Pharmacokinetics of recombinant human endostatin in rats

The pharmacokinetics of recombinant human endostatin (rh-Endo) has not been established in the rat, although this species of animal is commonly used in the pharmacological studies of rh-Endo. This study aimed to investigate the pharmacokinetics, tissue distribution, and excretion of rh-Endo in rats. 125I-radiolabeled rh-Endo was administered to healthy rats by intravenous (i.v) bolus injection at 1.5, 4.5 and 13.5 mg/kg. The maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC) of rh-Endo increased proportionally with the increase of the dosage. There were no significant differences in total body clearance (CL) and elimination half-life (t1/2beta) of rh-Endo among the three dosages used. A 93.5% and 2.2% of the radioactivity was recovered in the urine and feces, respectively, in bile-duct intact rats; whereas only 0.1% of the total radioactivity was excreted into the bile in bile-duct cannulated rats. rh-Endo was rapidly and widely distributed in the liver, kidneys, spleen and lungs. Furthermore, a significant allometric relationship between CL, but not volume of distribution (Vd) and t1/2beta of rh-Endo, and the body weight was observed across mouse, rat and monkey, with the predicted values in humans significantly lower than those observed in cancer patients. rh-Endo exhibited a linear pharmacokinetics in rats and it is mainly excreted through the urine.

Pharmacokinetic mechanisms for reduced toxicity of irinotecan by coadministered Thalidomide

The clinical use of irinotecan (CPT-11) is hindered by dose-limiting diarrhea and myelosuppression. Recent clinical studies indicate that thalidomide, a known tumor necrosis factor-alpha inhibitor, ameliorated the toxicities induced by CPT-11. However, the mechanisms for this are unknown. This study aimed to investigate whether combination of thalidomide modulated the toxicities of CPT-11 using a rat model and the possible role of the altered pharmacokinetic component in the toxicity modulation using in vitro models. The toxicity model was constructed by treatment of healthy rats with CPT-11 at 60 mg/kg per day by intravenous (i.v.) injection. Body weight, acute and delayed-onset diarrhea, blood cell counts, and macroscopic and microscopic intestinal damages were monitored in rats treated with CPT-11 alone or combined therapy with thalidomide at 100 mg/kg administered by intraperitoneal (i.p.) injection. Single dose and 5-day multiple-dose studies were conducted in rats to examine the effects of concomitant thalidomide on the plasma pharmacokinetics of CPT-11 and its major metabolites SN-38 and SN-38 glucuronide (SN-38G). The effect of CPT-11 on thalidomide's pharmacokinetics was also checked. Rat liver microsomes and a rat hepatoma cell line, H4-II-E cells, were used to study the in vitro metabolic interactions between these two drugs. H4-II-E cells were also used to investigate the effect of thalidomide and its hydrolytic products on the transport of CPT-11 and SN-38. In addition, the effect of thalidomide and its hydrolytic products on rat plasma protein binding of CPT-11 and SN-38 was examined. Administration of CPT-11 by i.v. for 4 consecutive days to rats induced significant body weight loss, decrease in neutrophil and lymphocyte counts, severe acute- and delayed-onset diarrhea, and intestinal damages. These toxicities were alleviated when CPT-11 was combined with thalidomide. In both single-dose and 5-day multiple-dose pharmacokinetic study, coadministered thalidomide significantly increased the area under the plasma concentration-time curve (AUC) of CPT-11, but the AUC and elimination half-life (t(1/2)) of SN-38 were significantly decreased. However, CPT-11 did not significantly alter the pharmacokinetics of thalidomide. Thalidomide at 25 and 250 microM and its hydrolytic products at a total concentration of 10 microM had no significant effect on the plasma protein binding of CPT-11 and SN-38, except for that thalidomide at 250 microM caused a significant increase in the unbound fraction (f(u)) of CPT-11 by 6.7% (P < 0.05). The hydrolytic products of thalidomide (total concentration of 10 microM), but not thalidomide, significantly decreased CPT-11 hydrolysis by 16% in rat liver microsomes (P < 0.01). The formation of both SN-38 and SN-38G from CPT-11, SN-38 glucuronidation, or intracellular accumulation of both CPT-11 and SN-38 in H4-II-E cells followed Michaelis-Menten kinetics with the one-binding site model being the best fit for the kinetic data. Coincubation or 2-hr preincubation of thalidomide at 25 microM and 250 microM and its hydrolytic products at 10 microM did not show any significant effects on CPT-11 hydrolysis and SN-38 glucuronidation. However, preincubation of H4-II-E cells with thalidomide (250 microM), its hydrolytic products (total concentration of 10 microM), or phthaloyl glutamic acid (one major thalidomide hydrolytic product, 10 microM) significantly increased the intracellular accumulation of SN-38, but not CPT-11 (P < 0.01). The dose-limiting toxicities of CPT-11 were alleviated by combination with thalidomide in rats and the pharmacokinetic modulation by thalidomide may partially explain its antagonizing effects on the toxicities of CPT-11. The hydrolytic products of thalidomide, instead of the parental drug, modulated the hepatic hydrolysis of CPT-11 and intracellular accumulation of SN-38, probably contributing to the altered plasma pharmacokinetics of CPT-11 and SN-38. Further studies are needed to explore the role of both pharmacokinetics and pharmacodynamic components in the protective effect of thalidomide against the toxicities of CPT-11.

