Clincial pharmacogenetics and potential application in personalized medicine

The current `fixed-dosage strategy' approach to medicine, means there is much inter-individual variation in drug response. Pharmacogenetics is the study of how inter-individual variations in the DNA sequence of specific genes affect drug responses. This article will highlight current  pharmacogenetic knowledge on important drug metabolizing enzymes, drug transporters and drug targets to understand interindividual variability in drug clearance and responses in clinical practice and potential use in  personalized medicine. Polymorphisms in the cytochrome P450 (CYP) family may have had the most impact on the fate of pharmaceutical drugs. CYP2D6, CYP2C19 and CYP2C9 gene polymorphisms and gene duplications account for the most frequent variations in phase I metabolism of drugs since nearly 80% of drugs in use today are metabolised by these enzymes. Approximately 5% of Europeans and 1% of Asians lack CYP2D6 activity, and these  individuals are known as poor metabolizers. CYP2C9 is another clinically significant drug metabolising enzyme that demonstrates genetic variants. Studies into CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and CYP2C9*3 alleles. Extensive polymorphism also occurs in a majority of Phase II drug metabolizing enzymes. One of the most important polymorphisms is thiopurine S-methyl transferases (TPMT) that catalyzes the S-methylation of thiopurine drugs. With respect to drug transport  polymorphism, the most extensively studied drug transporter is  P-glycoprotein (P-gp/MDR1), but the current data on the clinical impact is limited. Polymorphisms in drug transporters may change drug's distribution, excretion and response. Recent advances in molecular research have revealed many of the genes that encode drug targets demonstrate genetic polymorphism. These variations, in many cases, have altered the targets sensitivity to the specific drug molecule and thus have a profound effect on drug efficacy and toxicity. For example, the β2-adrenoreceptor, which is encoded by the ADRB2 gene, illustrates a clinically significant genetic variation in drug targets. The variable number tandem repeat polymorphisms in serotonin transporter (SERT/SLC6A4) gene are associated with response to antidepressants. The distribution of the common variant alleles of genes that encode drug metabolizing enzymes, drug transporters and drug targets has been found to vary among different populations. The promise of pharmacogenetics lies in its potential to identify the right drug at the right dose for the right individual. Drugs with a narrow therapeutic index are thought to benefit more from pharmacogenetic studies. For example, warfarin serves as a good practical example of how pharmacogenetics can be utilized prior to commencement of therapy in order to achieve maximum efficacy and minimum toxicity. As such, pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and licensed drugs.

Mechanical properties of porous Ti-26NB alloy for regenerative medicine

Porous titanium-26at.%niobium (hereafter, Ti-26Nb) alloys with different porosities were prepared by space-holder sintering. The porous structure of the alloys was characterized by scanning electron microscopy (SEM). Mechanical properties of the porous alloys were investigated using compression test. Results indicate that the porous alloys with 60, 70 and 80% porosities exhibit interconnected porous structure with pore sizes of 100-300 µm. The porous structure has the potential to provide new bone tissue ingrowth ability. The mechanical properties of these porous alloys decrease with the increase of porosity. The mechanical properties of the porous Ti-26Nb alloys can be tailored to match those of human bone.

Reaching and influencing consumers in the prescription medicine market

Purpose – Celebrex became the first of a new class of drugs known as COX-2 selective non-steroidal anti-inflammatory drugs. It improves treatment for arthritis sufferers without compromising the protective lining of the stomach. The purpose of this paper is to illustrate how direct-to-consumer advertising (DTCA) of prescription medicines can be used to rebuild faith in the cyclooxygenase-2 (COX-2) product category.

Design/methodology/approach – The case is developed using published sources and no input is required from company representatives. The presentation style follows the classic comprehensive case format used in postgraduate teaching programmes.

Findings – Business executives and strategic marketing students would benefit from a discussion on how external environmental factors can suddenly impose a review of marketing strategy. The reader learns how management addresses the business dilemma using DTCA.

Research limitations/implications – A blockbuster rival drug Vioxx is withdrawn due to cardiovascular (CV) health safety concerns. A resulting dominant market situation soon becomes a business dilemma. The Federal Drug Administration calls for a “black box” warning label on Celebrex, the most serious type of warning.

Practical implications – The implications are that having a product in a class of its own is not enough. It highlights the need to communicate to different audiences, to both the medical profession and the end-user. Getting doctors to recommend the medicine and pulling the product through the channel by stimulating patient demand after a health scare are paramount.

Originality/value – This is the first pharmaceutical business case where the withdrawal of a rival product leaves the dominant competitor in a monopoly situation. Contrary to expectation, market share plummets despite the absence of competition.

