Role of the ATP-binding cassette drug transporters in the intestinal absorption of tanshinone IIB, one of the major active diterpenoids from the root of Salvia miltiorrhiza

There is an increasing use of herbal medicines worldwide, and the extracts from the root of Salvia miltiorrhiza are widely used in the treatment of angina and stroke. In this study, we investigated the mechanism for the intestinal absorption of tanshinone IIB (TSB), a major constituent of S. miltiorrhiza. The oral bioavailability of TSB was about 3% in rats with less proportional increase in its maximum plasma concentration (C_max) and area under the plasma concentration-time curve (AUC) with increasing dosage. The time to C_max (T_max) was prolonged at higher oral dosage. In a single pass rat intestinal perfusion model, the permeability coefficients (P_app) based on TSB disappearance from the lumen (P_lumen) were 6.2- to 7.2-fold higher (p < 0.01) than those based on drug appearance in mesenteric venous blood (P_blood). The uptake and efflux of TSB in Caco-2 cells were also significantly altered in the presence of an inhibitor for P-glycoprotein (PgP) or for multi-drug resistance associated protein (MRP1/2). TSB transport from the apical (AP) to basolateral (BL) side in Caco-2 monolayers was 3.3- to 5.7-fold lower than that from BL to AP side, but this polarized transport was attenuated by co-incubation of PgP or MRP1/2 inhibitors. The P_app values of TSB in the BL-AP direction were significantly higher in MDCKII cells over-expressing MDR1 or MRP1, but not in cells over-expressing MRP2-5, as compared with the wild-type cells. The plasma AUC_0-24hr in mdr1a and mrp1 gene-deficient mice was 10.2- to 1.7-fold higher than that in the wild-type mice. Furthermore, TSB significantly inhibited the uptake of digoxin and vinblastine in membrane vesicles containing PgP or MRP1. TSB also moderately stimulated PgP ATPase activity. Taken collectively, our findings indicate that TSB is a substrate for PgP and MRP1 and that drug resistance to TSB therapy and drug interactions may occur through PgP and MRP1 modulation.

Transport of cryptotanshinone, a major active triterpenoid in Salvia miltiorrhiza Bunge widely used in the treatment of stroke and Alzheimers disease, across the blood-brain

Cryptotanshinone (CTS), a major constituent from the roots of Salvia miltiorrhiza (Danshen), is widely used in the treatment of coronary heart disease, stroke and less commonly Alzheimer's disease. Our recent study indicates that CTS is a substrate for Pglycoprotein (PgP/MDR1/ABCB1). This study has investigated the nature of the brain distribution of CTS across the brain-blood barrier (BBB) using several in vitro and in vivo rodent models. A polarized transport of CTS was found in rat primary microvascular endothelial cell (RBMVEC) monolayers, with facilitated efflux from the abluminal side to luminal side. Addition of a PgP (e.g. verapamil and quinidine) or multi-drug resistance protein 1/2 (MRP1/2) inhibitor (e.g. probenecid and MK-571) in both luminal and abluminal sides attenuated the polarized transport. In a bilateral in situ brain perfusion model, the uptake of CTS into the cerebrum increased from 0.52 ± 0.1% at 1 min to 11.13 ± 2.36 ml/100 g tissue at 30 min and was significantly greater than that of sucrose. Co-perfusion of a PgP/MDR1 (e.g. verapamil) or MRP1/2 inhibitor (e.g. probenecid) significantly increased the brain distribution of CTS by 35.1-163.6%. The brain levels of CTS were only about 21% of those in plasma, and were significantly increased when coadministered with verapamil or probenecid in rats. The brain levels of CTS in rats subjected to middle cerebral artery occlusion and rats treated with quinolinic acid (a neurotoxin) were about 2- to 2.5-fold higher than the control rats. Moreover, the brain levels in mdr1a(-/-) and mrp1(-/-) mice were 10.9- and 1.5-fold higher than those in the wild-type mice, respectively. Taken collectively, these findings indicate that PgP and Mrp1 limit the brain penetration of CTS in rodents, suggesting a possible role of PgP and MRP1 in limiting the brain penetration of CTS in patients and causing drug resistance to Danshen therapy and interactions with conventional drugs that are substrates of PgP and MRP1. Further studies are needed to explore the role of other drug transporters in restricting the brain penetration of CTS and the clinical relevance.