Alteration of the pharmacokinetics of COL-3, a matrix metalloproteinase inhibitor, due to actue gastrointestinal tosicity of doxorubicin

Purpose Combination of COL-3, a matrix metalloproteinase inhibitor, and doxorubicin (DOX) might be a promising anticancer regimen. The present study was to examine the potential pharmacokinetic interactions and toxicity profile following their coadministration in rats.
Methods Normal rats were treated with single agent or different combinations with oral or intravenous COL-3 and DOX, and the bile-duct cannulated (BDC) rats received oral COL-3 plus DOX. In a separate disposition study, the effects of DOX on the biliary, urinary, and fecal excretion of COL-3 were examined. In addition, the effects of DOX on in vitro protein binding, metabolism, and transport of COL-3 across Caco-2 monolayers were investigated.
Results COL-3 did not affect the pharmacokinetics of DOX in rats. However, treatment with DOX significantly decreased the oral absorption, and prolonged the elimination, of COL-3 in the normal rats, but not in the BDC rats. DOX did not alter the biliary and urinary excretion of COL-3, but significantly decreased the fecal excretion of COL-3. DOX significantly enhanced the basolateral to apical flux of COL-3 across Caco-2 monolayers, but had no apparent effects on the protein binding and metabolism of COL-3. The combination of DOX with oral COL-3 did not significantly (p > 0.05) increase the acute diarrhea score and intestinal damage compared to rats receiving DOX alone.
Conclusions These results indicated that DOX altered the oral absorption and elimination of COL-3, largely resulting from gastrointestinal toxicity caused by biliary excretion of DOX. Further studies are required to explore the efficacy and optimized dosage regimen of this promising combination.

