Using pharmacogenetics and pharmacogenomics in the treatment of psychiatric disorders: some ethical and economic considerations"

Current pharmacotherapies for psychiatric disorders are generally incompletely effective. Many patients do not respond well or suffer adverse reactions to these drugs, which can result in poor patient compliance and poor treatment outcome. Adverse drug reactions and non-response are likely to be influenced by genetic polymorphisms. Pharmacogenetics holds some promise for improving the treatment of mood disorders by utilising information about genetic polymorphisms to match patients to the drug therapy that is the most effective with the fewest side effects. Pharmacogenomics promises to facilitate the development of new drugs for treatment. However, these technologies raise many ethical, economic and regulatory issues that need to be addressed before they can be integrated into psychiatry, and medicine more generally. We discuss ethical and policy issues arising from pharmacogenetic testing and pharmacogenomics research, such as informed consent, privacy and confidentiality, research on vulnerable persons and discrimination; and economic viability of pharmacogenetics and pharmacogenomics. We conclude with recommendations for the regulation and distribution of pharmacogenetic testing services and pharmacogenomic drugs.

A cost-effectiveness analysis of fluvastatin in patients with diabetes after successful percutaneous coronary intervention

Background: The Lescol Intervention Prevention Study (LIPS) was a multinational randomized controlled trial that showed a 47% reduction in the relative risk of cardiac death and a 22% reduction in major adverse cardiac events (MACEs) from the routine use of fluvastatin, compared with controls, in patients undergoing percutaneous coronary intervention (PCI, defined as angioplasty with or without stents). In this study, MACEs included cardiac death, nonfatal myocardial infarction, and subsequent PCI and coronary artery bypass graft. Diabetes was the greatest risk factor for MACEs. Objective: This study estimated the cost-effectiveness of fluvastatin when used for secondary prevention of MACEs after PCI in people with diabetes. Methods: A post hoc subgroup analysis of patients with diabetes from the LIPS was used to estimate the effectiveness of fluvastatin in reducing myocardial infarction, revascularization, and cardiac death. A probabilistic Markov model was developed using United Kingdom resource and cost data to estimate the additional costs and quality-adjusted life-years (QALYs) gained over 10 years from the perspective of the British National Health Service. The model contained 6 health states, and the transition probabilities were derived from the LIPS data. Crossover from fluvastatin to other lipid-lowering drugs, withdrawal from fluvastatin, and the use of lipid-lowering drugs in the control group were included. Results: In the subgroup of 202 patients with diabetes in the LIPS trial, 18 (15.0%) of 120 fluvastatin patients and 21 (25.6%) of 82 control participants were insulin dependent (P = NS). Compared with the control group, patients treated with fluvastatin can expect to gain an additional mean (SD) of 0.196 (0.139) QALY per patient over 10 years (P < 0.001) and will cost the health service an additional mean (SD) of 10 (E448) (P = NS) (mean [SD] US $16 [$689]). The additional cost per QALY gained was;(51 (US $78). The key determinants of cost-effectiveness included the probabilities of repeat interventions, cardiac death, the cost of fluvastatin, and the time horizon used for the evaluation. Conclusion: Fluvastatin was an economically efficient treatment to prevent MACEs in these patients with diabetes undergoing PCI.

Apnea diving: Long-term neurocognitive sequelae of repeated hypoxemia

This article examines the neurocognitive sequelae of repeated exposure to hypoxemia in apnea (breath-hold) divers. A brief review of the literature on the physiological and neurological adaptations involved in the human diving reflex is presented. The results from a neuropsychological investigation of N = 21 elite apnea divers are evaluated. Standard neuropsychological tests, with known sensitivity to mild brain insults, included speed of visuo-motor responding, speed of language comprehension, response inhibition, and visual and verbal attention and recall tasks. Results indicated that the breath-hold divers performed tasks within the average range compared to norms on all tests, suggesting that 1-20 years of repeated exposure to hypoxemia including multiple adverse neurological events did not impact on performance on standard neuropsychological tasks. The results are discussed in relation to implications for clinical conditions such as sleep apnea, respiratory disorders, altitude sickness, and recreational apnea activities.

