Age-related changes in hepatic function: An update on implications for drug therapy

The accumulation of deficits with increasing age results in a decline in the functional capacity of multiple organs and systems. These changes can have a significant influence on the pharmacokinetics and pharmacodynamics of prescribed drugs. Although alterations in body composition and worsening renal clearance are important considerations, for most drugs the liver has the greatest effect on metabolism. Age-related change in hepatic function thereby causes much of the variability in older people’s responses to medication. In this review, we propose that a decline in the ability of the liver to inactivate toxins may contribute to a proinflammatory state in which frailty can develop. Since inflammation also downregulates drug metabolism, medication prescribed to frail older people in accordance with disease-specific guidelines may undergo reduced systemic clearance, leading to adverse drug reactions, further functional decline and increasing polypharmacy, exacerbating rather than ameliorating frailty status. We also describe how increasing chronological age and frailty status impact liver size, blood flow and protein binding and enzymes of drug metabolism. This is used to contextualise our discussion of appropriate prescribing practices. For example, while the general axiom of ‘start low, go slow’ should underpin the initiation of medication (titrating to a defined therapeutic goal), it is important to consider whether drug clearance is flow or capacity-limited. By summarising the effect of age-related changes in hepatic function on medications commonly used in older people, we aim to provide a guide that will have high clinical utility for practising geriatricians.

Osmolality electrolyte and carbohydrate type and oral rehydration solutions: A controlled study to compare the efficacy of two commercially available solutions (osmolalities 240 mmol/L and 340 mmol/L)

An open-label, inpatient study was undertaken to compare the efficacy of two oral rehydration solutions (ORS) given randomly to children aged 1-10 years who had acute gastroenteritis with mild or moderate dehydration (n = 45). One solution contained 60 mmol/L sodium and 1.8% glucose, total osmolality 240 mosm/l (gastrolyte, Rhone-poulenc, Rorer) and the other contained 26 mmol/l sodium, 2.7% glucose and 3.6% sucrose, total osmolality 340 mOsm/l (Glucolyte, Gilseal). Analysis of data indicated that Gastrolyte therapy resulted in significantly fewer episodes and volume of vomiting over all time periods in comparison to Glucolyte and significantly less stool volume during the first 8 h and in the 0-24 h period. The differences between treatments in degree of dehydration at each follow-up period, duration of diarrhea, and duration of hospital stay were not significant. No adverse drug reactions occurred. Six patients received intravenous rehydration treatment and were considered treatment failures. We conclude that oral rehydration therapy is safe and efficacious in the management of dehydration in acute diarrhoea and that the lower osmolar rehydration solution has clinically marginal advantages.

Comparison of two oral rehydration solutions in children with gastroenteritis in Australia

An open-label inpatient study is in progress to compare the efficacy and safety of two oral rehydration solutions in children and infants with acute diarrhea and mild to moderate dehydration. One solution (ORS-60) contains 60 mmol/L of sodium and 1.8% glucose, with a total osmolatity of 240 mosm/kg; the other (ORS-26) contains 26 mmol/L of sodium, 2.7% glucose, and 3.6% sucrose, with a total osmolality of 340 mosm/kg. An outcome analysis of 28 children with gastroenteritis indicated that ORS-60 (n = 13) reduced stool volume during the first eight hours after admission to a significantly greater (P < 0.05) extent than did ORS-26 (n = 15). Diarrhea had ceased by 24 hours in 64% of ORS-60 patients but in only 31% of ORS-26 patients, and the patients' clinical conidition was improved at eight hours in 84% of ORS-60 patients versus 60% of ORS-26 patients. Differences between treatments in degree of dehydration at each follow-up point, total duration of diarrhea, and duration of hospital stay were not detected. No adverse drug reactions occurred. Four patients received intravenous rehydration therapy, but none was considered a treatment failure. We conclude that the lower osmolar solution, ORS-60, conferred earlier recovey and reduced continuing fluid losses in the management of gastroenteritis.

The psychological management of adult grief reactions

Despite the severe challenges which are posed by the loss of a close friend or relative, bereavement has a relatively benign outcome in most cases. While the majority of patients cope with bereavement, a significant minority develop problems. A behavioural approach may help the bereaved avoid adverse grief reactions.

