Structural and functional properties of human multidrug resistance protein 1 (MRP1/ABCC1)

Multidrug ABC transporters such as P-glycoprotein (P-gp/MDR1/ABCB1) and multidrug resistance protein 1 (MRP1/ABCC1) play an important role in the extrusion of drugs from the cell and their overexpression can be a cause of failure of anticancer and antimicrobial chemotherapy. Recently, the mouse P-gp/Abcb1a structure has been determined and this has significantly enhanced our understanding of the structure-activity relationship (SAR) of mammalian ABC transporters. This paper highlights our current knowledge on the structural and functional properties and the SAR of human MRP1/ABCC1. Although the crystal structure of MRP1/ABCC1 has yet to be resolved, the current topological model of MRP1/ABCC1 contains two transmembrane domains (TMD1 and TMD2) each followed by a nucleotide binding domain (NBD) plus a third NH2-terminal TMD0. MRP1/ABCC1 is expressed in the liver, kidney, intestine, brain and other tissues. MRP1/ABCC1 transports a structurally diverse array of important endogenous substances (e.g. leukotrienes and estrogen conjugates) and xenobiotics and their metabolites, including various conjugates, anticancer drugs, heavy metals, organic anions and lipids. Cells that highly express MRP1/ABCC1 confer resistance to a variety of natural product anticancer drugs such as vinca alkaloids (e.g. vincristine), anthracyclines (e.g. etoposide) and epipodophyllotoxins (e.g. doxorubicin and mitoxantrone). MRP1/ABCC1 is associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. However, most compounds that efficiently reverse P-gp/ABCB1-mediated multidrug resistance have only low affinity for MRP1/ABCC1 and there are only a few effective and relatively specific MRP1/ABCC1 inhibitors available. A number of site-directed mutagenesis studies, biophysical and photolabeling studies, SAR and QSAR, molecular docking and homology modeling studies have documented the role of multiple residues in determining the substrate specificity and inhibitor selectivity of MRP1/ABCC1. Most of these residues are located in the TMs of TMD1 and TMD2, in particular TMs 4, 6, 7, 8, 10, 11, 14, 16, and 17, or in close proximity to the membrane/cytosol interface of MRP1/ABCC1. The exact transporting mechanism of MRP1/ABCC1 is unclear. MRP1/ABCC1 and other multidrug transporters are front-line mediators of drug resistance in cancers and represent important therapeutic targets in future chemotherapy. The crystal structure of human MRP1/ABCC1 is expected to be resolved in the near future and this will provide an insight into the SAR of MRP1/ABCC1 and allow for rational design of anticancer drugs and potent and selective MRP1/ABCC1 inhibitors.

Assessing body condition and energy budget components by scoring abdominal profiles in free-ranging pink-footed geese Anser brachyrhynchus

An abdominal profile index (API) was developed for pink-footed geese Anser brachyrhynchus as a measure of body condition. On basis of carcass analysis of 56 adult geese with known API prior to collection, we found significant linear relationships between API against body mass, abdominal fat and total energy content. Hence, changes in API reflect net energy intake rates. As an example of the applicability of the calibration, we compared APIs of individually marked geese before and after long migration episodes and estimated the cost of flight at 8.9 kJ/km. In addition we estimated gain rates at three major staging sites along the spring flyway indicating an increase in fueling rates with latitude. Calibration of APIs and energy contents offers new opportunities for field studies of waterfowl energetics.

I don't know anyone that has two drinks a day : young people, alcohol and the government of pleasure

Problematic alcohol consumption is a major public health, health education and health promotion issue in Australia and internationally. In an effort to better understand young people's drinking patterns and motivations we investigated the cultural drivers of drinking in 14–24 year-old Australians. We interviewed 60 young people in the state of Victoria aged 20–24 about their drinking biographies. At the time of interviewing, the draft guidelines on low-risk drinking were released by the National Health and Medical Research Council, Australia, and we asked our participants what they knew about them and if they thought they would affect their drinking patterns. Their responses indicate that pleasure and sociability are central to young people's drinking cultures which is supported by a range of research. However, O’Malley and Valverde claim that pleasure is silenced and/or deployed strategically in neo-liberal governance discourses about drugs and alcohol such as these guidelines which raises questions about the limits of such discourses to affect changes in drinking patterns.

Elite athletes' perceptions of the effects of illicit drugs use on athletic performance

Objective: To investigate the perceived risks and benefits that elite athletes associate with illicit drugs and their beliefs concerning the effects of recreational drug use on athletic performance.