Serious adverse events in the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD)

Aims The study estimated serious adverse event (SAE) rates among entrants to pharmacotherapies for opioid dependence, during treatment and after leaving treatment. Design A longitudinal study based on data from 12 trials included in the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD). Participants and settings A total of 1.244 heroin users and methadone patients treated in hospital, community and GP settings. Intervention Six trials included detoxification; all included treatment with methadone, buprenorphine, levo-alpha-acetyl-methadol (LAAM) or naltrexone. Findings During 394 person-years of observation, 79 SAEs of 28 types were recorded. Naltrexone participants experienced 39 overdoses per 100 person-years after leaving treatment (44% occurred within 2 weeks after stopping naltrexone). This was eight times the rate recorded among participants who left agonist treatment. Rates of all other SAEs were similar during treatment versus out of treatment, for both naltrexone-treated and agonist-treated participants. Five deaths occurred, all among participants who had left treatment, at a rate of six per 100 person-years. Total SAE rates during naltrexone and agonist treatments were similar (20, 14 per 100 person-years, respectively). Total SAE and death rates observed among participants who had left treatment were three and 19 times the corresponding rates during treatment. Conclusions Individuals who leave pharmacotherapies for opioid dependence experience higher overdose and death rates compared with those in treatment. This may be due partly to a participant self-selection effect rather than entirely to pharmacotherapy being protective. Clinicians should alert naltrexone treatment patients in particular about heroin overdose risks. Duty of care may extend beyond cessation of dosing.

A prospective multicentre study of pharmacist initiated changes to drug therapy and patient management in acute care government funded hospitals

Aims To determine the cost savings of pharmacist initiated changes to hospitalized patients' drug therapy or management in eight major acute care government funded teaching hospitals in Australia. Methods This was a prospective study performed in eight hospitals examining resource implications of pharmacists' interventions assessed by an independent clinical panel. Pharmacists providing clinical services to inpatients recorded details of interventions, defined as any action that directly resulted in a change to patient management or therapy. An independent clinical review panel, convened at each participating centre, confirmed or rejected the clinical pharmacist's assessment of the impact on length of stay (LOS), readmission probability, medical procedures and laboratory monitoring and quantified the resultant changes, which were then costed. Results A total of 1399 interventions were documented. Eight hundred and thirty-five interventions impacted on drug costs alone. Five hundred and eleven interventions were evaluated by the independent panels with three quarters of these confirmed as having an impact on one or more of: length of stay, readmission probability, medical procedures or laboratory monitoring. There were 96 interventions deemed by the independent panels to have reduced LOS and 156 reduced the potential for readmission. The calculated savings was $263 221 for the eight hospitals during the period of the study. This included $150 307 for length of stay reduction, $111 848 for readmission reduction. Conclusions The annualized cost savings relating to length of stay, readmission, drugs, medical procedures and laboratory monitoring as a result of clinical pharmacist initiated changes to hospitalized patient management or therapy was $4 444 794 for eight major acute care government funded teaching hospitals in Australia.

Audit of selective and non-selective non-steroidal anti-inflammatory drug use in rural general practice

Aim: To identify the demographics and risk factors in a selected patient population prescribed non-selective and cyclo-oxygenase-2 (COX- 2) selective non-steroidal anti-inflammatory drugs (NSAIDs). Method: A structured clinical self-audit form was distributed in January to March 2001 to 155 interested general practitioners (GPs) in rural Queensland. Results: Seventy one GPs participated in the audit and contributed 1417 patient records - 790 patients had received nonselective NSAIDs and 627 had received COX-2 inhibitors (celecoxib or rofecoxib). Patients who received COX-2 inhibitors were significantly older, more likely to have clinically important concomitant illness, and more likely to be taking medication known to interact with NSAIDs. They were also twice as likely to have two or more risk factors for adverse effects. The most common reasons for switching from an NSAID to a COX-2 inhibitor were reported to be a previous side effect from an NSAID (primarily related to gastrointestinal effects) or the doctor's perception of the superior efficacy of COX-2 inhibitor therapy. Conclusions: This study has shown that COX-2 inhibitors were used in a distinctly different patient population compared to non-selective NSAIDs. There were significant variations in the demographics and number of risk factors - for example, cardiovascular and renal - between the two identified populations. These differences may be due to doctors selecting COX-2 inhibitors for patients at high risk of gastrointestinal complications. However, the prescribing pattern may also be partly due to misconceptions about the relative safety and efficacy of COX-2 inhibitor drugs.

