Pharmacokinetic studies of a Chinese triple herbal drug formula

Yin Chen Hao Tang preparation (YCHTP) is a classic traditional Chinese medicine formula, which is commonly used for clinical treatment of hepatological diseases. In this study, a rapid and validated high-performance liquid chromatography (HPLC) method was developed to simultaneously identify 6,7-dimethylesculetin and geniposide in rat plasma. This assay was performed on a Dikma Diamonsil RP(18) column (200 mmx4.6 mm, 5 mum) with acetonitrile-methanol-water (0.1% formic acid) as the mobile phase, showing acceptable linearity, intra- and inter-day precision and accuracy (R.S.D.=5%), and absolute recovery for two analytes (74%); the limits of quantitation were 0.4 and 1.12 mug/ml, and the limits of detection were 0.06 and 0.09 mug/ml for two analytes. The developed method was successfully applied to study the effect of formula compatibility on the pharmacokinetics of 6,7-dimethylesculetin and geniposide in YCHTP when orally administrating an effective human daily dose of YCHTP to rats. We surmise that formula compatibility can significantly influence the pharmacokinetics of YCHTP, and we have elucidated and validated the compatible administration of YCHTP.

Justifications and limits in the politically motivated lawbreaking of environmental activist groups

In recent events, notions of political protest, civil disobedience, extremism, and criminal action have become increasingly blurred. The London Riots, the Occupy movement, and the actions of hacking group Anonymous have all sparked heated debate about the limits of legitimate protest, and the distinction between an acceptable action and a criminal offence. Long before these events, environmental activists were challenging convention in protest actions, with several groups engaging in politically motivated law-breaking. The emergence of the term ‘eco-tage’ (the sabotage of equipment in order to protect the environment) signifies the important place environmental activists hold in challenging the traditional boundaries between illegal action and legitimate protest. Many of these groups establish their own boundaries of legitimacy, with some justifying their actions on the basis of civil disobedience or extensional self-defence. This paper examines the statements of environmental activist organisations that have engaged in politically motivated law breaking. It identifies the parameters that these groups set on their illegal actions, as well as the justifications that they provide, with a view to determining where these actions fit in the vast grey area between legal protest and violent extremism.

Alveolar dose comparison of ultrafine particles for Australian and Italian children

Epidemiological studies have demonstrated that exposure to particulate air pollution is associated with several adverse health effects. Recently, interest has focused on ultrafine particles (UFPs, diameter ≤ 100 nm), due to the adverse health effects caused by their ability to induce inflammation and deposit in secondary organs [1]. These effects are much more pronounced in children because they inhale a higher dose of UFPs relative to both lung size (when compared with adults) [2] and increased breathing rates, since they are generally more physically active than adults ...

Alveolar dose of ultrafine particles for children in urban environments

The aim of this study was to quantify school children’s exposure to ultrafine particles (UFP) in urban environments. The study was conducted as part of a larger epidemiological project aiming to determine the association between exposures to UFPs and children’s health, titled “Ultrafine Particles from Traffic Emissions and Children’s Health”1 (UPTECH). School children aged 8-11 years old at 24 state schools within the Brisbane Metropolitan Area participated in the present study. This paper presents the methodology and results for calculating deposited UFP surface area in the alveolar region (dose), where UFP deposition is more efficient for particles larger than 6 nm...

A randomised, controlled clinical trial comparing chlorhexidine gel and low-dose fluoride toothpaste to prevent early childhood caries

Objectives This randomised, controlled trial compared the effectiveness of 0.12% chlorhexidine (CHX) gel and 304% fluoride toothpaste to prevent early childhood caries (ECC) in a birth cohort by 24 months. Methods The participants were randomised to receive either (i) twice daily toothbrushing with toothpaste and once daily 0.12% CHX gel (n = 110) or (ii) twice daily toothbrushing with toothpaste only (study controls) (n = 89). The primary outcome measured was caries incidence and the secondary outcome was percentage of children with mutans streptococci (MS). All mothers were contacted by telephone at 6, 12, and 18 months. At 24 months, all children were examined at a community dental clinic. Results At 24 months, the caries prevalence was 5% (3/61) in the CHX and 7% (4/58) in the controls (P = 0.7). There were no differences in percentages of MS-positive children between the CHX and control groups (54%vs 53%). Only 20% applied the CHX gel once daily and 80% less than once daily. Conclusions Toothbrushing using 304% fluoride toothpaste with or without the application of chlorhexidine gel (0.12%) reduces ECC from 23% found in the general community to 5–7%. The lack of effect with chlorhexidine is likely to be due to low compliance.