Design: Self-administered survey.

Participants: Nine hundred seventy-four elite athletes (mean age, 23 years; range, 18-30 years) were recruited from 8 national sporting organizations in Australia and the Australian Institute of Sport.

Interventions: Participants completed a self-administered survey that included questions exploring participants’ perceptions regarding the effects of illicit drug use on physical performance.

Setting: National sporting organization meetings or competitions.

Main Outcome Measures: The main outcome measure was risk perception on athletic performance associated with illicit drug use.

Results: The majority of athletes believed that illicit drug use would impact negatively on athletic performance. The main perceived effects of illicit drugs on athletic performance were physical and mental functioning. A minority of athletes indicated that drug use would not impact on physical performance when taken during the offseason or in moderation.

Conclusions: The main risks perceived in association with illicit drug use were short-term consequences, such as physical and mental functioning, rather than long-term health consequences. The current findings may contribute to the development of harm reduction strategies that communicate drug-related consequences to elite athletes in an appropriate and effective manner.

Chemotoxicity of doxorubicin and surface expression of P-glycoprotein (MDR1) is regulated by the Pseudomonas aeruginosa toxin Cif

P-glycoprotein (Pgp), a member of the adenosine triphosphate-binding cassette (ABC) transporter superfamily, is a major drug efflux pump expressed in normal tissues, and is overexpressed in many human cancers. Overexpression of Pgp results in reduced intracellular drug concentration and cytotoxicity of chemotherapeutic drugs and is thought to contribute to multidrug resistance of cancer cells. The involvement of Pgp in clinical drug resistance has led to a search for molecules that block Pgp transporter activity to improve the efficacy and pharmacokinetics of therapeutic agents. We have recently identified and characterized a secreted toxin from Pseudomonas aeruginosa, designated cystic fibrosis transmembrane conductance regulator (CFTR) inhibitory factor (Cif). Cif reduces the apical membrane abundance of CFTR, also an ABC transporter, and inhibits the CFTR-mediated chloride ion secretion by human airway and kidney epithelial cells. We report presently that Cif also inhibits the apical membrane abundance of Pgp in kidney, airway, and intestinal epithelial cells but has no effect on plasma membrane abundance of multidrug resistance protein 1 or 2. Cif increased the drug sensitivity to doxorubicin in kidney cells expressing Pgp by 10-fold and increased the cellular accumulation of daunorubicin by 2-fold. Thus our studies show that Cif increases the sensitivity of Pgp-overexpressing cells to doxorubicin, consistent with the hypothesis that Cif affects Pgp functional expression. These results suggest that Cif may be useful to develop a new class of specific inhibitors of Pgp aimed at increasing the sensitivity of tumors to chemotherapeutic drugs, and at improving the bioavailability of Pgp transport substrates.

Herb-drug interactions and mechanistic and clinical considerations

Herbal medicines are often used in combination with conventional drugs, and this may give rise to the potential of harmful herb-drug interactions. This paper updates our knowledge on clinical herb-drug interactions with an emphasis of the mechanistic and clinical consideration. In silico, in vitro, animal and human studies are often used to predict and/or identify drug interactions with herbal remedies. To date, a number of clinically important herb-drug interactions have been reported, but many of them are from case reports and limited clinical observations. Common herbal medicines that interact with drugs include St John's wort (Hypericum perforatum), ginkgo (Ginkgo biloba), ginger (Zingiber officinale), ginseng (Panax ginseng), and garlic (Allium sativum). For example, St John's wort significantly reduced the area under the plasma concentration-time curve (AUC) and blood concentrations of cyclosporine, midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline. The common drugs that interact with herbal medicines include warfarin, midazolam, digoxin, amitriptyline, indinavir, cyclosporine, tacrolimus and irinotecan. Herbal medicines may interact with drugs at the intestine, liver, kidneys, and targets of action. Importantly, many of these drugs have very narrow therapeutic indices. Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (P-gp). The underlying mechanisms for most reported herb-drug interactions are not fully understood, and pharmacokinetic and/or pharmacodynamic mechanisms are implicated in many of these interactions. In particular, enzyme induction and inhibition may play an important role in the occurrence of some herbdrug interactions. Because herb-drug interactions can significantly affect circulating levels of drug and, hence, alter the clinical outcome, the identification of herb-drug interactions has important implications.

