The -Omics in drug development

New advancement in genomics, proteomics, and metabonomics created significant excitement about the use of these relatively new technologies in drug design, discovery, development, and molecular-targeted therapeutics by identifying new drug targets and better tools for safety and efficacy studies in preclinical and clinical stages of drug development as well as diagnostics. In this chapter, we will briefly discuss the application of genomics, proteomics, and metabonomics in drug discovery and development

Proteins, drug targets and the mechanisms they control : the simple truth about complex networks

Realizing the promise of molecularly targeted inhibitors for cancer therapy will require a new level of knowledge about how a drug target is wired into the control circuitry of a complex cellular network. Here we review general homeostatic principles of cellular networks that enable the cell to be resilient in the face of molecular perturbations, while at the same time being sensitive to subtle input signals. Insights into such mechanisms may facilitate the development of combination therapies that take advantage of the cellular control circuitry, with the aim of achieving higher efficacy at a lower drug dosage and with a reduced probability of drug-resistance development.

Steady state and transient dynamometer vehicle emission measurements using a DiSC

Analysis of the particulate size and number concentration emissions from a fleet of inner city medium duty CNG buses was conducted using the newly available Diffusion Size Classifier in comparison with more traditional SMPS's and CPC's. Studies were conducted at both steady state and transient driving modes on a vehicle dynamometer utilising a CVS dilution system. Comparative analysis of the results showed that the DiSC provided equivalent information during steady state conditions and was able to provide additional information during transient conditions, namely, the modal diameter of the particle size distribution.

Better cars or older cars?: Assessing CO2 emission reduction potential of passenger vehicle replacement programs

The primary motivation for the vehicle replacement schemes that were implemented in many countries was to encourage the purchase of new cars. The basic assumption of these schemes was that these acquisitions would benefit both the economy and the environment as older and less fuel-efficient cars were scrapped and replaced with more fuel-efficient models. In this article, we present a new environmental impact assessment method for assessing the effectiveness of scrappage schemes for reducing CO2 emissions taking into account the rebound effect, driving behavior for older versus new cars and entire lifecycle emissions for during the manufacturing processes of new cars. The assessment of the Japanese scrappage scheme shows that CO2 emissions would only decrease if users of the scheme retained their new gasoline passenger vehicles for at least 4.7 years. When vehicle replacements were restricted to hybrid cars, the reduction in CO2 achieved by the scheme would be 6-8.5 times higher than the emissions resulting from a scheme involving standard, gasoline passenger vehicles. Cost-benefit analysis, based on the emission reduction potential, showed that the scheme was very costly. Sensitivity analysis showed that the Japanese government failed to determine the optimum, or target, car age for scrapping old cars in the scheme. Specifically, scrapping cars aged 13 years and over did not maximize the environmental benefits of the scheme. Consequently, modifying this policy to include a reduction in new car subsidies, focused funding for fuel-efficient cars, and modifying the target car age, would increase environmental benefits. © 2013 Elsevier Ltd.

Testing the effects of the Japanese vehicle emission-control law on the international palladium futures market

This paper tested the effects of the 2005 vehicle emission-control law issued in Japan on the market linkages between the U.S. and Japanese palladium futures markets, To determine these effects, we applied a cointegration test both with and without break points in the time series and found that the market linkages between the two countries changed after the break in October 2005. Our results show that the 2005 long-term regulation of vehicle emissions enacted in Japan influenced the international palladium futures market.

The topography of multiple drug use among adolescent Australians : findings from the National Drug Strategy Household Survey

Introduction and aims: Despite evidence that many Australian adolescents have considerable experience with various drug types, little is known about the extent to which adolescents use multiple substances. The aim of this study was to examine the degree of clustering of drug types within individuals, and the extent to which demographic and psychosocial predictors are related to cluster membership. Design and method: A sample of 1402 adolescents aged 12-17. years were extracted from the Australian 2007 National Drug Strategy Household Survey. Extracted data included lifetime use of 10 substances, gender, psychological distress, physical health, perceived peer substance use, socioeconomic disadvantage, and regionality. Latent class analysis was used to determine clusters, and multinomial logistic regression employed to examine predictors of cluster membership. Result: There were 3 latent classes. The great majority (79.6%) of adolescents used alcohol only, 18.3% were limited range multidrug users (encompassing alcohol, tobacco, and marijuana), and 2% were extended range multidrug users. Perceived peer drug use and psychological distress predicted limited and extended multiple drug use. Psychological distress was a more significant predictor of extended multidrug use compared to limited multidrug use. Discussion and conclusion: In the Australian school-based prevention setting, a very strong focus on alcohol use and the linkages between alcohol, tobacco and marijuana are warranted. Psychological distress may be an important target for screening and early intervention for adolescents who use multiple drugs.

Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia

We show that imatinib, nilotinib, and dasatinib possess weak off-target activity against RAF and, therefore, drive paradoxical activation of BRAF and CRAF in a RAS-dependent manner. Critically, because RAS is activated by BCR-ABL, in drug-resistant chronic myeloid leukemia (CML) cells, RAS activity persists in the presence of these drugs, driving paradoxical activation of BRAF, CRAF, MEK, and ERK, and leading to an unexpected dependency on the pathway. Consequently, nilotinib synergizes with MEK inhibitors to kill drug-resistant CML cells and block tumor growth in mice. Thus, we show that imatinib, nilotinib, and dasatinib drive paradoxical RAF/MEK/ERK pathway activation and have uncovered a synthetic lethal interaction that can be used to kill drug-resistant CML cells in vitro and in vivo.

Intravitreal drug delivery in retinal disease : are we out of our depth?

Introduction With the ever-increasing global burden of retinal disease, there is an urgent need to vastly improve formulation strategies that enhance posterior eye delivery of therapeutics. Despite intravitreal administration having demonstrated notable superiority over other routes in enhancing retinal drug availability, there still exist various significant physical/biochemical barriers preventing optimal drug delivery into the retina. A further complication lies with an inability to reliably translate laboratory-based retinal models into a clinical setting. Several formulation approaches have recently been evaluated to improve intravitreal therapeutic outcomes, and our aim in this review is to highlight strategies that hold the most promise. Areas covered We discuss the complex barriers faced by the intravitreal route and examine how formulation strategies including implants, nanoparticulate carriers, viral vectors and sonotherapy have been utilized to attain both sustained delivery and enhanced penetration through to the retina. We conclude by highlighting the advances and limitations of current in vitro, ex vivo and in vivo retinal models in use by researchers globally. Expert opinion Various nanoparticle compositions have demonstrated the ability to overcome the retinal barriers successfully; however, their utility is limited to the laboratory setting. Optimization of these formulations and the development of more robust experimental retinal models are necessary to translate success in the laboratory into clinically efficacious outcomes.

Profiling contextual factors which influence safety in heavy vehicle industries

A significant proportion of worker fatalities within Australia result from truck-related incidents. Truck drivers face a number of health and safety concerns. Safety culture, viewed here as the beliefs, attitudes and values shared by an organisation’s workers, which interact with their surrounding context to influence behaviour, may provide a valuable lens for exploring safety-related behaviours in heavy vehicle operations. To date no major research has examined safety culture within heavy vehicle industries. As safety culture provides a means to interpret experiences and generate behaviour, safety culture research should be conducted with an awareness of the context surrounding safety. The current research sought to examine previous health and safety research regarding heavy vehicle operations to profile contextual factors which influence health and safety. A review of 104 peer-reviewed papers was conducted. Findings of these papers were then thematically analysed. A number of behaviours and scenarios linked with crashes and non-crash injuries were identified, along with a selection of health outcomes. Contextual factors which were found to influence these outcomes were explored. These factors were found to originate from government departments, transport organisations, customers and the road and work environment. The identified factors may provide points of interaction, whereby culture may influence health and safety outcomes.

Boosting the effects of a curriculum based injury prevention program through a school connectedness intervention : final report to NRMA-ACT Road Safety Trust

Injury is the leading cause of death among young people (AIHW, 2008). A primary contributing factor to injury among adolescents is risk taking behaviour, including road related risks such as risky bicycle and motorcycle use and riding with dangerous or drink-drivers. Injury rates increase dramatically throughout adolescence, at the same time as adolescents are becoming more involved in risk taking behaviour. Also throughout this period, adolescents‟ connectedness to school is decreasing (Monahan, Oesterle & Hawkins, 2010; Whitlock, 2004). School connectedness refers to „the extent to which students feel personally accepted, respected, included, and supported by others in the school‟ (Goodenow, 1993, p. 80), and has been repeatedly shown to be a critical protective factor in adolescent development. For example, school connectedness has been shown to be associated with decreased risk taking behaviour, including violence and alcohol and other drug use (e.g., Resnick et al., 1997), as well as with decreased transport risk taking and vehicle related injuries (Chapman et al., accepted April 2011). This project involved the pilot evaluation of a school connectedness intervention (a professional development program for teachers) to reduce adolescent risk taking behaviour and injury. This intervention has been developed for use as a component of the Skills for Preventing Injury in Youth (SPIY) curriculum based injury prevention program for early adolescents. The objectives of this research were to: 1. Implement a trial School Connectedness intervention (professional development program for teachers) in ACT high schools, and evaluate using comparison high schools. 2. Determine whether the School Connectedness program impacts on adolescent risk taking behaviour and associated injuries (particularly transport risks and injuries). 3. Evaluate the process effectiveness of the School Connectedness program.

