Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs

Consistent with its highest abundance in humans, cytochrome P450 (CYP) 3A is responsible for the metabolism of about 60% of currently known drugs. However, this unusual low substrate specificity also makes CYP3A4 susceptible to reversible or irreversible inhibition by a variety of drugs. Mechanism-based inhibition of CYP3A4 is characterised by nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)-, time- and concentration-dependent enzyme inactivation, occurring when some drugs are converted by CYP isoenzymes to reactive metabolites capable of irreversibly binding covalently to CYP3A4. Approaches using in vitro, in silico and in vivo models can be used to study CYP3A4 inactivation by drugs. Human liver microsomes are always used to estimate inactivation kinetic parameters including the concentration required for half-maximal inactivation (K(I)) and the maximal rate of inactivation at saturation (k(inact)).Clinically important mechanism-based CYP3A4 inhibitors include antibacterials (e.g. clarithromycin, erythromycin and isoniazid), anticancer agents (e.g. tamoxifen and irinotecan), anti-HIV agents (e.g. ritonavir and delavirdine), antihypertensives (e.g. dihydralazine, verapamil and diltiazem), sex steroids and their receptor modulators (e.g. gestodene and raloxifene), and several herbal constituents (e.g. bergamottin and glabridin). Drugs inactivating CYP3A4 often possess several common moieties such as a tertiary amine function, furan ring, and acetylene function. It appears that the chemical properties of a drug critical to CYP3A4 inactivation include formation of reactive metabolites by CYP isoenzymes, preponderance of CYP inducers and P-glycoprotein (P-gp) substrate, and occurrence of clinically significant pharmacokinetic interactions with coadministered drugs.Compared with reversible inhibition of CYP3A4, mechanism-based inhibition of CYP3A4 more frequently cause pharmacokinetic-pharmacodynamic drug-drug interactions, as the inactivated CYP3A4 has to be replaced by newly synthesised CYP3A4 protein. The resultant drug interactions may lead to adverse drug effects, including some fatal events. For example, when aforementioned CYP3A4 inhibitors are coadministered with terfenadine, cisapride or astemizole (all CYP3A4 substrates), torsades de pointes (a life-threatening ventricular arrhythmia associated with QT prolongation) may occur.However, predicting drug-drug interactions involving CYP3A4 inactivation is difficult, since the clinical outcomes depend on a number of factors that are associated with drugs and patients. The apparent pharmacokinetic effect of a mechanism-based inhibitor of CYP3A4 would be a function of its K(I), k(inact) and partition ratio and the zero-order synthesis rate of new or replacement enzyme. The inactivators for CYP3A4 can be inducers and P-gp substrates/inhibitors, confounding in vitro-in vivo extrapolation. The clinical significance of CYP3A inhibition for drug safety and efficacy warrants closer understanding of the mechanisms for each inhibitor. Furthermore, such inactivation may be exploited for therapeutic gain in certain circumstances.

Relationship between genotype and enzyme activity of glutathione S-transferases M1 and P1 in Chinese