Community variation in adolescent alcohol use in Australia and the Netherlands

To investigate the cross-national relevance of community health promotion, this paper compared community variation in alcohol use and risk and protective factors for adolescents in Australia (State of Victoria, 2009) and the Netherlands (2007/2008). Multi-level analyses examined community variation in heavy episodic (binge) alcohol use [≥5 drinks in a session ≥once in the prior fortnight (>63 ml of ethanol)] and associations with predictors. Representative community samples of adolescents (12–17 years) were recruited. The participants were 7812 students from 36 Australian communities and 15 082 adolescents from 124 Dutch communities. Predictors included adolescent reports of family, school, peer and neighbourhood environments and community predictors (rural, disadvantage). The overall prevalence of alcohol use prevalence was similar in both nations. Australia had higher use at younger ages and no difference between genders. In the Netherlands older adolescents and males used alcohol at significantly higher rates. Although individual predictors were mostly similar, binge drinking was more strongly associated with poor family management, friends' use of drugs and community disorganization in Australia. Significant community variation in adolescent heavy alcohol use was observed in both countries, but was higher in the Netherlands [inter class correlation 6.1%, (95% CI: 4.5–8.3%)] than Australia (ICC 2.4%, 1.3–4.5%). Youth from rural areas drank at a higher level, especially in the Netherlands. Targeting community level adolescent alcohol use appears feasible in both countries. Although behavioural patterns and risk and protective influences are similar in the Netherlands and Australia, important differences should be taken into account in tailoring community interventions.

Targeted multimodal liposomes for nano-delivery and imaging: an avenger for drug resistance and cancer.

Understanding the cellular target structure and thereby proposing the best delivery system to achieve sustained release of drugs has always been a significant area of focus in biomedical research for translational benefits. Specific targeting of the receptors expressed on the target cell represents an effective strategy for increasing the pharmacological efficacy of the administered drug. Liposomes offer enhanced conveyance as a potential carrier of biomacromolecules such as anti-cancer proteins, drugs and siRNA for targeting tumour cell death. Commonly used liposomal constructs for various therapies are Doxil, Myocet, DepoCyt and Abraxanes. However, recent strategy of using multifunctional liposomes for the sustained release of drugs with increased plasma residence time and monoclonal antibody-based targeting of tumours coupled with imaging modalities have attracted enormous scientific attention. The ability of liposomes coated with specific ligands such as Apo-E derived RGD R9 and Tat peptide, to reverse the conceptualisation of drug resistance and cross the blood brain barrier, provides promising future for their use as an efficient drug delivery system. By outlining the recent advancements and innovations in the established concept of liposomal drug delivery, this review will focus on the multifunctional liposomes as an emerging novel lipid based drug delivery system.

Multifunctional and multitargeted nanoparticles for drug delivery to overcome barriers of drug resistance in human cancers

The recurrence and metastatic spread of cancer are major drawbacks in cancer treatment. Although chemotherapy is one of the most effective methods for the treatment of metastatic cancers, it is nonspecific and causes significant toxic damage. The development of drug resistance to chemotherapeutic agents through various mechanisms also limits their therapeutic potential. However, as we discuss here, the use of nanodelivery systems that are a combination of diagnostics and therapeutics (theranostics) is as relatively novel concept in the treatment of cancer. Such systems are likely to improve the therapeutic benefits of encapsulated drugs and can transit to the desired site, maintaining their pharmaceutical properties. The specific targeting of malignant cells using multifunctional nanoparticles exploits theranostics as an improved agent for delivering anticancer drugs and as a new solution for overriding drug resistance.

Anti-inflammatory and chondroprotectivity of dominant-negative survivan and nutraceuticals, lactoferrin and herbs

Osteoarthritis is a highly problematic and debilitating medical issues affecting over 630 million people worldwide. Current treatments include anti-inflammatory drugs and joint injections which are painful and cause systemic side effects. The present study, investigates the activity of nanoformulated bioactive proteins and herbals as potential therapeutics for chronic inflammatory arthritis.

The influence of protective and risk factors in individual, peer and school domains on Thai adolescents' alcohol and illicit drug use: a survey

This study investigates risk and protective factors for substance abuse in a sample of 1778 students attending technical colleges in Bangkok and Nakhon Ratchasima provinces of Thailand using a self-report questionnaire modified from the Communities That Care youth survey. Low school commitment was strongly associated with illicit drug use, with adjusted odds ratios ranging from 2.84 (glue sniffing) to 10.06 (ecstasy). Having friends using drugs, and friends with delinquent behaviors increased the risk of using alcohol and illegal drugs, with adjusted odds ratios of 6.84 and 6.72 respectively for marijuana use. For protective factors, approximately 40-60% of students with high levels of moral belief, participation in religious activities, and social skills were less likely to use alcohol. It is concluded that peer influence is a significant contributor to Thai adolescents' participation in substance abuse and that engaging in religiosity may assist adolescents to internalize negative aspects of harmful drugs into positive perceptions and encourage them to avoid alcohol and illegal drugs.