The identification of therapeutic targets in metastatic melanoma

Metastatic melanoma, a cancer historically refractory to chemotherapeutic strategies, has a poor prognosis and accounts for the majority of skin cancer related mortality. Although the recent approval of two new drugs combating this disease, Ipilimumab and Vemurafenib (PLX4032), has demonstrated for the first time in decades an improvement in overall survival; the clinical efficacy of these drugs has been marred by severe adverse immune reactions and acquired drug resistance in patients, respectively. Thus, understanding the etiology of metastatic melanoma will contribute to the improvement of current therapeutic strategies while leading to the development of novel drug approaches. In order to identify recurrently mutated genes of therapeutic relevance in metastatic melanoma, a panel of stage III local lymph node melanomas were extensively characterised using high-throughput genomic technologies. This led to the identification of mutations in TFG in 5% of melanomas from a candidate gene sequencing approach using SNP array analysis, 24% of melanomas with mutations in MAP3K5 or MAP3K9 though unbiased whole-exome sequencing strategies, and inactivating mutations in NF1 in BRAF/NRAS wild type tumours though pathway analysis. Lastly, this thesis describes the development of a melanoma specific mutation panel that can rapidly identify clinically relevant mutation profiles that could guide effective treatment strategies through a personalised therapeutic approach. These findings are discussed in respect to a number of important issues raised by this study including the current limitation of next-generation sequencing technology, the difficulty in identifying ‘driver’ mutations critical to the development of melanoma due to high carcinogenic exposure by UV radiation, and the ultimate application of mutation screening in a personalised therapeutic setting. In summary, a number novel genes involved in metastatic melanoma have been identified that may have relevance for current therapeutic strategies in treating this disease.

Incorporating adverse event relatedness into dose-finding clinical trial designs

Dose-finding designs estimate the dose level of a drug based on observed adverse events. Relatedness of the adverse event to the drug has been generally ignored in all proposed design methodologies. These designs assume that the adverse events observed during a trial are definitely related to the drug, which can lead to flawed dose-level estimation. We incorporate adverse event relatedness into the so-called continual reassessment method. Adverse events that have ‘doubtful’ or ‘possible’ relationships to the drug are modelled using a two-parameter logistic model with an additive probability mass. Adverse events ‘probably’ or ‘definitely’ related to the drug are modelled using a cumulative logistic model. To search for the maximum tolerated dose, we use the maximum estimated toxicity probability of these two adverse event relatedness categories. We conduct a simulation study that illustrates the characteristics of the design under various scenarios. This article demonstrates that adverse event relatedness is important for improved dose estimation. It opens up further research pathways into continual reassessment design methodologies.

Non-invasive, quantitative analysis of drug mixtures in containers using spatially offset Raman spectroscopy (SORS) and multivariate statistical analysis

In this paper, spatially offset Raman spectroscopy (SORS) is demonstrated for non-invasively investigating the composition of drug mixtures inside an opaque plastic container. The mixtures consisted of three components including a target drug (acetaminophen or phenylephrine hydrochloride) and two diluents (glucose and caffeine). The target drug concentrations ranged from 5% to 100%. After conducting SORS analysis to ascertain the Raman spectra of the concealed mixtures, principal component analysis (PCA) was performed on the SORS spectra to reveal trends within the data. Partial least squares (PLS) regression was used to construct models that predicted the concentration of each target drug, in the presence of the other two diluents. The PLS models were able to predict the concentration of acetaminophen in the validation samples with a root-mean-square error of prediction (RMSEP) of 3.8% and the concentration of phenylephrine hydrochloride with an RMSEP of 4.6%. This work demonstrates the potential of SORS, used in conjunction with multivariate statistical techniques, to perform non-invasive, quantitative analysis on mixtures inside opaque containers. This has applications for pharmaceutical analysis, such as monitoring the degradation of pharmaceutical products on the shelf, in forensic investigations of counterfeit drugs, and for the analysis of illicit drug mixtures which may contain multiple components.