Glutathione S-transferases (GSTs) are the major detoxifying Phase II enzyme for eliminating electrophilic compounds. Mutations in GSTM1, GSTP1 and GSTT1 in Caucasian and GSTA1 in Chinese have been found to reduce enzyme activity. However, data on the impact of common genetic polymorphisms of GSTM1 and GSTP1 on enzyme activity in Chinese is lacking. This study aimed to investigate the effect of common GSTP1 and GSTM1 polymorphisms on erythrocyte GST activity in healthy Chinese (n = 196). GSTM1 null mutation (GSTM1*0) was analyzed by a PCR-Multiplex procedure, whereas GSTP1 313A → G polymorphism (resulting in Ile105Val at codon 105) was analyzed by PCR-restriction fragment length polymorphism (RFLP) analysis. Erythrocyte GST activity was measured using 1-chloro-2,4-dinitro-bezene (CDNB) as the model substrate. The frequency of GSTM1 null genotype was 54.3% and the frequency of GSTP1-Ile/Ile, -Ile/Val, and -Val/Val genotype was 60.7%, 35.2% and 4.1%, respectively, with a frequency of 21.7% for the 105 valine allele. Age, gender and smoking did not significantly affect the erythrocyte GST activities. The mean erythrocyte GST enzyme activity for GSTP1*-Ile/Val genotype group (3.53 ± 0.63 U/g Hb) was significantly lower than that for subjects with GSTP1-Ile/Ile genotype (4.25 ± 1.07 U/g Hb, P = 0.004), while subjects with the GSTP1-Val/Val genotype had the lowest enzyme activity (2.44 ± 0.67 U/g Hb). In addition, the GST activity in carriers of GSTM1*0/GSTP1-Ile/Ile was significantly higher than that of subjects inherited GSTM1*0/GSTP1-Ile/Val or GSTM1*0/GSTP1-Val/Val. However, there is no association between GSTM1 null mutation and reduced enzyme activity. GSTP1 codon 105 mutation led to reduced erythrocyte GST activity in Chinese. A combined GSTP1 and GSTM1 null mutations also resulted in significantly reduced GST activity. Further studies are needed to explore the clinical implications of GSTM1 and GSTP1 polymorphisms.

Cost implications of specific and non-specific treatment for young persons at ultra high risk of developing a first episode of psychosis

Aim: Costs associated with mental health treatment for young persons at 'ultra' high risk (UHR) of developing a psychotic disorder have not previously been reported. This paper reports cost implications of providing psychological and pharmacological intervention for individuals at UHR for psychosis compared with minimal psychological treatment.

Method: Mental health service costs associated with a randomized controlled trial of two treatments (Specific Preventive Intervention: SPI and Needs-Based Intervention: NBI) for UHR young persons were estimated and compared at three time points: treatment phase, short-term follow up and medium-term follow up.

Results: Although the SPI group incurred significantly higher treatment costs than the NBI group over the treatment phase, they incurred significantly lower outpatient treatment costs over the longer term.

Conclusion: This study indicates that specific interventions designed to treat young persons who are identified as being at UHR of psychosis might be associated with some cost savings compared with non-specific interventions.

Improving collaboration between private psychiatrists, the public mental health sector and general practitioners : evaluation of the Partnership Project

Objectives: We describe the evaluation of the Partnership Project, which was designed to improve linkages between public and private sector mental health services. We consider the Project's key elements: a Linkage Unit, designed to improve collaborative arrangements for consumers and promote systems-level and cultural change; and the expansion of private psychiatrists' roles to include supervision and training, case conferencing and secondary consultation. The evaluation aimed to describe the impacts and outcomes of these elements.

Method: The evaluation used de-identified data from the Linkage Unit database, the Project's billing system, and the Health Insurance Commission (HIC). It drew on consultations with key stakeholders (semistructured interviews with 36 key informants, and information from a forum attended by over 40 carers and a meeting of five public sector and three private sector psychiatrists) and a series of case studies.

Results: The Linkage Unit facilitated 224 episodes of collaborative care, many of which had positive outcomes for providers, consumers and carers. It had a significant impact at a systems level, raising consciousness about collaboration and influencing procedural changes. Thirty-two private psychiatrists consented to undertaking expanded roles, and the Project was billed $78 032 accordingly. Supervision and training were most common, involving 16 psychiatrists and accounting for approximately 80% of the total hours and cost. Commonwealth expenditure on private psychiatrists' participation in the expanded roles was not associated with a reduction in benefits paid by the HIC. Key informants were generally positive about the expanded roles.

Conclusions: The Project represented a considered, innovative approach to dealing with poor collaboration between the public mental health sector, private psychiatrists and GPs. The Linkage Unit achieved significant systems-level and cultural change, which has the potential to be sustained. Expanded roles for private psychiatrists, particularly supervision and training, may improve collaboration, and warrant further exploration in terms of costs and benefits.