Knowledge management in a major construction firm in Tawian: a case study-examining the impacts of KM initiatives within the firm.

This paper addresses knowledge management (KM) in a project management organisation through a case study. The case study organisation is a small- edium sized Taiwanese-owned construction company (staff size of approximately 50) with an annual turnover of approximately TWD50 (AUD$1.85) billion. Approximately one half of the company comprised project-related staff (e.g. construction project management, project documentation, estimation, procurement, and design), while the other comprised administrative and business-related staff (e.g. office administration and management, business development, and finance and accounting). The researcher undertook a series of surveys and one-on-one interviews whilst ‘embedded’ for several months with the organisation. As part of a larger research project, this case study was one of four case studies conducted in major construction organisations in Singapore, Taiwan, and Australia. The study revealed the recognition, importance and commitment of organisational culture to KM, and the effects the knowledge management initiatives have on the organisation’s ability to manage knowledge across its projects and deliver the projects at various ‘levels’ of the organisation (individual, project, departmental, and corporate). It concludes that a technologically and functionally sound KM infrastructure does not necessarily assure an organisation with a capability to manage knowledge. Organisations need to ensure that the KM repository is made up of quality and relevant contents (not just quantity), and that corporate culture (especially the willingness of individuals to share what they know) is a critical determining factor to the organisation’s ability to share, apply and create knowledge (i.e. low sharing capability leads to low application and creation capabilities).

Policing in the 'communal spaces' of major event venues

The recent re-conceptualization of 'mass private property' as one form of 'communal spaces' raises a series of questions concerning policing and security in these domains. This paper applies the concept of 'communal spaces' to an analysis of policing in 'major event venues.' We assess the character of policing in these communal spaces by drawing upon interviews conducted with policing—private and public—personnel operating in major event venues. The paper identifies different perspectives on the nature of policing in these communal spaces and tension between public and private police personnel concerning their respective roles and responsibilities. We conclude by raising issues concerning the implications for the 'public good' in policing at major event venues.

Are knowledge management infrastructructures capable of managing knowledge?: Case study of a major construction firm in Taiwan

This paper addresses knowledge management (KM) in a project management organisation through a case study.

The case study organisation is a small-medium sized Taiwanese-owned construction company (staff size of approximately 50) with an annual turnover of approximately TWD50 (AUD$1.85) billion. Approximately one half of the company comprised project-related staff (e.g. construction project management, project documentation, estimation, procurement, and design), while the other comprised administrative and business-related staff (e.g. office administration and management, business development, and finance and accounting).

The researcher undertook a series of surveys and one-on-one interviews whilst ‘embedded’ for several months with the organisation. This study is part of an on-going international comparison involving major construction organisations in Singapore, Australia, and Taiwan.

This study examines the recognition, importance and commitment of organisational culture to KM, and the effects the knowledge management initiatives have on the organisation’s ability to manage knowledge across its projects and deliver the projects at various ‘levels’ of the organisation (individual, project, departmental, and corporate).

It concludes that a technologically and functionally sound KM infrastructure did not necessarily assure that an organisation had a capability to manage knowledge. Organisations need to ensure that their KM repository is made up of relevant and quality contents (not just quantity), and that corporate culture (especially the willingness of individuals to share what they know) is a critical determining factor to the organisation’s ability to share, apply and create knowledge (i.e. low sharing capability leads to low application and creation capabilities).