Impairment of simulated motorcycle riding performance under low dose alcohol

Crash statistics that include the blood alcohol concentration (BAC) of vehicle operators reveal that crash involved motorcyclists are over represented at low BACs (e.g., ≤0.05%). This riding simulator study compared riding performance and hazard response under three low dose alcohol conditions (sober, 0.02% BAC, 0.05% BAC). Forty participants (20 novice, 20 experienced) completed simulated rides in urban and rural scenarios while responding to a safety-critical peripheral detection task (PDT). Results showed a significant increase in the standard deviation of lateral position in the urban scenario and PDT reaction time in the rural scenario under 0.05% BAC compared with zero alcohol. Participants were most likely to collide with an unexpected pedestrian in the urban scenario at 0.02% BAC, with novice participants at a greater relative risk than experienced riders. Novices chose to ride faster than experienced participants in the rural scenario regardless of BAC. Not all results were significant, emphasising the complex situation of the effects of low dose BAC on riding performance, which needs further research. The results of this simulator study provide some support for a legal BAC for motorcyclists below 0.05%.

A single dose of azithromycin does not improve clinical outcomes of children hospitalised with bronchiolitis : a randomised, placebo-controlled trial

Objective Bronchiolitis, one of the most common reasons for hospitalisation in young children, is particularly problematic in Indigenous children. Macrolides may be beneficial in settings where children have high rates of nasopharyngeal bacterial carriage and frequent prolonged illness. The aim of our double-blind placebo-controlled randomised trial was to determine if a large single dose of azithromycin (compared to placebo) reduced length of stay (LOS), duration of oxygen (O2) and respiratory readmissions within 6 months of children hospitalised with bronchiolitis. We also determined the effect of azithromycin on nasopharyngeal microbiology. Methods Children aged ≤18 months were randomised to receive a single large dose (30 mg/kg) of either azithromycin or placebo within 24 hrs of hospitalisation. Nasopharyngeal swabs were collected at baseline and 48hrs later. Primary endpoints (LOS, O2) were monitored every 12 hrs. Hospitalised respiratory readmissions 6-months post discharge was collected. Results 97 children were randomised (n = 50 azithromycin, n = 47 placebo). Median LOS was similar in both groups; azithromycin = 54 hours, placebo = 58 hours (difference between groups of 4 hours 95%CI -8, 13, p = 0.6). O2 requirement was not significantly different between groups; Azithromycin = 35 hrs; placebo = 42 hrs (difference 7 hours, 95%CI -9, 13, p = 0.7). Number of children re-hospitalised was similar 10 per group (OR = 0.9, 95%CI 0.3, 2, p = 0.8). At least one virus was detected in 74% of children. The azithromycin group had reduced nasopharyngeal bacterial carriage (p = 0.01) but no difference in viral detection at 48 hours. Conclusion Although a single dose of azithromycin reduces carriage of bacteria, it is unlikely to be beneficial in reducing LOS, duration of O2 requirement or readmissions in children hospitalised with bronchiolitis. It remains uncertain if an earlier and/or longer duration of azithromycin improves clinical and microbiological outcomes for children.

A phase II study of the modulation of 5-fluorouracil and folinic acid with high-dose infusional hydroxyurea in metastatic colorectal carcinoma