Ethics in a capitalistic society

The problem of semantics is inherent in any discussion of ethics. The general term "ethics" is itself commonly confused. In addition, systems of ethics must be built upon assumptions, and assumptions are necessarily subject to lengthy debate. These two problems are encountered in my investigation of the ethical practices of the modern business community and to remedy the situation I have taken two steps: the first being an attempt to clarify the meaning of terms used therein;-and the second being a clear description of the assumptions utilized to further my analysis. To satisfy those who would disagree with these assumptions, I have attempted to outline the consequences of differing premises. The first assumption in my discussion is that the capitalistic economy is powered by the motivation supplied by man's self-interest. We are conditioned to basing our courses of action upon an orientation toward gratifying this self-interest. Careers are chosen by blending aptitude, interest, and remuneration. of course, some people are less materially inclined than others, but the average member of our capitalistic society is concerned with the physical rewards derived from his employment. Status and happiness are all-important considerations in pursuing a chosen course of action, yet all too often they are measured in physical terms. The normal self-interest natural to mankind is heightened in capitalism, due to the emphasis placed upon material compensation. Our thinking becomes mechanistic as life devolves into a complex game played by the rules. We are accustomed to performing meaningless or unpleasant duties to fulfill our gratifications. Thought, consequently, interferes with the completion of our everyday routines. We learn quickly not to be outspoken, as the outspoken one threatens the security of his fellow man. The majority of the people are quite willing to accept others views on morality, and indeed this is the sensible thing to do as one does not risk his own neck. The unfortunate consequence of this situation has been the substitution of the legal and jural for the moral and ethical. Our actions are guided by legal considerations and nowhere has this been more evident than in the business community. The large legal departments of modern corporations devote full time to inspecting the legality of corporate actions. The business community has become preoccupied with the law, yet this is necessarily so. Complex, modern, capitalistic society demands an elaborate framework of rules and regulations. Without this framework it would be impossible to have an orderly economy, to say nothing of protecting the best interests of the people. However, the inherent complexities, contradictions, and sometimes unfair aspects of our legal system can tempt men to take things into their own hands. From time to time cases arise where men have broken laws while acting in good faith, and other cases where men have been extremely unethical without being illegal. Examples such as these foster the growth of cynicism, and generally create an antagonistic attitude toward the law on the part of business. My second assumption is that the public, on the whole, has adopted an apathetic attitude toward business morality. when faced with an ethical problem, far too many people choose to cynically assume that, if I don't do it someone else will. "The danger of such an assumption lies in that it eliminates many of the inhibitions that normally would preclude unethical action. The preventative factor in contemplating an unethical act not only lies in it going against the "right course of action", but also in that it would display the actor as one of the few, immoral practitioners. However, if the contemplator feels that many other people follow the same course of action, he would not feel himself to be so conspicuous. These two assumptions underly my entire discussion of modern business ethics., and in my judgment are the two most important causal factors in unethical acts perpetrated by the business community. The future elimination of these factors seems improbable, if not futile, yet there is no reason to consider things worse than they ever have been before. The heightened public interest in business morality undoubtedly lies in part in the fact that examples of corporate malpractice are of such magnitude in scope, and hence more newsworthy.

Squalene supplementation alters genes associated with liver cholesterol metabolism

Background – Squalene is a component of shark liver oil and has been speculated to have cholesterol reducing properties. High levels of total and LDL cholesterol have been shown to contribute to the development of chronic heart disease. The liver is central to the regulation of cholesterol metabolism and dietary intervention has long been recognized as a primary means to reduce the risks of chronic heart disease and related ailments.
Objectives – To determine the effect of dietary squalene supplementation on gene transcripts associated with liver cholesterol metabolism. Specifically the effect of squalene supplementation on mRNA levels for proteins that
regulate cholesterol biosynthesis (HMDH & ERG1), cholesterol elimination (SRB1), bile synthesis (CP7A1 & CP27A) and cholesterol excretion by the liver into bile (ABCG5 & ABCG8) was investigated.
Design – Rats (n=32) were divided into four groups and supplemented for 12 weeks. Groups one and two were fed a cholesterol rich diet for six weeks followed by six weeks of a cholesterol rich diet plus 1.75mg/day of squalene or 3.5 mg/day. Group three was fed a cholesterol rich diet for 12 weeks and group four was fed standard rat chow for 12 weeks. Blood lipid levels were monitored during the study and liver gene expression was determined at the
conclusion of the feeding trial via RT-PCR.
Outcomes – 3.5 mg/day of squalene lowered total and LDL cholesterol in rats consuming a cholesterol rich diet. This dose of squalene also resulted in constant levels of HMDH and ERG1 whereas the cholesterol rich diet halved mRNA levels of these enzymes. Furthermore 3.5 mg/day of squalene caused a greater than 3.0 fold increase in mRNA levels of the proteins SRB1, CP7A1, CP27A and ABCG5.
Conclusion – Dietary squalene supplementation at a dose of 3.5 mg/day lowers total and LDL cholesterol in rats consuming a cholesterol rich diet. These reductions in cholesterol levels may be due to increased cholesterol
elimination, bile synthesis and cholesterol excretion by the liver into bile mediated by changes in gene expression of key enzymes involved in these metabolic pathways