Models of South-East Asian organised crime drug operations in Queensland

In 2002, the United Nations Office on Drugs and Crime (UNODC) issued a report entitled Results of a pilot survey of forty selected organized criminal groups in sixteen countries which established five models of organised crime. This paper reviews these and other common organised crime models and drug trafficking models, and applies them to cases of South East Asian drug trafficking in the Australian state of Queensland. The study tests the following hypotheses: (1) South-East Asian drug trafficking groups in Queensland will operate within a criminal network or core group; (2) Wholesale drug distributors in Queensland will not fit consistently under any particular UN organised crime model; and (3) Street dealers will have no organisational structure. The study concluded that drug trafficking or importation closely resembles a criminal network or core group structure. Wholesale dealers did not fit consistently into any UN organised crime model. Street dealers had no organisational structure as an organisational structure is typically found in mid- to high-level drug trafficking.

Mathematical modelling of controlled drug release from polymer micro-spheres : incorporating the effects of swelling, diffusion and dissolution via moving boundary problems

Controlled drug delivery is a key topic in modern pharmacotherapy, where controlled drug delivery devices are required to prolong the period of release, maintain a constant release rate, or release the drug with a predetermined release profile. In the pharmaceutical industry, the development process of a controlled drug delivery device may be facilitated enormously by the mathematical modelling of drug release mechanisms, directly decreasing the number of necessary experiments. Such mathematical modelling is difficult because several mechanisms are involved during the drug release process. The main drug release mechanisms of a controlled release device are based on the device’s physiochemical properties, and include diffusion, swelling and erosion. In this thesis, four controlled drug delivery models are investigated. These four models selectively involve the solvent penetration into the polymeric device, the swelling of the polymer, the polymer erosion and the drug diffusion out of the device but all share two common key features. The first is that the solvent penetration into the polymer causes the transition of the polymer from a glassy state into a rubbery state. The interface between the two states of the polymer is modelled as a moving boundary and the speed of this interface is governed by a kinetic law. The second feature is that drug diffusion only happens in the rubbery region of the polymer, with a nonlinear diffusion coefficient which is dependent on the concentration of solvent. These models are analysed by using both formal asymptotics and numerical computation, where front-fixing methods and the method of lines with finite difference approximations are used to solve these models numerically. This numerical scheme is conservative, accurate and easily implemented to the moving boundary problems and is thoroughly explained in Section 3.2. From the small time asymptotic analysis in Sections 5.3.1, 6.3.1 and 7.2.1, these models exhibit the non-Fickian behaviour referred to as Case II diffusion, and an initial constant rate of drug release which is appealing to the pharmaceutical industry because this indicates zeroorder release. The numerical results of the models qualitatively confirms the experimental behaviour identified in the literature. The knowledge obtained from investigating these models can help to develop more complex multi-layered drug delivery devices in order to achieve sophisticated drug release profiles. A multi-layer matrix tablet, which consists of a number of polymer layers designed to provide sustainable and constant drug release or bimodal drug release, is also discussed in this research. The moving boundary problem describing the solvent penetration into the polymer also arises in melting and freezing problems which have been modelled as the classical onephase Stefan problem. The classical one-phase Stefan problem has unrealistic singularities existed in the problem at the complete melting time. Hence we investigate the effect of including the kinetic undercooling to the melting problem and this problem is called the one-phase Stefan problem with kinetic undercooling. Interestingly we discover the unrealistic singularities existed in the classical one-phase Stefan problem at the complete melting time are regularised and also find out the small time behaviour of the one-phase Stefan problem with kinetic undercooling is different to the classical one-phase Stefan problem from the small time asymptotic analysis in Section 3.3. In the case of melting very small particles, it is known that surface tension effects are important. The effect of including the surface tension to the melting problem for nanoparticles (no kinetic undercooling) has been investigated in the past, however the one-phase Stefan problem with surface tension exhibits finite-time blow-up. Therefore we investigate the effect of including both the surface tension and kinetic undercooling to the melting problem for nanoparticles and find out the the solution continues to exist until complete melting. The investigation of including kinetic undercooling and surface tension to the melting problems reveals more insight into the regularisations of unphysical singularities in the classical one-phase Stefan problem. This investigation gives a better understanding of melting a particle, and contributes to the current body of knowledge related to melting and freezing due to heat conduction.