Background: Hydroxyurea (HU), an inhibitor of ribonucleotide reductase, may potentiate the activity of 5-fluorouracil (5-FU) and folinic acid (FA) by reducing the deoxyribonucleotide pool available for DNA synthesis and repair. However as HU may inhibit the formation of 5-fluoro-2-deoxyuridine-5- monophosphate (FdUMP), one of the principal active metabolites of 5-FU, the scheduling of HU may be critical. In vitro experiments suggest that administration of HU following 5-FU, maintaining the concentration in the region of I mM for six or more hours, significantly enhances the efficacy of 5-FU. Patients and methods: 5-FU/FA was given as follows: days 1 and 2 - FA 250 mg/m 2 (max. 350 mg) over two hours followed by 5-FU 400 mg/m 2 by intravenous bolus (ivb) over 15 minutes and subsequently 5-FU 400 mg/m 2 infusion (ivi) over 22 hours. HU was administered on day 3 immediately after the 5-FU with 3 g ivb over 15 minutes followed by 12 g ivi over 12 hours. Results: Thirty patients were entered into the study. Median survival was nine months (range 1-51 + months). There were eight partial responses (28%, 95% CI: 13%-47%). The median duration of response was 6.5 (range 4-9 months). Grade 3-4 toxicities included neutropenia (grade 3 in eight patients and grade 4 in five), anaemia (grade 3 in one patient) and diarrhoea (grade 3 in two patients). Neutropenia was associated with pyrexia in two patients. Phlebitis at the infusion site occurred in five patients. The treatment was complicated by pulmonary embolism in one patient and deep venous thrombosis in another. Conclusion: HU administered in this schedule is well tolerated. Based on these results and those of other phase II studies, a randomised phase III study of 5-FU, FA and HU versus 5-FU and FA using the standard de Gramont schedule is recommended.

A phase I dose-escalating study of DaunoXome, liposomal daunorubicin, in metastatic breast cancer

The aims of this phase I study were to establish the maximum tolerated dose, safety profile and activity of liposomal daunorubicin, DaunoXome (NeXstar Pharmaceuticals), in the treatment of metastatic breast cancer. DaunoXome was administered intravenously over 2 h in 21 day cycles and doses were increased from 80 to 100, 120 and 150 mg m 2. Sixteen patients were enrolled. A total of 70 cycles of DaunoXome were administered. The maximum tolerated dose was 120 mg m 2, the dose-limiting toxicity being prolonged grade 4 neutropenia or neutropenic pyrexia necessitating dose reductions at 120 and 150 mg m 2. Asymptomatic cardiotoxicity was observed in three patients: grade 1 in one treated with a cumulative dose of 800 mg m 2 and grade 2 in two, one who received a cumulative dose of 960 mg m 2 and the other a cumulative dose of 600 mg m 2 with a previous neoadjuvant doxorubicin chemotherapy of 300 mg m 2. Tumour response was evaluable in 15 patients, of whom two had objective responses, six had stable disease and seven had progressive disease. In conclusion, DaunoXome is associated with mild, manageable toxicities and has anti-tumour activity in metastatic breast cancer. The findings support further phase II evaluation of DaunoXome alone and in combination with other standard non-anthracycline cytotoxic or novel targeted agents. Although the dose-limiting toxicity for DaunoXome was febrile neutropenia at 120 mg m 2, we would recommend this dose for further evaluation, as the febrile neutropenia occurred after four or more cycles in three of the four episodes seen, was short lived and uncomplicated. © 2002 Cancer Research UK.

Gemcitabine and paclitaxel associated pneumonitis in non-small cell lung cancer : report of a phase I/II dose-escalating study

The aim of this phase I/II dose escalating study was to establish the maximum tolerated dose (MTD) of gemcitabine and paclitaxel given in combination in non-small cell lung cancer (NSCLC). 12 patients with stage IIIB and IV NSCLC received paclitaxel administered intravenously over 1 h followed by gemcitabine given over 30 min on days 1, 8 and 15 every 28 days. Pneumonitis was the principal side-effect observed with 4 patients affected. Of these, 1 experienced grade 3 toxicity after one cycle of treatment and the others had grade 2 toxicity. All 4 cases responded to prednisolone. No other significant toxicities were observed. Of the 8 evaluable patients, 3 had a partial response and 2 had minor responses. The study was discontinued due to this dose-limiting toxicity. The combination of paclitaxel and gemcitabine shows promising antitumour activity in NSCLC, however, this treatment schedule may predispose to pneumonitis. (C) 2000 Elsevier Science Ltd.