Strategic review of enhancements and culture-based fisheries

Enhancements are interventions in the life cycle of common-pool aquatic resources. Enhancement technologies include culture-based fisheries, habitat modifications, fertilization, feeding and elimination of predators/competitors. Enhancements are estimated to yield about two million mt per year, mostly from culture-based fisheries in fresh waters where they account for some 20 percent of capture, or 10 percent of combined capture and culture production. Marine enhancements are still at an experimental stage, but some have reached commercial production. Enhancements use limited external feed and energy inputs, and can provide very high returns for labour and capital input. Moreover, enhancement initiatives can facilitate institutional change and a more active management of aquatic resources, leading to increased productivity, conservation and wider social benefits. Enhancements may help to maintain population abundance, community structure and ecosystem functioning in the face of heavy exploitation and/or environmental degradation. Negative environmental impacts may arise from ecological and genetic interactions between enhanced and wild stocks. Many enhancements have not realised their full potential because of a failure to address specific institutional, technological, management and research requirements emanating from two key characteristics. Firstly, enhancement involves investment in common-pool resources and can only be sustained under institutional arrangements that allow regulation of use and a flow of benefits to those who bear the costs of enhancement. Secondly, interventions are limited to certain aspects of the life cycle of stocks, and outcomes are strongly dependent on natural conditions beyond management control. Hence, management must be adapted to local conditions to be effective, and certain conditions may preclude successful enhancement altogether. Governments have a major role to play in facilitating enhancement initiatives through the establishment of conducive institutional arrangements, appropriate research support, and the management of environmental and other impacts on and from enhancements.

Women, minorities, and proportional representation in Parliament : a proposal for voting reform

The right to vote permits the voices of the electorate to be heard in democracies. However, voting is often insufficient for minorities to obtain representation by their preferred candidates. For traditional political ‘minorities’ including women, self-representation is essential to political equality and social equity. Despite holding roughly 50% of the electoral vote in Australia for 100 years, women comprise only 22% of the Commonwealth Members and 29% of Senators. This paper proposes a new vote counting system, STV with Borda elimination or STV-B. STV-B retains proportional representation but much greater voter control over selection of candidates. STV-B would provide women with a mechanism that yields proportional representation for women without undermining party representation.

Child labour and supply chain : profitability or (mis)management

Purpose – The purpose of this paper is to provide a realistic assessment, with an historical perspective, of the current practises and progress made by organisations towards elimination of child labour in global supply chains.

Design/methodology/approach – Literature review in the area of use of child labour within the global supply chain was combined with additional information obtained from the company searches of the GRI database, company ranking tables, and other sources.

Findings – Child labour is one of a number of areas of concern in global supply chains. Continued exploitation of child labour indicates an imbalanced state and consequently forces can be unleashed through standardization, collaboration and communication amongst all stakeholders to ensure protection of the vulnerable. This paper is part of the broader analysis informing incremental changes to supply chain management to preserve the rights and welfare of children in the present and future generations. Research/limitations/implications – The analysis is based on secondary data sources and further research is thus needed to verify the individual weightings of the criteria used in the primary ranking of the companies.

Practical implications – The findings provide encouragement for policy and decision makers to implement incremental changes to global supply chains in order to protect the rights and welfare of children, according to the standards of Social Accountability (SA) 8000, the International Labour Organisation (ILO), and other world trade stakeholders.

Originality/value – This paper questions the view that child labour incidences have diminished proportional to economic development. A swinging fulcrum with hidden traps for developed and developing nations in light of cross border transactions through supply chains has been proposed.

Fine grained AZ31 produced by conventional thermo-mechanical processing

The magnesium alloy AZ31 was processed by severe hot rolling and annealing. This processing was optimised to produce recrystallised grain sizes as small as 2.2 μm. The texture of the processed plate was similar to that of the as-received material, with a strong basal alignment in the normal direction. Tensile testing of the fine grained material showed an increase in the strength and elongation compared to the as-received plate. It is  concluded that the improved mechanical properties of the fine grained material results from a refinement in the grain size and the elimination of shear bands that pre-exist in the as-received material.

