Disposition of naproxen, naproxen acyl glucuronide and its rearrangement isomers in the isolated perfused rat liver

1. An isolated perfused rat liver (IPRL) preparation was used to investigate separately the disposition of the non-steroidal anti-inflammatory drug (NSAID) naproxen (NAP), its reactive acyl glucuronide metabolite (NAG) and a mixture of NAG rearrangement isomers (isoNAG), each at 30 mug NAP equivalents ml(-1) perfusate (n = 4 each group). 2. Following administration to the IPRL, NAP was eliminated slowly in a log-linear manner with an apparent elimination half-life (t(1/2)) of 13.4 +/-4.4 h. No metabolites were detected in perfusate, while NAG was the only metabolite present in bile in measurable amounts (3.9 +/-0.8%, of the dose). Following their administration to the IPRL, both NAG and isoNAG were rapidly hydrolysed (t(1/2) in perfusate=57 +/-3 and 75 +/- 14min respectively). NAG also rearranged to isoNAG in the perfusate. Both NAG and isoNAG were excreted intact in bile (24.6 and 14.8% of the NAG and isoNAG doses, respectively). 3. Covalent NAP-protein adducts in the liver increased as the dose changed from NAP to NAG to isoNAG (0.20 to 0.34 to 0.48% of the doses, respectively). Similarly, formation of covalent NAP-protein adducts in perfusate were greater in isoNAG-dosed perfusions. The comparative results Suggest that isoNAG is a better substrate for adduct formation with liver proteins than NAG.

beta-hydroxy-beta-methylbutyrate (HMB) supplementation does not affect changes in strength or body composition during resistance training in trained men

This investigation evaluated the effects of oral beta -Hydroxy-beta -Methylbutyrate (HMB) supplementation on training responses in resistance-trained male athletes who were randomly administered HMB in standard encapsulation (SH), HMB in time release capsule (TRH), or placebo (P) in a double-blind fashion. Subjects ingested 3 g (.) day(-1) of HMB; or placebo for 6 weeks. Tests were conducted pre-supplementation and following 3 and 6 weeks of supplementation. The testing battery assessed body mass, body composition (using dual energy x-ray absorptiometry), and 3-repetition maximum isoinertial strength, plus biochemical parameters, including markers of muscle damage and muscle protein turnover. While the training and dietary intervention of the investigation resulted in significant strength gains (p < .001) and an increase in total lean mass (p =.01), HMB administration had no influence on these variables. Likewise, biochemical markers of muscle protein turnover and muscle damage were also unaffected by HMB supplementation. The data indicate that 6 weeks of HMB supplementation in either SH or TRH form does not influence changes in strength and body composition in response to resistance training in strength-trained athletes.

An identifiability analysis of a parent-metabolite pharmacokinetic model for ivabradine.

The paper considers the structural identifiability of a parent–metabolite pharmacokinetic model for ivabradine and one of its metabolites. The model, which is linear, is considered initially for intravenous administration of ivabradine, and then for a combined intravenous and oral administration. In both cases, the model is shown to be unidentifiable. Simplification of the model (for both forms of administration) to that proposed by Duffull et al. (1) results in a globally structurally identifiable model. The analysis could be applied to the modeling of any drug undergoing first-pass metabolism, with plasma concentrations available from drug and metabolite.

Analytical validation for a series of marker compounds used to assess renal drug elimination processes

Renal drug elimination is determined by glomerular filtration, tubular secretion, and tubular reabsorption. Changes in the integrity of these processes influence renal drug clearance, and these changes may not be detected by conventional measures of renal function such as creatinine clearance. The aim of the current study was to examine the analytic issues needed to develop a cocktail of marker drugs (fluconazole, rac-pindolol, para-aminohippuric acid, sinistrin) to measure simultaneously the mechanisms contributing to renal clearance. High-performance liquid chromatographic methods of analysis for fluconazole, pindolol, para-aminohippuric acid, and creatinine and an enzymatic assay for sinistrin were developed or modified and then validated to allow determination of each of the compounds in both plasma and urine in the presence of all other marker drugs. A pilot clinical study in one volunteer was conducted to ensure that the assays were suitable for quantitating all the marker drugs to the sensitivity and specificity needed to allow accurate determination of individual renal clearances. The performance of all assays (plasma and urine) complied with published validation criteria. All standard curves displayed linearity over the concentration ranges required, with coefficients of correlation greater than 0.99. The precision of the interday and intraday variabilities of quality controls for each marker in plasma and urine were all less than 11.9% for each marker. Recoveries of markers (and internal standards) in plasma and urine were all at least 90%. All markers investigated were shown to be stable when plasma or urine was frozen and thawed. For all the assays developed, there were no interferences from other markers or endogenous substances. In a pilot clinical study, concentrations of all markers could be accurately and reproducibly determined for a sufficient duration of time after administration to calculate accurate renal clearance for each marker. This article presents details of the analytic techniques developed for measuring concentrations of marker drugs for different renal elimination processes administered as a single dose to define the processes contributing to renal drug elimination.