Governing young people’s drug use: Crime, harm and contemporary drug use practices

Since the nineteenth century, drug use has been variously understood as a problem of epidemiology, psychiatry, physiology, and criminality. Consequently drug research tends to be underpinned by assumptions of inevitable harm, and is often directed towards preventing drug use or solving problems. These constructions of the drug problem have generated a range of law enforcement responses, drug treatment technologies and rehabilitative programs that are intended to prevent drug related harm and resituate drug users in the realm of neo-liberal functional citizenship. This paper is based on empirical research of young people’s illicit drug use in Brisbane. The research rejects the idea of a pre-given drug problem, and seeks to understand how drugs have come to be defined as a problem. Using Michel Foucault’s conceptual framework of governmentality, the paper explores how the governance of illicit drugs, through law, public health and medicine, intersects with self-governance to shape young people’s drug use practices. It is argued that constructions of the drug problem shape what drug users believe about themselves and the ways in which they use drugs. From this perspective, drug use practices are ‘practices of the self’, formed through an interaction of the government of illicit drugs and the drug users own subjectivity.

Satisfaction survey for a medication management program : satisfaction guaranteed?

BACKGROUND Providing clinical pharmacy services to patients in their homes after discharge from hospital has been reported to reduce health care costs and improve outcomes. The Medication Management Program of the Fraser Health Authority involves pharmacists making home visits to provide clinical pharmacy services to elderly patients who have recently been discharged from hospital and others considered to be at high risk for adverse drug events. Although clinical and economic outcomes of this program have been evaluated, humanistic outcomes such as satisfaction have not been assessed. Moreover, very little evaluation of patient satisfaction with home pharmacy services has been reported in the literature. OBJECTIVE To evaluate patient satisfaction with the Medication Management Program. METHODS A telephone survey instrument, consisting of 7 Likert-scale items and 2 open-ended questions, was developed and administered to patients who received a home pharmacist visit between September 1 and November 23, 2011. In addition to the survey responses, demographic and clinical data for both respondents and nonrespondents were collected. RESULTS Of the 175 patients invited to participate in the survey, 103 (58.9%) agreed to participate. The majority of respondents agreed or strongly agreed with all of the survey items, indicating satisfaction with the program. For example, 97 (94%) agreed or strongly agreed that they would recommend the pharmacist home visit program continue to be available, and all 103 (100%) agreed or strongly agreed that they were satisfied with the pharmacist home visit. Respondents provided some suggestions for program improvement. CONCLUSIONS The survey findings demonstrate that patients were satisfied with the home clinical pharmacy services offered through the Fraser Health Medication Management Program.

Role of intratumoural heterogeneity in cancer drug resistance : molecular and clinical perspectives

Drug resistance continues to be a major barrier to the delivery of curative therapies in cancer. Historically, drug resistance has been associated with over-expression of drug transporters, changes in drug kinetics or amplification of drug targets. However, the emergence of resistance in patients treated with new-targeted therapies has provided new insight into the complexities underlying cancer drug resistance. Recent data now implicate intratumoural heterogeneity as a major driver of drug resistance. Single cell sequencing studies that identified multiple genetically distinct variants within human tumours clearly demonstrate the heterogeneous nature of human tumours. The major contributors to intratumoural heterogeneity are (i) genetic variation, (ii) stochastic processes, (iii) the microenvironment and (iv) cell and tissue plasticity. Each of these factors impacts on drug sensitivity. To deliver curative therapies to patients, modification of current therapeutic strategies to include methods that estimate intratumoural heterogeneity and plasticity will be essential.

