of the SDQ for the 10 children in the first treatment group but not for the wait-list group. After the wait-list group used Microskinfor 5 weeks they too improved on all scales. Combining the results for all 20 children from before to after using Microskin there was a statistically significant improvement in the SDQ Emotional Symptoms and Total Difficulties. There was also improved perception of family functioning after using Microskin. Six-month follow-up data showed continued psychosocial improvement. Overall, children felt more confident, happier, and enjoyed social outings more when they had Microskin on, with 95% intending to continue to use Microskin. CONCLUSIONS: Microskin improves psychosocial functioning in pediatric burn patients and is well-tolerated and acceptable. The small sample size precludes sophisticated statistical analyses and generalization of results. There is a need for a full scale randomized controlled study of Microskin with a larger sample size.

PHARMAC funding of 9-week concurrent trastuzumab (Herceptin) for HER2-positive early breast cancer.

A 9-week regimen of trastuzumab (Herceptin) given concurrently with a taxane will be funded for HER2-positive early breast cancer patients in New Zealand. The use of trastuzumab in this population has been investigated in sequential (after chemotherapy) or concurrent (with taxane chemotherapy) settings. Five RCTs have been reported--HERA, NSABP B31, NCCTG N9831, BCIRG 006, and FinHer. Uncertainty persists about optimal regimen duration, dose and sequencing, how to minimise cardiotoxicity, and long-term clinical outcomes. The evidence for the 9-week concurrent regimen was sufficient to justify funding. This regimen has shown results comparable to longer duration treatments; allows more patients to be treated; is relatively cost-effective; and DHBs have indicated they can provide sufficient ancillary support services. Longer duration regimens remain unfunded because of uncertainty surrounding long term clinical benefits and risks; the high cost; effects on DHB services; and their consequential unfavourable relative cost effectiveness. New data--from the sequential treatment arm of trial N9831, showing benefits that were small and statistically non-significant, and the HERA 23-month follow-up, suggesting a waning in efficacy with time--have since cast further doubt on the extent and durability of the sequential 12-month regimen's efficacy. DHBs and PHARMAC remain open to funding longer duration regimens if cost effectiveness improves significantly and budget/resource implications become acceptable. PHARMAC has committed to international efforts (the SOLD trial) to resolve questions of optimal treatment duration.

The Toxicity of Soman in the African Green Monkey (Chlorocebus aethiops).

ABSTRACT This study determines soman toxicity in African green monkeys (Chlorocebus aethiops) and is the first step in exploring the suitability of this species as a model for nerve agent studies. Male African green monkeys were surgically implanted with telemetry devices to monitor electroencephalographic (EEG) and electrocardiographic (ECG) activity. Blood was taken at various times to measure whole blood acetylcholinesterase (AChE) activity and cardiac troponin I (cTnI). Blood AChE activity relative to baseline was 0.0% to 2.5% 6 h after soman exposure and recovered to 31.9% to 72.0% by 30 days after exposure. The 6 h postexposure cTnI levels varied from 0.64 to 6.55 ng/mL, suggesting cardiac damage. Soman was prepared in saline to a concentration of 100 mug/mL. Using an up-down design for small samples, subjects were exposed to 5.01, 6.31, or 7.94 mug/kg soman IM. The first subject was given 5.01 mug/kg soman IM and survived. Three subjects received 6.31 mug/kg soman IM and survived. Three subjects received 7.94 mug/kg soman IM and died within 25 min, 26 min, or 6 h. In all subjects, toxic signs of muscle fasciculation, tremors, chewing, and profuse salivation developed within 2 to 7 min. Tonic-clonic motor convulsions and EEG seizure began between 2 and 18 min after tremor onset. The 48 h IM LD50 of soman in saline in the African green monkey was calculated to be 7.15 mug/kg. The signs and speed of soman intoxication in African green monkeys were consistent with those described in rhesus, cynomolguscynomolgus, and baboons.