Fruit consumption of boys (8–11 years) is related to preference for sour taste

The present study investigated whether the most preferred balance between sweet and sour taste of children (n=50, 9.2±0.9 yrs of age) are related to their consumption of fruit. Taste preferences were measured with a rank-by-elimination procedure with seven sweet orangeades that differed in added citric acid (i.e. 0.009−0.065 M). Fruit consumption was assessed with a questionnaire that was completed by the children's parents. Results showed that boys' but not girls' most preferred balance between sweet and sour taste was positively correlated with their consumption of fruit: that is, the more added citric acid was preferred the more fruit was consumed. We conclude that preference for high concentrations of citric acid in a sweet context may be associated with the consumption of fruit in boys. In girls, the optimal balance between sweet and sour taste seems to be of less importance; their consumption of fruit may be more influenced by their parents, availability and health related motives.

Modelling of birds and locust-control operations in Eastern Australia

Locust outbreaks provide an abundant, but unpredictable food source for many native species in Australia. For economic reasons, locust control is unavoidable and can affect a considerable area in Eastern Australia. Depending on the pesticide applied, locust control operations may affect birds in treated areas, either directly through intoxication of the predator, or indirectly, through elimination of its prey. As a preliminary step in identifying the potential impact of these operations on native species, the co-occurrence of birds and locust control operations was assessed using GIS mapping techniques. Data from the Birds of Australia New Atlas provided information about species' distribution between latitudes 17 and 37 degree S, and longitudes 136 and 152 degree E. Of the 834 species present in this region, 292 were chosen on the basis of their geographical distribution and occurrence west of the Great Dividing Range. Sightings for each species were mapped using reporting rates and number of observations per half-degree grid cells. Birds were categorised by habitat, distribution, movement and feeding habits and those species reported to consume Orthopterans were noted. APLC locust survey (1987–2000) and spraying data (1977–2002) were analysed and overlapped with soil and vegetation maps obtained from Geoscience Australia and Environment Australia to find significant hotspots for locust occurrence. These maps were then overlayed with bird distributions to identify the species most likely to be in areas of locust presence and spraying operations.

Occupational health and safety management systems : system types and effectiveness

The aim of this thesis is to develop a framework to evaluate the relative performance of different types of health and safety management system. This objective is an analytical one, but it stems from a policy issue of public importance. Over the past decade Australia, like other countries, has seen the emergence and growth of interest in developing health and safety management systems. But are they all the same, and if not, do they differ in their effectiveness? The thesis does not seek to give a definitive answer to these questions. Given the novelty of the phenomenon and the lack of research on this subject, the research is exploratory. An hypothesis about the effectiveness of different health and safety management systems is developed rather than tested. The thesis proceeds by first defining health and safety management systems as a combination of the planning and review, the management arrangements, the consultative arrangements and the specific program elements that work together in an integrated way to improve health and safety performance. A research procedure is described involving twenty exploratory case studies. The thesis then - develops - from the literature and the case study research - an analytical framework to evaluate the performance of different health and safety management systems. That framework has two parts. First is a typology of health and safety management systems. This is constructed from two distinctions - between 'safe place' and 'safe person' approaches to health and safety; and between 'innovative' and traditional' management methods and structures. These distinctions yield four types of system. The typology was applied to the case studies which yielded a reasonable fit in most instances. The second part of the framework is a 'process evaluation' technique akin to Quality standards. Derived from the Victorian SafetyMAP audit criteria, the "e;process evaluation tool "e; is preferred to traditional outcome measures such as incident or claim rates. Using this measure, the twenty case study enterprises were classified as above average, average or below average in performance. These results correlated poorly with traditional incident trend and benchmark measures. The two elements of the framework are then combined to explore the relationship between the different types of system and their performance. Evidence from the twenty case studies showed a tendency for innovative/safe place firms to perform better than traditional/safe person firms. This finding can form the basis for a hypothesis that may be subject to statistical testing on a generalisable sample. In addition five 'best practice' cases were selected and subjected to a cross case analysis to search for common characteristics that might explain their performance. This analysis suggests the importance of a number of factors: senior managers who drive health and safety change and mobilise all possible resources in the pursuit of change; health and safety representatives who work with managers in a 'joint regulatory relationship' across system activities; the involvement of employees more generally, but not as a substitute for action by managers and health and safety representatives; a comprehensive approach to elimination of all hazards; and the introduction of innovative programs to continually improve systems and facilitate employee involvement in health and safety.

