The IMPROVE guidelines (Ischaemia Models: Procedural Refinements Of in Vivo Experiments)

Most in vivo models of ischaemic stroke target the middle cerebral artery and a spectrum of stroke severities, from mild to substantial, can be achieved. This review describes opportunities to improve the in vivo modelling of ischaemic stroke and animal welfare. It provides a number of recommendations to minimise the level of severity in the most common rodent models of middle cerebral artery occlusion, while sustaining or improving the scientific outcomes. The recommendations cover basic requirements pre-surgery, selecting the most appropriate anaesthetic and analgesic regimen, as well as intraoperative and post-operative care. The aim is to provide support for researchers and animal care staff to refine their procedures and practices, and implement small incremental changes to improve the welfare of the animals used and to answer the scientific question under investigation. All recommendations are recapitulated in a summary poster (see supplementary information)

Meandering Down the Road to Transparency

Decision-making, Pharmacoeconomics

Honoring Pioneers in Patient-Centered Outcomes Research

Outcomes-research, Patient-preference

Management of Rheumatoid Arthritis: Defining the Role of Leflunomide

Rheumatoid arthritis is a progressive, disabling disease which can lead to long-term deformity and disability. Leflunomide is a disease-modifying antirheumatic drug (DMARD) approved to reduce signs and symptoms, inhibit structural damage and improve physical function in adults with active rheumatoid arthritis. In clinical trials in patients with active rheumatoid arthritis, leflunomide had a more rapid onset of action than methotrexate, sulfasalazine and placebo. In trials of 24 months' duration, leflunomide was more effective than sulfasalazine and placebo and at least as effective as methotrexate in reducing rheumatoid arthritis disease activity (assessed using the American College of Rheumatology [ACR] criteria). In addition, leflunomide was as effective as sulfasalazine or methotrexate in decreasing the rate of radiological progression over 24 months. Over 12 months leflunomide was more effective than methotrexate and placebo in reducing the rate of structural damage. Data from a nonblind extension study suggests that the efficacy of leflunomide may be maintained when administered for periods up to 5 years. Leflunomide was significantly more effective than methotrexate, sulfasalazine and placebo in improving physical function measures among patients with active rheumatoid arthritis, and improved physical function was maintained after 2 years of treatment. Few well designed pharmacoeconomic analyses of leflunomide treatment in patients with rheumatoid arthritis exist. Economic studies to date show leflunomide to be either less cost effective or cost neutral compared to methotrexate. In addition, leflunomide has been shown to be a cost effective option compared with etanercept, infliximab and infliximab plus methotrexate. Leflunomide was generally well tolerated in clinical trials. Common adverse events associated with leflunomide treatment include diarrhea, respiratory infections, nausea and headache. Hematological and hepatotoxic adverse events are a concern, particularly in a setting of multiple risk factors such as concomitant hepatotoxins. Liver function monitoring should be adhered to in all patients receiving leflunomide and ACR guidelines should be followed in those receiving concomitant methotrexate. In conclusion, leflunomide is a DMARD which produces a rapid and sustained reduction in disease activity in patients with active rheumatoid arthritis. Leflunomide has a more rapid onset of action than sulfasalazine or methotrexate. Leflunomide is at least as effective as methotrexate and more effective than sulfasalazine in reducing disease activity after 24 months' treatment. In addition, leflunomide is more effective than both of these agents in improving physical function and health-related quality of life. Thus it is predicted that leflunomide therapy may improve the long-term outcome of patients with rheumatoid arthritis and reduce the substantial burden imposed by the disease for patient, healthcare provider and payers. Consequently, leflunomide should be considered as an important treatment option for those patients with active rheumatoid arthritis including those intolerant to methotrexate.Adis-Drug-Evaluations, Leflunomide, Pharmacoeconomics, Quality-of-life, Rheumatoid-arthritis

Management of Type 2 Diabetes Mellitus: Defining the Role of Nateglinide

Type 2 diabetes mellitus is a progressive disease with an insidious onset. It is thought to affect up to 10% of European and North American populations with a significantly higher incidence in non-White than in White populations. Complications of the disease are associated with considerable morbidity and mortality and their management consumes significant healthcare resources. Data from the United Kingdom Prospective Diabetes Study have shown that intensive glycemic control reduces the microvascular complications of type 2 disease and that intensive management of fasting plasma glucose (FPG) levels is insufficient over time to provide such control. Recent studies have demonstrated that lowering postprandial plasma (PPG) glucose levels provides some additional glycemic control and recent epidemiologic data suggest reducing PPG levels may be associated with a reduction in mortality. In patients with type 2 diabetes mellitus inadequately controlled by diet and exercise, nateglinide significantly improved glycemic control compared with placebo; a beneficial effect on both FPG and PPG levels was observed. In active comparator studies, nateglinide has been shown to be as effective as metformin (in pharmacotherapy-naive patients), acarbose and troglitazone in reducing glycosylated hemoglobin (HbA1c) levels. When used in combination with metformin (in patients inadequately controlled on maximum dosages of metformin monotherapy) nateglinide significantly improves glycemic control compared with placebo. In addition, nateglinide has been shown to display pronounced additive effects when added to troglitazone or metformin in patients inadequately controlled by diet and exercise alone. Nateglinide was generally well tolerated in clinical trials. The most common adverse event was hypoglycemia, although the incidence was low in comparison with sulfonylureas. The incidence of hypoglycemia was increased in patients using nateglinide in combination with metformin. By controlling HbA1c and PPG, nateglinide has the potential to provide substantial health and quality-of-life benefits; however, long-term outcome data and validated quality-of-life assessments are lacking. In economic modelling studies, the estimated cost-effectiveness ratios observed with nateglinide were well within the range for therapies considered to be cost-effective. In conclusion, nateglinide is a useful addition to the available treatments for type 2 diabetes mellitus. It significantly improved glycemic control in pharmacotherapy-naive patients as well as in patients not adequately controlled by metformin alone; however, until long-term clinical data become available, nateglinide can only be considered as an adjunct to metformin in patients inadequately controlled on metformin alone in whom PPG levels are elevated. Nateglinide is well tolerated and has low potential to cause hypoglycemia and bodyweight gain.Antihyperglycaemics, Cost analysis, Drug evaluations, Nateglinide, Pharmacoeconomics, Quality of life, Type 2 diabetes mellitus

Book Review

DOI: 10.2165/0019053-200826120-00008Cost-effectiveness, Outcomes-research, Pharmaceutical-services, Pharmacoeconomics