Issues in Australian Foreign Policy January to June 2001

The first half of 2001 saw traditional issues dominating the foreign policy agenda, with both Australia's relationship with the United States and the policy of Asian engagement still holding centre stage. But those old issues generated fresh anxieties. In the United States, the incoming Bush administration displayed a genuine radicalism in its approach to foreign policy, and that raised concerns in many Western capitals — including Canberra — about a new mood of unilateralism in Washington. At the same time, the emergence of the thesis that Australia was becoming a "branch office economy", where key decisions were taken in the capital markets of New York and London, made the government noticeably more cautious and selective in its endorsement of globalisation. Further, the issue of Asian engagement grew steadily more complex: Australian policy-makers searched unsuccessfully for a new focus for the policy of Asian engagement, as Japan's economy wallowed and Indonesia's democratic government tottered.

The social construction of PETE in higher education: Toward a research agenda

The focus of this paper is the social construction of physical education teacher education (PETE) and its fate within the broader process of curriculum change in the physical activity field. Our task is to map the dimensions of a research program centered on the social construction of the physical activity field and PETE in higher education. Debates in the pages of Quest and elsewhere over the past two decades have highlighted not only the contentious nature of PETE practices and structures but also that PETE is changing. This paper offers one way of making sense of the ongoing process of contestation and struggle through the presentation of a theoretical framework. This framework, primarily drawing upon the work of Lave and Wenger (1991) and Bernstein (1990, 1996), is described before it is used to study the social construction of PETE in Australia. We assess the progress that has been made in developing this research program, and the questions already evident for further developments of a program of study of the physical activity field in higher education.

The K5 gamble: National defence and nation building under the People's Republic of Kampuchea

The K5 Plan for the defence of the Cambodian-Thai border was the response of the People's Republic of Kampuchea and its Vietnamese mentors to the threat posed by the resistance forces, particularly the Khmer Rouge, to its efforts to rebuild the nation and consolidate its administration. The very real defence gains, however, were made at the cost of bitter popular resentment over the way those gains were made.

Mental health telemedicine programmes in Australia

A national survey of mental health telemedicine programmes was conducted and data collected on their catchment areas, organizational structure, equipment, clinical and non-clinical activity, and use by populations who traditionally have been poorly served by mental health services in Australia. Of 25 programmes surveyed, information was obtained for 23. Sixteen programmes had dealt with a total of 526 clients during the preceding three months. Of these, 397 (75%) were resident in rural or remote locations at the time of consultation. Thirty-seven (7%) were Aboriginals or Torres Strait Islanders. Only 19 (4%) were migrants from non-English-speaking backgrounds. The programmes provided both direct clinical and secondary support services. Overall, the number of videoconferencing sessions devoted to clinical activity was low, the average being 123 sessions of direct clinical care per programme per year. Videoconferencing was also used for professional education, peer support., professional supervision, administration and linking families. The results of the study suggest that telehealth can increase access to mental health services for people in rural and remote areas, particularly those who have hitherto been poorly served by mental health services in Australia.

Videoconferencing in the Queensland health service

Videoconferencing was introduced in the Queensland health service in 1995. By the end of 1999, there were more than 150 videoconferencing units in health facilities around the state. Six audits of videoconferencing usage were conducted using similar methodology at six-month intervals from November 1997 to May 2000. Between November 1997 and November 1999, the number of calls more than doubled, from 566 to 1378. Hours of usage almost trebled, from 671 to 1724. The average duration of calls remained similar, at about I h 12 min. The proportion of calls involving more than two sites (multipoint videoconferences) increased from 44% to 65%. The majority of the activity was for education (including training). Videoconferencing was also used for administration and clinical care. Mental health staff were the heaviest users, but use by health professionals from other specialty areas increased during the study period. The Queensland health service has realized a number of important benefits from telehealth.

Australia, the United States and a 'China growing strong': managing conflict avoidance

How to deal with a rising China constitutes one of the most seminal challenges facing the ANZUS alliance since its inception a half a century ago. Australia must reconcile its geography and economic interests in Asia with its post-war strategic and historic cultural orientation towards the United States. It must succeed in this policy task without alienating either Beijing or Washington in the process. The extent to which this is achieved will shape Australia's national security posture for decades to come. Three specific components of the 'Sino-American-Australian' triangle are assessed here: the future of Taiwan, the American development of a National Missile Defence (NMD), and the interplay between Sino-American power balancing and multilateral security politics. The policy stakes for Australia and for the continued viability of ANZUS are high in all three policy areas as a new US Administration takes office in early 2001. The article concludes that Australia's best interest is served by applying deliberate modes of decisionmaking in its own relations with both China and the US and by facilitating consistent and systematic dialogue and consultations with both of those great powers on key strategic issues.