Casting yield improvement in graphite iron castings

A well designed runner and feeding system should produce castings with minimal defects and low pour weight. This thesis investigates how the filling regime and solidification of the mould influences defects in the castings produced from that mould. Design guidelines to reduce such defects are proposed and tested. An existing shrinkage fault in a Grey Iron disc brake casting is simulated using a commercial finite-difference computer program. Three criteria are used to predict the defect and the effect of changes to the feeder geometry. Critical Fraction Solidification analysis is used to determine whether the feeder remains in liquid contact with the casting during solidification and this approach is shown to correctly predict the presence or absence of porosity* The feeder block is extended below the ingate of the casting to improve liquid contact between the casting and feeder without significantly increasing the feeder mass. Plant trials confirm the change to the feeder eliminates the porosity defect. The runner system and mould venting for a thin walled Ductile Iron casting are investigated. Trials show that by setting the total mould vent area to be greater than the net ingate area of the castings, the cold-shut frequency is halved. A method for runner system design based on peak linear flow velocity in the runner during mould filling is proposed. A new pressurised runner system produces castings with significantly fewer defects and reduced pour weight when runner areas are designed to maintain peak velocity below 1 m/s. Peak velocity and magnesium levels are demonstrated to be critical factors in the elimination of cold-shut defects. A pressurised runner system is also shown to isolate inclusion defects from castings more effectively than an unpressurised system. From this work, a technique is proposed which allows the yield of an existing runner and feeder system for iron castings to be improved with confidence in the results.

Nano related research in fibres and textiles

With the increasing hype surrounding what nanotechnology can actually deliver, research emphasis in this area needs to be placed on how nanotechnology can bring tangible benefits to existing industries and ordinary consumers. This paper gives selected examples of real world applications of nano-structured materials, including nano fibrous and particulate materials. It reviews recent research into nano-structured surface coating of textile substrates for enhanced functionalities, and the development of fine and uniform nanofibres for advanced applications. Emphasis has been placed on relevant research activities in the Centre for Material and Fibre Innovation at Deakin University, Australia. In the nano-structured surface coating area, several examples of enhancing fabric performance and functionality are provided, including silica coating for photochromic textiles, superhydrophobic surface coating and transparent ZnO coating to reduce colour fading of textiles exposed to UV radiation. In the nanofibre area, these activities include: elimination of beaded fibres without increasing the average diameter of the electrospun nanofibres, electrospinning of side-by-side bi-component nanofibres, new insight into the evolution of fibre morphology in electrospinning and the electrospinning technology itself.

Heightened sour preferences during childhood

Basic research has revealed that the chemical sensory world of children is different from that of adults, as evidenced by their heightened preferences for sweet and salty tastes. However, little is known about the ontogeny of sour taste preferences, despite the growing market of extreme sour candies. The present study investigated whether the level of sourness most preferred in a food matrix and the ability to discriminate differences in sour intensity differed between 5- to 9-year-old children and their mothers, by using a rank-by-elimination procedure embedded in the context of a game. Mothers also completed a variety of questionnaires and children were asked several questions to assess whether children's temperament and food preferences and habits related to sour preferences. The results indicated that, although every mother and all but two of the children (92%) were able to rank the gelatins from most to least sour, more than one-third (35%) of the children, but virtually none of the adults, preferred the high levels of sour taste (0.25 M citric acid) in gelatin. Those children who preferred the extreme sour tastes were significantly less food neophobic (P < 0.05) and tended to experience a greater variety of fruits when compared with the remaining children (P = 0.11). Moreover, the children's preference for sour tastes generalized to other foods, such as candies and lemons, as reported by both children and mothers. These findings are the first experimental evidence to demonstrate that sour taste preferences are heightened during childhood and that such preferences are related to children's food habits and preferences. Further research is needed to unfold the relationship between the level of sour taste preferred and the actual consumption of sour-tasting foods and flavors in children.