Descriptive epidemiology of Australian football injuries presenting to sports medicine clinics

Sports injury prevention has been the focus of a number of recent public health initiatives due to the acknowledgement that sports injuries are a significant public health problem in Australia Whilst Australian football is one of the most popular participation sports in the country, only very limited data is available about football injuries The majority of sports injury data available for this sport is from hospital emergency departments and elite-level injury surveillance Overall there is a paucity of data from treatment settings other than hospitals In particular, there is a lack of information about the injuries sustained by community-level, junior and recreational Australian football participants. One good potential source of football injury data is sports medicine clinics. Analysis of injury presentations to sports medicine clinics was undertaken to provide a detailed description of the epidemiology of Australian football injuries that present to this treatment setting and to determine the implications for injury prevention in this sport. In addition, the data from sports medicine clinics was compared with existing sources of Australian football injury data to determine how representative sports medicine clinic data is of other football injury data sources and to provide recommendations for future injury surveillance n Australian football. The results contained in this thesis show that Australian football is the sport most associated with injury presentation at sports medicine clinics. The majority of injured Australian football players presenting to sports medicine clinics are community-level or junior participants which suggests that sports medicine clinics are a good source of information on the injuries sustained by sub-elite football participants. Competition is the most common context in which Australian football players presenting to sports medicine clinics are injured. The major causes of injuries to Australian football players are being struck by another player, collisions and overuse. Injuries to Australian football players predominantly involve the lower limb. Adult players, players who stopped participating immediately after noticing their injury and players with overuse injuries are the most likely to sustain a more severe injury (i.e. more than four weeks before a full return to football participation and a moderate/significant amount of treatment expected). The least experienced players (five or less years of participation) are more likely to require a significant amount of treatment than the more experienced players. The prevention of lower limb injuries, injuries caused by body contact and injuries caused by overuse should be a priority for injury prevention research in Australian football due to the predominance of these injury types in the pattern of Australian football injuries Additionally, adult players, as a group, should be a focus of injury prevention activities in Australian football due to the association between age and injury severity. Overall, the pattern of Australian football injuries presenting to sports medicine clinics appears to be different than reported by club-based and hospital emergency department injury surveillance activities. However, detailed comparison of sports medicine clinic Australian football data with other sources of Australian football injury data is difficult due to the variable methods of collecting and reporting injury information used by hospital emergency department and club-based injury surveillance activities. The development of a standardised method for collecting and reporting injury data in Australian football is strongly recommended to overcome the existing limitations of data collection in this sport. In summary, sports medicine clinics provide a rich source of Australian football injury data, especially from the community and junior levels of participation. The inclusion of sports medicine clinic data provides a broader epidemiological picture of Australian football injuries. This broader understanding of the pattern of Australian football injuries provides a better basis for the development of injury prevention measures in this sport.

The ethics of surrogate decision making in medicine : autonomy, paternalism, or a different approach?

Knowing who to involve in treatment decisions when a patient is incapacitated has been the subject of discussion in bioethical, health law and clinical research. The major issues tend to revolve around the tension between exercising a degree of medical paternalism and respecting patient autonomy. Patients are encouraged to exert their autonomy even when they may not be capable of doing so, by means of surrogate consent or advanced directives. While liberal concepts of autonomy are exemplified in western bioethics and legal systems, clinically these decisions remain difficult, and input from medical professionals is sought, raising the issue of paternalism. A framework of bioethics, which places the patient in a relational context rather than a strictly autonomous one, may be a more helpful way of deliberating these difficult decisions

Renegade judgement : a study of madness in medicine and literature

Explores socio-historical understandings and treatments of madness, examining literary works alongside contemporary medical texts. Incorporating notions of scientific objectivity, individual subjectivity and social totality, the thesis shows conceptual overlaps between art and science, identifying continuities and conflicts between fictional, clinical and cultural investigations into madness.

Naval instruction : a comparative research study

Naval training communities use a systems approach to training. This study considers the question "what is effectiveness in naval training?" Instructor courses of five navies were observed and naval instructors surveyed. Conclusions and recommednations are drawn from the data. It is proposed that most problems of effectiveness identified can be overcome without investment in technology or significant system changes.

Biodegradable Mg-Ca and Mg-Ca-Y alloys for regenerative medicine

In this study, Mg-xCa (x = 0.5, 1.0, 2.0, 5.0, 10.0, 15.0 and 20.0 %, wt.%, hereafter) and Mg-1Ca-1Y alloys were investigated as new biodegradable bone implant materials. The compressive strength, ultimate strength and hardness of the Mg-Ca alloys increased, whilst the corrosion rate and biocompatibility decreased, with the increase of the Ca content in the Mg-Ca alloys; higher Ca content caused the Mg-Ca alloy to become brittle. Solutions of simulated body fluid (SBF) and modified minimum essential media (MMEM) with the immersion of Mg-xCa and Mg-1Ca-1Y alloys showed strong alkalisation. The yttrium addition to the Mg-Ca alloys does not improve the corrosion resistance of the Mg-1Ca-1Y alloy as expected compared to the Mg-1Ca alloy. It is suggested that Mg-Ca alloys with Ca additions less than 1.0 wt.% exhibited good biocompatibility and low corrosion rate.

Food as a medicine : healthful oleocanthal in Australian olive oil

Oleocanthal has gained much interest as a natural anti-inflammatory phenolic component in olive oil. The studies conducted as part of this thesis demonstrate that oleocanthal is a stable olive oil phenolic with potential to be a prime health benefiting compound.