Women and ADR

Alternative dispute resolution, or ‘ADR’, is defined by the National Alternative Dispute Resolution Advisory Council as: … an umbrella term for processes, other than judicial determination, in which an impartial person assists those in a dispute to resolve the issues between them. ADR is commonly used as an abbreviation for alternative dispute resolution, but can also be used to mean assisted or appropriate dispute resolution. Some also use the term ADR to include approaches that enable parties to prevent or manage their own disputes without outside assistance. A broad range of ADR processes are used in legal practice contexts, including, for example, arbitration, conciliation, mediation, negotiation, conferencing, case appraisal and neutral evaluation. Hybrid processes are also used, such as med-arb in which the practitioner starts by using mediation, and then shifts to using arbitration. ADR processes generally fall into one of three general categories: facilitative, advisory or determinative. In a facilitative process, the ADR practitioner has the role of assisting the parties to reach a mutually agreeable outcome to the dispute by helping them to identify the issues in dispute, and to develop a range of options for resolving the dispute. Mediation and facilitated negotiation are examples of facilitative processes. ADR processes that are advisory involve the practitioner appraising the dispute, providing advice as to the facts of the dispute, the law and then, in some cases, articulating possible or appropriate outcomes and how they might be achieved. Case appraisal and neutral evaluation are examples of advisory processes. In a determinative ADR process, the practitioner evaluates the dispute (which may include the hearing of formal evidence from the parties) and makes a determination. Arbitration is an example of a determinative ADR process. The use of ADR processes has increased significantly in recent years. Indeed, in a range of contemporary legal contexts the use of an ADR process is now required before a party is able to file a matter in court. For example, Juliet Behrens discusses in Chapter 11 of this book how the Family Law Act 1975 (Cth) now effectively mandates attendance at pre-filing family dispute resolution in parenting disputes. At the state level, in Queensland, for example, attendance at a conciliation conference can be required in anti-discrimination matters, and is encouraged in residential tenancy matters, and in personal injuries matters the parties must attend a preliminary compulsory conference. Certain ADR processes are used more commonly in the resolution of particular disputes. For example, in family law contexts, mediation and conciliation are generally used because they provide the parties with flexibility in terms of process and outcome while still ensuring that the negotiations occur in a positive, structured and facilitated framework. In commercial contexts, arbitration and neutral evaluation are often used because they can provide the parties with a determination of the dispute that is factually and legally principled, but which is also private and more timely than if the parties went to court. Women, as legal personalities and citizens of society, can find themselves involved in any sort of legal dispute, and therefore all forms of ADR are relevant to women. Perhaps most commonly, however, women come into contact with facilitative ADR processes. For example, through involvement in family law disputes women will encounter family dispute resolution processes, such as mediation. In this chapter, therefore, the focus is on facilitative ADR processes and, particularly, issues for women in terms of their participation in such processes. The aim of this chapter is to provide legal practitioners with an understanding of issues for women in ADR to inform your approach to representing women clients in such processes, and to guide you in preparing women clients for their participation in ADR. The chapter begins with a consideration of the ways in which facilitative ADR processes are positive for women participants. Next, some of the disadvantages for women in ADR are explored. Finally, the chapter offers ways in which legal practitioners can effectively prepare women clients for participation in ADR. Before embarking on a discussion of issues for women in ADR, it is important to acknowledge that women’s experiences in these dispute resolution environments, whilst often sharing commonalities, are diverse and informed by a range of factors specific to each individual woman; for example, her race or socio-economic background. This discussion, therefore, addresses some common issues for women in ADR that are fundamentally gender based. It must be noted, however, that providing advice to women clients about participating in ADR processes requires legal practitioners to have a very good understanding of the client as an individual, and her particular needs and interests. Some sources of diversity are discussed in Chapters 13, 14 and 15.

Pituitary volume and early treatment response in drug-naïve first-episode psychosis patients

BACKGROUND: An early response to antipsychotic treatment in patients with psychosis has been associated with a better course and outcome. However, factors that predict treatment response are not well understood. The onset of schizophrenia and related disorders has been associated with increased levels of stress and hyper-activation of the hypothalamic-pituitary-adrenal (HPA) axis. This study examined whether pituitary volume at the onset of psychosis may be a potential predictor of early treatment response in first-episode psychosis (FEP) patients. METHODS: We investigated the relationship between baseline pituitary volume and symptomatic treatment response over 12 weeks using mixed model analysis in a sample of 42 drug-naïve or early treated FEP patients who participated in a controlled dose-finding study of quetiapine fumarate. Logistic regression was used to examine predictors of treatment response. Pituitary volume was measured from magnetic resonance imaging scans that were obtained upon entry into the trial. RESULTS: Larger pituitary volume was associated with less improvement in overall psychotic symptoms (Brief Psychiatric Rating Scale (BPRS) P=0.031) and positive symptoms (BPRS positive symptom subscale P=0.010). Regardless of gender, patients with a pituitary volume at the 25th percentile (413 mm(3)) were approximately three times more likely to respond to treatment by week 12 than those at the 75th percentile (635 mm(3)) (odds ratio=3.07, CI: 0.90-10.48). CONCLUSION: The association of baseline pituitary volumes with early treatment response highlights the importance of the HPA axis in emerging psychosis. Potential implications for treatment strategies in early psychosis are discussed.