A mechanistic study of the intestinal absorption of crypotanshinone, the major active constituent of Saliva miltiorrhiza

The nature of intestinal absorption of most herbal medicine is unknown. Cryptotanshinone (CTS) is the principal active constituent of the widely used cardiovascular herb Salvia miltiorrhiza (Danshen). We investigated the oral bioavailability of CTS in rats and the mechanism for its intestinal absorption using several in vitro and in vivo models:1) Caco-2 cell monolayers; 2) monolayers of MDCKII cells overexpressing P-glycoprotein
(PgP); and 3) single-pass rat intestinal perfusion with mesenteric vein cannulation. The systemic bioavailabilities of CTS after oral and intraperitoneal administration at 100 mg/kg were 2.05 and 10.60%, respectively. In the perfused rat intestinal model, permeability coefficients based on CTS disappearance from the luminal perfusate (P_lumen) were 6.7- to 10.3-fold higher than permeability coefficients based on drug appearance in venous blood (P_blood). P_blood significantly increased in the presence of the P-gP inhibitor, verapamil. CTS transport across Caco-2 monolayers was pH-, temperature- and ATP-dependent. The transport from the apical (AP) to the basolateral (BL) side was 3- to 9-fold lower than that from the BL to the AP side. Inclusion of verapamil (50 µM) in both AP and BL sides abolished the polarized CTS transport across Caco-2 cells. Moreover, CTS was significantly more permeable in the BL to AP than in the AP to BL direction in MDCKII and MDR1-MDCKII cells. The permeability coefficients in the BL to AP direction were significantly higher in MDCKII cells overexpressing PgP. These findings indicate that CTS is a substrate for PgP that can pump CTS into the luminal side.

Cost-effectiveness of cognitive behavioural therapy and selective serotonin reuptake inhibitors for major depression in children and adolescents

Objective:
To assess from a health sector perspective the incremental cost-effectiveness of cognitive behavioural therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) for the treatment of major depressive disorder (MDD) in children and adolescents, compared to ‘current practice’.
Method:
The health benefit is measured as a reduction in disability-adjusted life years (DALYs), based on effect size calculations from meta-analysis of randomised controlled trials. An assessment on second stage filter criteria (‘equity’; ‘strength of evidence’, ‘feasibility’ and ‘acceptability to stakeholders’) is also undertaken to incorporate additional factors that impact on resource allocation decisions. Costs and benefits are tracked for the duration of a new episode of MDD arising in eligible children (age 6–17 years) in the Australian population in the year 2000. Simulation-modelling techniques are used to present a 95% uncertainty interval (UI) around the cost-effectiveness ratios.
Results:
Compared to current practice, CBT by public psychologists is the most costeffective intervention for MDD in children and adolescents at A$9000 per DALY saved (95% UI A$3900 to A$24 000). SSRIs and CBT by other providers are less cost-effective but likely to be less than A$50 000 per DALY saved (> 80% chance). CBT is more effective than SSRIs in children and adolescents, resulting in a greater total health benefit (DALYs saved) than could be achieved with SSRIs. Issues that require attention for the CBT intervention include equity concerns, ensuring an adequate workforce, funding arrangements and acceptability to various stakeholders.
Conclusions:
Cognitive behavioural therapy provided by a public psychologist is the most
effective and cost-effective option for the first-line treatment of MDD in children and adolescents. However, this option is not currently accessible by all patients and will require change in policy to allow more widespread uptake. It will also require ‘start-up’ costs and attention to ensuring an adequate workforce.

Managing sport facilities and major events

A comprehensive introduction to sports events and facility management, this book guides students through the on-the-job issues and technical problems that sports managers have to address every day.

Changing lifestyles: a major responsibility for physical education

Nutritionists, physical and health educators and the medical profession have all expressed concern about the eating habits and sedentary lifestyle of Australian children and the short and long term consequences if we do not change our ways, states the author. Can schools solve the problem? The author examines the effort to strengthen physical education in Australian schools and considers why the subject remains marginal in the curriculum.