Effect of atorvastatin on cyclosporine pharmacokinetics in liver transplant recipients

BACKGROUND: The development of hyperlipidemia after liver transplant is frequently treated with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) such as atorvastatin. As atorvastatin and the primary immunosuppressant drug, cyclosporine, are metabolized by the same pathway, there is the potential for an interaction. OBJECTIVE: To determine the effect of atorvastatin on cyclosporine pharmacokinetics in liver transplant recipients. METHODS: Six stable, long-term adult liver transplant recipients from a single center who developed posttransplant dyslipidemia were recruited to participate in a 14-day, open-label study of atorvastatin 10 mg/d coadministered with standard posttransplant immunosuppression using constant oral doses-of cyclosporine and corticosteroids. A 10-point pharmacokinetic profile was performed prior to and on day 14 after commencement of atorvastatin therapy. Cyclosporine concentrations were measured by HPLC-electrospray-tandem mass spectrometry. The AUC was calculated by the linear trapezoidal rule, with other parameters determined by visual inspection. RESULTS: Atorvastatin coadministration increased the cyclosporine AUC by 9% (range 0-20.6%; 3018 vs 3290 ng(.)h/mL; p = 0.04). No significant change was evident for other cyclosporine pharmacokinetic parameters. Total cholesterol and low-density lipoprotein cholesterol levels were significantly lower on day 14 than at baseline (p < 0.02). One patient developed a twofold increase in transaminases after 2 weeks of atorvastatin therapy, but no other clinical or biochemical adverse events were recorded. CONCLUSIONS: Atorvastatin coadministration increases the cyclosporine AUC by approximately 10% in stable liver transplant recipients. This change in systemic exposure to cyclosporine is of questionable clinical significance. Atorvastatin is effective in reducing cholesterol levels in liver transplant recipients.

Use of tissue Doppler imaging to facilitate the prediction of events in patients with abnormal left ventricular function dobutamine echocardiography

The extent of abnormality in patients with positive do-butamine echocardiography (DE) is predictive of risk, but the wall motion score (WMS) has low concordance among observers. We sought whether quantifying the extent of abnormal wall motion using tissue Doppler (TD) could guide risk assessment in patients with abnormal DE in 576 patients with known or suspected coronary artery disease; standard DE was combined with color TD imaging at peak dose. WMS was assessed by an expert observer and studies were identified as abnormal in the presence of 2:1 segments with resting or stress-induced wall motion abnormalities. Patients with abnormal DE had peak systolic velocity measured in each segment. Tissue tracking was used to measure myocardial displacement. Follow-up for death or infarction was per-formed after. 16 +/- 12 months. Of 251 patients with abnormal DE, 22 patients died (20 from cardiac causes) and 7 had nonfatal myocardial infarctionis. The average WMS in patients with events was 1.8 +/- 0.5, compared with 1.7 +/- 0.5 in patients without events (p = NS). The average systolic velocity in patients with events was 4.9 +/- 1.7 cm/s and 6.4 +/- 6.5 cm/s in the patients without events (p <0.001). The average tissue tracking in patients with events was 4.5 +/- 1.5 mm and was significant. (5.7 +/- 3.1 mm),in those,without events (p <0.001). Thus, TD is an alternative to WMS for quantifying the total extent of abnormal left ventricular function-at DE, and appears to be superior for predicting adverse outcomes. (C) 2004 by Excerpta Medica, Inc.