Public and private psychiatry : can they work together and is it worth the effort?

OBJECTIVE: Partnerships in mental health care, particularly between public and private psychiatric services, are being increasingly recognized as important for optimizing patient management and the efficient organization of services. However, public sector mental health services and private psychiatrists do not always work well together and there seem to be a number of barriers to effective collaboration. This study set out to investigate the extent of collaborative 'shared care' arrangements between a public mental health service and private psychiatrists practising nearby. It also examined possible barriers to collaboration and some possible solutions to the identified problems.

METHOD: A questionnaire examining the above factors was sent to all public sector mental health clinicians and all private psychiatrists in the area.

RESULTS: One hundred and five of the 154 (68.2%) public sector clinicians and 103 of the 194 (53.1%) private psychiatrists returned surveys. The main barriers to successful collaboration identified by members of both sectors were: 'Difficulty communicating' endorsed by 71.4% of public clinicians and 72% of private psychiatrists, 'Confusion of roles and responsibilities' endorsed by 62.9% and 66%, respectively, and 'Different treatment approach' by 47.6% and 45.6%, respectively. Over 60% of private psychiatrists identified problems with access to the public system as a barrier to successful shared care arrangements. It also emerged, as hypothesized, that the public and private systems tend to manage different patient populations and that public clinicians in particular are not fully aware of the private psychiatrists' range of expertise. This would result in fewer referrals for shared care across the sectors.

CONCLUSIONS: A number of barriers to public sector clinicians and private psychiatrists collaborating in shared care arrangements were identified. The two groups surveyed identified similar barriers. Some of these can potentially be addressed by changes to service systems. Others require cultural shifts in both sectors. Improved communications including more opportunities for formal and informal meetings between people working in the two sectors would be likely to improve the understanding of the complementary sector's perspective and practice. Further changes would be expected to require careful work between the sectors on training, employment and practice protocols and initiatives, to allow better use of the existing services and resources.

Minimal force jump within human and assistive robot cooperation

When an assistant robotic manipulator cooperatively performs a task with a human and the task is required to be highly reliable, then fault tolerance is essential. To achieve the fault tolerance force within the human robot cooperation, it is required to map the effects of the faulty joint of the robot into the manipulator’s healthy joints’ torque space and the human force. The objective is to optimally maintain the cooperative force within the human robot cooperation. This paper aims to analyze the fault tolerant force within the cooperation and two frameworks are proposed. Then they have been validated through a fault scenario. Finally, the minimum force jump which is the optimal fault tolerance has been achieved.

Reinforcing silk scaffolds with silk particles

Silk fibroin is a useful protein polymer for biomaterials and tissue engineering. In this work, porogen leached scaffolds prepared from aqueous and HFIP silk solutions were reinforced through the addition of silk particles. This led to about 40 times increase in the specific compressive modulus and the yield strength of HFIP-based scaffolds. This increase in mechanical properties resulted from the high interfacial cohesion between the silk matrix and the reinforcing silk particles, due to partial solubility of the silk particles in HFIP. The porosity of scaffolds was reduced from ≈90% (control) to ≈75% for the HFIP systems containing 200% particle reinforcement, while maintaining pore interconnectivity. The presence of the particles slowed the enzymatic degradation of silk scaffolds.

Ingrowth of human mesenchymal stem cells into porous silk particle reinforced silk composite scaffolds : an in vitro study