Synthesis and toxicological evaluation of a chitosan‑L‑leucine conjugate for pulmonary drug delivery applications

Herein are reported the synthesis of a conjugate of chitosan with L-leucine, the preparation of nanoparticles from both chitosan and the conjugate for use in pulmonary drug delivery, and the in vitro evaluation of toxicity and inflammatory effects of both the polymers and their nanoparticles on the bronchial epithelial cell line, BEAS-2B. The nanoparticles, successfully prepared both from chitosan and the conjugate, had a diameter in the range of 10−30 nm. The polymers and their nanoparticles were tested for their effects on cell viability by MTT assay, on trans-epithelial permeability by using sodium fluorescein as a fluid phase marker, and on IL-8 secretion by ELISA. The conjugate nanoparticles had a low overall toxicity (IC50 = 2 mg/mL following 48 h exposure; no induction of IL-8 release at 0.5 mg/mL concentration), suggesting that they may be safe for pulmonary drug delivery applications.

Colloidal drug probe : Method development and validation for adhesion force measurement using Atomic Force Microscopy

This study demonstrates a novel technique of preparing drug colloid probes to determine the adhesion force between a model drug salbutamol sulphate (SS) and the surfaces of polymer microparticles to be used as carriers for the dispersion of drug particles from dry powder inhaler (DPI) formulations. Model silica probes of approximately 4 lm size, similar to a drug particle used in DPI formulations, were coated with a saturated SS solution with the aid of capillary forces acting between the silica probe and the drug solution. The developed method of ensuring a smooth and uniform layer of SS on the silica probe was validated using X-ray Photoelectron Spectroscopy (XPS) and Scanning Electron Microscopy (SEM). Using the same technique, silica microspheres pre-attached on the AFM cantilever were coated with SS. The adhesion forces between the silica probe and drug coated silica (drug probe) and polymer surfaces (hydrophilic and hydrophobic) were determined. Our experimental results showed that the technique for preparing the drug probe was robust and can be used to determine the adhesion force between hydrophilic/ hydrophobic drug probe and carrier surfaces to gain a better understanding on drug carrier adhesion forces in DPI formulations.

Characteristics of low-speed vehicle run-over events in children : an 11-year review

Objectives: The purpose of this study was to investigate the characteristics associated with fatal and non-fatal low-speed vehicle run-over (LSVRO) events in relation to person, incident and injury characteristics, in order to identify appropriate points for intervention and injury prevention. Methods: Data on all known LSVRO events in Queensland, Australia, over 11 calendar years (1999–2009) were extracted from five different databases representing the continuum of care ( prehospital to fatality) and manually linked. Descriptive and multivariate analyses were used to analyse the sample characteristics in relation to demographics, health service usage, outcomes, incident characteristics, and injury characteristics. Results: Of the 1641 LSVRO incidents, 98.4% (n=1615) were non-fatal, and 1.6% were fatal (n=26). Over half the children required admission to hospital (56%, n=921); mean length of stay was 3.4 days. Younger children aged 0–4 years were more frequently injured, and experienced more serious injuries with worse outcomes. Patterns of injury (injury type and severity), injury characteristics (eg, time of injury, vehicle type, driver of vehicle, incident location), and demographic characteristics (such as socioeconomic status, indigenous status, remoteness), varied according to age group. Almost half (45.6%; n=737) the events occurred outside major cities, and approximately 10% of events involved indigenous children. Parents were most commonly the vehicle drivers in fatal incidents. While larger vehicles such as four-wheel drives (4WD) were most frequently involved in LSVRO events resulting in fatalities, cars were most frequently involved in non-fatal events. Conclusions: This is the first study, to the authors’ knowledge, to analyse the characteristics of fatal and non-fatal LSVRO events in children aged 0–15 years on a state-wide basis. Characteristics of LSVRO events varied with age, thus age-specific interventions are required. Children living outside major cities, and indigenous children, were over-represented in these data. Further research is required to identify the burden of injury in these groups.