Biomedical subjects
Publications and source records attributed to Sheila A Doggrell.
Recent developments highlighted from the First International Conference in Vascular Medicine, held in Melbourne, Australia, August 26-28, 2005, are in nitric oxide signaling, oxidative stress, homeostasis, the angiotensin-aldosterone system, diabetes, new vessel formation and P-selectin.
From the World Congress on Inflammation, held August 20-24, 2005 in Melbourne, Australia, new targets and new drugs for inflammation of the respiratory system (asthma, allergic rhinitis, chronic obstructive pulmonary disease and cystic fibrosis), inflammatory bowel disease (ulcerative colitis and Crohn's disease), arthritis (rheumatoid and osteoarthritis), atherosclerosis and cancer are discussed.
Despite the use of the statins to lower low-density lipoprotein-cholesterol, leading to major reductions in the mortality and morbidity that is associated with coronary artery disease, considerable mortality and morbidity remains. Increasing high-density lipoprotein (HDL)-cholesterol levels has been associated with reduced coronary artery disease mortality and morbidity in several studies. Inhibition of cholesteryl ester transfer protein (CETP) activity leads to increased HDL-cholesterol. In cholesterol-fed rabbits, antibodies against CETP increased HDL-cholesterol and decreased atherosclerotic lesions. In healthy subjects with mild dyslipidaemia, the CETP inhibitors JTT-705 and torcetrapib increased HDL-cholesterol and decreased low-density lipoprotein-cholesterol. Increasing HDL-cholesterol with CETP inhibitors is a new approach to dyslipidaemia that requires further investigation, especially in patients who have coronary artery disease.
Glucagon-like peptide 1 is an intestinal peptide hormone that is secreted in response to food to regulate the postprandial blood glucose concentration. Exendin-4 is a 39-amino acid peptide that acts as an agonist at the glucagon-like peptide 1 receptor. Synthetic exendin-4 (exenatide) has recently been trialled in patients with Type 2 diabetes taking either metformin alone or a combination of metformin and a sulfonylurea. In both trials, exenatide 5 and 10 microg s.c. was shown to improve glycaemic control, with few adverse events. Exenatide represents a new and useful addition to the medicines used to treat Type 2 diabetes.
The choice of treatment after failure of selective serotonin re-uptake inhibitors in the treatment of depression largely depends on the preferences of the physician. The STAR*D (Sequenced Treatment Alternatives to Relieve Depression) trials set out to rationalise the treatment of depression after the failure of citalopram. When subjects who were unresponsive or intolerant to citalopram were switched to sustained-release bupropion, sertaline or extended-release venlafaxine, remission rates were similar (21, 18 and 25%, respectively). When subjects who were unresponsive to citalopram had sustained-release bupropion or buspirone added to citalopram, there were similar remission rates of 29.7 and 30.1%, respectively. The interpretation of this data are complicated by the lack of placebo groups. One interpretation is that sustained-release bupropion, sertaline or extended-release venlafaxine are equally effective in subjects with major depression after the failure of citalopram, and that sustained-release bupropion or buspirone are equally effective when added to citalopram in subjects with major depression after the failure of citalopram. An alternative explanation is that none of the drugs are effective in citalopram failure, and the responses are the placebo effect.
Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the CNS. In a Phase II clinical trial, natalizumab was shown to reduce the relapses in patients with relapsing MS, without improving the disability score. After 1-year of Phase III clinical trials, natalizumab was approved by the FDA for use in relapsing MS but was withdrawn 3 months later, due to two reported cases of progressive multifocal leukoencephalopathy (PML). The completed clinical trials with natalizumab for relapsing MS have recently been reported. In a trial of 1171 subjects with relapsing MS, natalizumab alone was shown to reduce the relapse rate and lesions, without causing PML. Although natalizumab was also shown to reduce the relapse rates and lesions in patients taking IFN-beta, two cases of PML with natalizumab occurred in these patients. An assessment of patients who had taken natalizumab for 1 - 2 years (approximately 3000), showed the incidence of PML to be 1/1000. A drug that is useful in relapsing MS will be used as a long-term therapy in large numbers of patients. For instance, in the 3 months that natalizumab was registered, 5000 patients commenced taking it. In the author's opinion, large numbers of patients should not be allowed to take natalizumab until its safety has been monitored in the long-term use in a clinical trial environment.
Exenatide has been shown to improve glycaemic control (over 30 weeks) in subjects with Type 2 diabetes. A recent extension study has shown that, in metformin-treated subjects with Type 2 diabetes, exenatide remained beneficial at 82 weeks. For those subjects who completed the study, in addition to the 1% fall in glycosylated haemoglobin (HbA1c) at 30 weeks, there was another 0.2% fall in HbA1c by 82 weeks. The weight loss achieved was a mean of 3 kg after 30 weeks, and this increased to 5.3 kg after 82 weeks in the completer cohort. In another extension study, continued benefit with exenatide was shown in subjects treated with metformin and/or sulfonylureas. For those subjects who completed the study, in addition to the 0.9% fall in HbA(1c) at 30 weeks, there was another 0.2% fall in HbA(1c) by 82 weeks. The weight loss achieved was a mean of 1.6 kg after 30 weeks, and this increased to 2.1 kg after 82 weeks in the completer cohort. The subjects taking exenatide with metformin had a greater weight loss (5.3 kg), compared with those treated with a sulfonylurea (3.9 kg) and those taking metformin and a sulfonylurea (4.1 kg). In conclusion, extension studies have confirmed that exenatide is an exciting new and useful medicine for Type 2 diabetes.
Alcoholism is the third leading cause of preventable mortality and morbidity in the US. In the COMBINE (Combined Pharmacotherapies and Behavioural Interventions) study, the co-primary end points were the percentage of days abstinent and the time to first heavy drinking day after 16 weeks, and 1 year. The biggest difference observed in COMBINE was that seen between combined behavioural intervention (CBI; percentage of abstinent days = 66.6%) and CBI and medical management with placebos (79.8%). This illustrated a major effect of the medical management of nine sessions and/or the placebo pills. Acamprosate had no effect alone or in combination with naltrexone. At 16 weeks with medical management, there were 75.1% of the patients who were abstinent for placebos, and this was improved by naltrexone, CBI, and naltrexone with CBI (80.6, 78.2 and 77.1%, respectively). There was a follow up after 1 year, which showed that, with medical management, the amount of those who were abstinent for placebos was 61.4%, and this was improved by naltrexone, CBI, and naltrexone with CBI (66.2, 66.6 and 67.3%, respectively), but this improvement no longer reached statistical significance. After 1 year, there was no difference between groups in the overall frequency of hospitalisation, emergency treatment for alcohol problems, use of medication for drinking or emotional problems and detoxification. Being part of a study for alcohol dependence is known to increase the percentage of abstinent days. In COMBINE, this percentage was high in the group having medical management and placebo pills, and naltrexone or additional behavioural therapy only had modest additional effects.
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Hyperglycaemia in Type 2 diabetes has a major role in the development of microvascular complications, whereas the dyslipidaemia is the major cause of macrovascular complications. In patients with Type 2 diabetes, activation of PPAR-alpha and PPAR-gamma with the fibrates and glitazones improves dyslipidaemia and increases insulin sensitivity, respectively. Muraglitazar is an agonist at both of these receptors and has been shown to increase high-density lipoprotein cholesterol, decrease triglycerides and improve insulin sensitivity. However, there is also some evidence that muraglitazar has detrimental effects on the cardiovascular system. Before muraglitazar is widely used in the treatment of Type 2 diabetes, more safety testing needs to be undertaken.
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