Silk fibroin protein is biodegradable and biocompatible, exhibiting excellent mechanical properties for various biomedical applications. However, porous three-dimensional (3-D) silk fibroin scaffolds, or silk sponges, usually fall short in matching the initial mechanical requirements for bone tissue engineering. In the present study, silk sponge matrices were reinforced with silk microparticles to generate protein-protein composite scaffolds with desirable mechanical properties for in vitro osteogenic tissue formation. It was found that increasing the silk microparticle loading led to a substantial increase in the scaffold compressive modulus from 0.3 MPa (non-reinforced) to 1.9 MPa for 1:2 (matrix:particle) reinforcement loading by dry mass. Biochemical, gene expression, and histological assays were employed to study the possible effects of increasing composite scaffold stiffness, due to microparticle reinforcement, on in vitro osteogenic differentiation of human mesenchymal stem cells (hMSCs). Increasing silk microparticle loading increased the osteogenic capability of hMSCs in the presence of bone morphogenic protein-2 (BMP-2) and other osteogenic factors in static culture for up to 6 weeks. The calcium adsorption increased dramatically with increasing loading, as observed from biochemical assays, histological staining, and microcomputer tomography (μCT) analysis. Specifically, calcium content in the scaffolds increased by 0.57, 0.71, and 1.27 mg (per μg of DNA) from 3 to 6 weeks for matrix to particle dry mass loading ratios of 1:0, 1:1, and 1:2, respectively. In addition, μCT imaging revealed that at 6 weeks, bone volume fraction increased from 0.78% for non-reinforced to 7.1% and 6.7% for 1:1 and 1:2 loading, respectively. Our results support the hypothesis that scaffold stiffness may strongly influence the 3-D in vitro differentiation capabilities of hMSCs, providing a means to improve osteogenic outcomes.

Sustainable funding of health initiatives in Wonju, Republic of Korea via a tobacco consumption tax

Wonju is the first municipality in the Republic of Korea to fund the Healthy City project through municipal revenues from the local tobacco consumption tax. We investigated the process of the local tobacco consumption tax being approved as the main source of financing for the local Healthy City project. We also examined the sustainability and sufficiency of the funding by looking at the pricing policies instituted for cigarettes, smoking prevalence, cigarette consumption and revenues from local tobacco consumption as well as the budgetary allocations among programs in the city. The strong initiative of the mayor of Wonju was one of the factors that enabled the earmarking of the local tobacco consumption tax for the Healthy City Wonju project. He consulted academic counselors and persuaded the municipal government and the City Council to approve the bill. Despite the increasing price of cigarettes in Korea, adequate funding can be sustained to cover the short-term and mid-term programs in Wonju for at least 5 years of the mayor's term, because the smoking rate is persistently high. Analyzing the effects of strong leadership on the part of local authorities and the balance between revenues from the tobacco tax and the prevalence of smoking in the face of anti-smoking policies would be helpful for other countries and communities interested in developing sustainable Healthy Cities projects.

Setting the stage : from prodrome to treatment resistance in bipolar disorder

Bipolar disorder is common, and both difficult to detect and diagnose. Treatment is contingent on clinical needs, which differ according to phase and stage of the illness. A staging model could allow examination of the longitudinal course of the illness and the temporal impact of interventions and events. It could allow for a structured examination of the illness, which could set the stage for algorithms that are tailored to the individuals needs. A staging model could further provide as structure for assessment, gauging treatment and outcomes. The model incorporates prodromal stages and emphasizes early detection and algorithm appropriate intervention where possible. At the other end of the spectrum, the model attempts to operationalize treatment resistance. The utility of the model will need to be validated by empirical research.

Developing a peace education curriculum for Vietnamese primary schools : a case study of participatory action research in cross-cultural design

In 2003, the International Conflict Resolution Centre at the University of Melbourne, Australia, produced a primary school teaching manual for UNESCO Vietnam. The finished manual included lesson plans and materials for a five year, 50 lesson peace education course. The manual is one of the first examples of a systematic core national curriculum in peace education worldwide. Development of the Teaching Manual posed a number of challenges including differences in language, culture, government and education system. To meet these challenges, a participatory action research approach was central in the project’s development and curriculum design. This case study is offered as a model for effective crosscultural curriculum development of peace education materials. In particular, the use of games and reflective materials and the use of UNESCO’s peace keys are outlined as innovative outcomes of the project.