The Royal Commission into the NSW Police Service : process corruption and the limits of judicial reflexivity

This paper will offer an examination of the Reports of the Royal Commission into the NSW Police Service (Interim Report February 1996; Interim Report: Immediate Measures November 1996; Final Report Vol I: Corruption; Final Report Vol II: Reform; Final Report Vol III: Appendices May 1997) excluding the Report on Paedophilia, August 1997. The examination will be confined essentially to one question: to what extent do the published Reports consider the part played by the judiciary, prosecutors and lawyers, in the construction of a form of criminal justice revealed by the Commission itself, to be disfigured by serious process corruption? The examination will be conducted by way of a chronological trawl through the Reports of the Commission in an attempt to identify all references to the role of the judiciary, prosecutors and lawyers. The adequacy of any such treatment will then be considered. In order to set the scene a brief and generalised overview of the Wood Commission will be offered together with the Commission's definition of process corruption.

The influence of Monte Carlo source parameters on detector design and dose perturbation in small field dosimetry

To obtain accurate Monte Carlo simulations of small radiation fields, it is important model the initial source parameters (electron energy and spot size) accurately. However recent studies have shown that small field dosimetry correction factors are insensitive to these parameters. The aim of this work is to extend this concept to test if these parameters affect dose perturbations in general, which is important for detector design and calculating perturbation correction factors. The EGSnrc C++ user code cavity was used for all simulations. Varying amounts of air between 0 and 2 mm were deliberately introduced upstream to a diode and the dose perturbation caused by the air was quantified. These simulations were then repeated using a range of initial electron energies (5.5 to 7.0 MeV) and electron spot sizes (0.7 to 2.2 FWHM). The resultant dose perturbations were large. For example 2 mm of air caused a dose reduction of up to 31% when simulated with a 6 mm field size. However these values did not vary by more than 2 % when simulated across the full range of source parameters tested. If a detector is modified by the introduction of air, one can be confident that the response of the detector will be the same across all similar linear accelerators and the Monte Carlo modelling of each machine is not required.

Novel sequential methods in dose-finding designs : extensions of the continual reassessment method

Dose-finding trials are a form of clinical data collection process in which the primary objective is to estimate an optimum dose of an investigational new drug when given to a patient. This thesis develops and explores three novel dose-finding design methodologies. All design methodologies presented in this thesis are pragmatic. They use statistical models, incorporate clinicians' prior knowledge efficiently, and prematurely stop a trial for safety or futility reasons. Designing actual dose-finding trials using these methodologies will minimize practical difficulties, improve efficiency of dose estimation, be flexible to stop early and reduce possible patient discomfort or harm.

Factors affecting the extraction of absorbed dose information in a 3D polymer gel dosimeter by X ray computed tomography (IAEA-CN-96/122P)

Two sources of uncertainty in the X ray computed tomography imaging of polymer gel dosimeters are investigated in the paper.The first cause is a change in postirradiation density, which is proportional to the computed tomography signal and is associated with a volume change. The second cause of uncertainty is reconstruction noise.A simple technique that increases the residual signal to noise ratio by almost two orders of magnitude is examined.

Polycaprolactone scaffold and reduced rhBMP-7 dose for the regeneration of critical-sized defects in sheep tibiae

The transplantation of autologous bone graft as a treatment for large bone defects has the limitation of harvesting co-morbidity and limited availability. This drives the orthopaedic research community to develop bone graft substitutes. Routinely, supra-physiological doses of bone morphogenetic proteins (BMPs) are applied perpetuating concerns over undesired side effects and cost of BMPs. We therefore aimed to design a composite scaffold that allows maintenance of protein bioactivity and enhances growth factor retention at the implantation site. Critical-sized defects in sheep tibiae were treated with the autograft and with two dosages of rhBMP-7, 3.5 mg and 1.75 mg, embedded in a slowly degradable medical grade poly(ε-caprolactone) (PCL) scaffold with β-tricalcium phosphate microparticles (mPCL-TCP). Specimens were characterised by biomechanical testing, microcomputed tomography and histology. Bridging was observed within 3 months for the autograft and both rhBMP-7 treatments. No significant difference was observed between the low and high rhBMP-7 dosages or between any of the rhBMP-7 groups and autograft implantation. Scaffolds alone did not induce comparable levels of bone formation compared to the autograft and rhBMP-7 groups. In summary, the mPCL-TCP scaffold with the lower rhBMP-7 dose led to equivalent results to autograft transplantation or the high BMP dosage. Our data suggest a promising clinical future for BMP application in scaffold-based bone tissue engineering, lowering and optimising the amount of required BMP.