The other side of the coin: safety of complementary and alternative medicine

Most consumers consider complementary and alternative medicine (CAM) products inherently safe. The growing simultaneous use of CAM products and pharmaceutical drugs by Australian consumers increases the risk of CAM-drug interactions. The Therapeutic Goods Administration (TGA) has a two-tier, risk-based regulatory system for therapeutic goods - CAM products are regulated as low risk products and are assessed for quality and safety; and sponsors of products must hold the evidence for any claim of efficacy made about them. Adverse reactions to CAM products can be classified as intrinsic (innate to the product), or extrinsic (where the risk is not related to the product itself, but results from the failure of good manufacturing practice). Adverse reactions to CAM practices can be classified as risks of commission (which includes removal of medical therapy) and risks of omission (which includes failure to refer when appropriate). While few systematic studies of adverse events with CAM exist, and under-reporting is likely, most CAM products and practices do not appear to present a high risk; their safety needs to be put into the perspective of wider safety issues. A priority for research is to rigorously define the risks associated with both CAM products and practices so that their potential impact on public health can be assessed.

Continuous infusion of ticarcillin-clavulanate for home treatment of serious infections: clinical efficacy, safety, pharmacokinetics and pharmacodynamics

Continuous infusion (CI) ticarcillin-clavulanate is a potential therapeutic improvement over conventional intermittent dosing because the major pharmacodynamic (PD) predictor of efficacy of beta-lactams is the time that free drug levels exceed the MIC. This study incorporated a 6-year retrospective arm evaluating efficacy and safety of CI ticarcillin-clavulanate in the home treatment of serious infections and a prospective arm additionally evaluating pharmacokinetics (PK) and PD. In the prospective arm, steady-state serum ticarcillin and clavulanate levels and MIC testing of significant pathogens were performed. One hundred and twelve patients (median age, 56 years) were treated with a CI dose of 9.3-12.4 g/day and mean CI duration of 18.0 days. Infections treated included osteomyelitis (50 patients), septic arthritis (6), cellulitis (17), pulmonary infections (12), febrile neutropenia (7), vascular infections (7), intra-abdominal infections (2), and Gram-negative endocarditis (2); 91/112 (81%) of patients were cured, 14 (13%) had partial response and 7 (6%) failed therapy. Nine patients had PICC line complications and five patients had drug adverse events. Eighteen patients had prospective PK/PD assessment although only four patients had sufficient data for a full PK/PD evaluation (both serum steady-state drug levels and ticarcillin and clavulanate MICs from a bacteriological isolate), as this was difficult to obtain in home-based patients, particularly as serum clavulanate levels were found to deteriorate rapidly on storage. Three of four patients with matched PK/PD assessment had free drug levels exceeding the MIC of the pathogen. Home Cl of ticarcillin-clavulanate is a safe, effective, convenient and practical therapy and is a therapeutic advance over traditional intermittent dosing when used in the home setting. (c) 2005 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Mefloquine and doxycycline malaria prophylaxis in Australian soldiers in East Timor

Objectives: To describe the tolerability of mefloquine in Australian soldiers for malaria prophylaxis, including a comparison with doxycycline. Design: Open-label, prospective study and cross-sectional questionnaire and interview. Setting and participants: Two contingents of Australian soldiers, each deployed to East Timor for peacekeeping duties over a 6-month period (April 2001-October 2001 and October 2001-May 2002). Outcome measures: Withdrawals during the study; adverse events relating to mefloquine prophylaxis; willingness to use mefloquine again on deployment. Results: Of 1157 soldiers starting on mefloquine, 75 (6.5%) withdrew because of adverse responses to the drug. There were three serious adverse events of a neuropsychiatric nature, possibly relating to mefloquine. Fifty-seven per cent of soldiers using mefloquine prophylaxis reported at least one adverse event, compared with 56% using doxycycline. The most commonly reported adverse effects of both drugs were sleep disturbance, headache, tiredness and nausea. Of the 968 soldiers still taking mefloquine at the end of their deployments, 94% indicated they would use mefloquine again. Of 388 soldiers taking doxycycline prophylaxis who were deployed with the first mefloquine study contingent, 89% indicated they would use doxycycline again. Conclusions: Mefloquine was generally well tolerated by Australian soldiers and should continue to be used for those intolerant of doxycycline.