Distilled technical cashew nut shell liquid (DT-CNSL) as an effective biofuel and additive to stabilize triglyceride biofuels in diesel

We report distilled technical cashew nut shell liquid (DT-CNSL) as a non-transesterified biofuel and also as an additive to convert triglycerides to biofuel, without the need for the formation of methyl esters. DT-CNSL blends of diesel obey physico-chemical parameters of diesel. DT-CNSL offers stability to blends of straight vegetable oil (SVO) and tallow oil in diesel. Fluorescence studies using charge transfer probes show that the blend of DT-CNSL, triglycerides and diesel is a uniform solution, and fluorescence behavior is similar to that of diesel. The economics for the cultivation of cashew (Anacardium occidentale), its industrial use and rich carbon sink properties indicate that DT-CNSL could complement or replace traditional biodiesel crops like Jatropha and improve income for farmers. © 2014 Elsevier Ltd.

Generic drug prices and policy in Australia: room for improvement? A comparative analysis with England

To assess the degree to which reimbursement prices in Australia and England differ for a range of generic drugs, and to analyse the supply- and demand-side factors that may contribute to these differences.

Nucleic acid-based aptamers: applications, development and clinical trials

Short single-stranded oligonucleotides called aptamers, often termed as chemical antibodies, have been developed as powerful alternatives to traditional antibodies with respect to their obvious advantages like high specificity and affinity, longer shelf-life, easier manufacturing protocol, freedom to introduce chemical modifications for further improvement, etc. Reiterative selection process of aptamers over 10-15 cycles starting from a large initial pool of random nucleotide sequences renders them with high binding affinity, thereby making them extremely specific for their targets. Aptamer-based detection systems are well investigated and likely to displace primitive detection systems. Aptamer chimeras (combination of aptamers with another aptamer or biomacromolecule or chemical moiety) have the potential activity of both the parent molecules, and thus hold the capability to perform diverse functions at the same time. Owing to their extremely high specificity and lack of immunogenicity or pathogenicity, a number of other aptamers have recently entered clinical trials and have garnered favorable attention from pharmaceutical companies. Promising results from the clinical trials provide new hope to change the conventional style of therapy. Aptamers have attained high therapeutic relevance in a short time as compared to synthetic drugs and/or other modes of therapy. This review follows the various trends in aptamer technology including production, selection, modifications and success in clinical fields. It focusses largely on the various applications of aptamers which mainly depend upon their selection procedures. The review also sheds light on various modifications and chimerizations that have been implemented in order to improve the stability and functioning of the aptamers, including introduction of locked nucleic acids (LNAs). The application of various aptamers in detection systems has been discussed elaborately in order to stress on their role as efficient diagnostic agents. The key aspect of this review is focused on success of aptamers on the basis of their performance in clinical trials for various diseases.

Midwives experiences of establishing partnerships: working with pregnant women who use illicit drugs

OBJECTIVE: To present the interpreted experiences of midwives who choose to work with pregnant women who also use illicit drugs. DESIGN: Twelve (n=12) Australian midwives were interviewed. Each interview was audio-taped, de-identified and transcribed. The interviews were analysed using a systematic, thematic analysis approach informed by Heideggarian hermeneutic phenomenology. FINDINGS: Three themes identified from the data that encapsulate the experience were establishing partnerships, making a difference, and letting go and redefining practice. The interpretations of establishing partnerships which includes engagement, genuine regard and compassion, with a subtheme courting the system are presented in this paper. The midwives' experiences were both positive and negative, as they were rewarded and challenged by the needs of women who use illicit drugs and the systems in which they worked. CONCLUSION: The midwives in this study found that establishing partnerships was essential to their work. They appraised their experience of working with pregnant women who used illicit drugs and found strategies that attempted to meet the needs of the women, the system and themselves. The participants revealed that to support women and families who use illicit drugs in their community, partnerships must be based on deep respect and trust. Significant components engagement, genuine regard and compassion that are central to midwifery partnerships require revisiting to address the needs of this vulnerable population of women.