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Stevenage, United Kingdom

Wierzbicki A.S.,Guys and St. Thomas Hospitals | Viljoen A.,Lister Hospital
Expert Opinion on Biological Therapy | Year: 2013

Homozygous lipoprotein lipase (LPL) deficiency is an ultra-orphan disease associated with increased rates of pancreatitis. Current treatments based on acute plasmapheresis allied with ultra-low fat diets are inadequate as responses to fibrates or other triglyceride-lowering therapies tend to be poor. Alipogene tiparvovec is an adeno-associated virus type I (AAV1) gene therapy using a hyper-functional LPL serine447-stop (S447X) insert administered intramuscularly under general anaesthetic with allied immunosuppression. Treatment results in histological muscle expression of LPL allied with a transient 40% reduction in triglycerides and improvements in postprandial chylomicron triglyceride content. Alipogene tiparvovec is the first possibly curative treatment for LPL deficiency. © 2013 Informa UK, Ltd. Source

No imaging technique is more popular or more in demand than ultrasound. But should it be considered a specialist technique to be employed only by highly trained professionals or as a readily available tool to be used by many? This paper will discuss some of the implications of having ultrasound performed by a range of individuals and will emphasize the importance of training and regulation. Source

Wierzbicki A.S.,St. Thomas Hospital Campus | Hardman T.C.,NICHE | Viljoen A.,Lister Hospital
Expert Opinion on Investigational Drugs | Year: 2012

Introduction: Pre-protein convertase subtilisin kexin (PCSK)-9 is a newly discovered protein involved in intracellular and extracellular regulation of low-density lipoprotein receptor (LDLR) expression. Autosomal dominant activating mutations in PCSK-9 cause familial hypercholesterolaemia whereas inactivating mutations in man reduce LDL cholesterol (LDL-C) and are associated with a decreased lifetime risk of cardiovascular events. Areas covered: As PCSK-9 binds to the LDLR, a number of approaches involving small molecule or peptide inhibition of binding, antibody-mediated inactivation of binding and the use of antisense oligonucleotides are being investigated as therapeutic approaches to lower LDL-C in man. This article reviews the biochemistry and physiology of PCSK-9 and details the efforts made to design novel molecules with the ability to inhibit PCSK-9 activity. Work in animal models has confirmed that reducing PCSK-9 expression can reduce atherosclerosis in mice, rats and primates. Monoclonal antibodies such as REGN-727 and AMG-145 have been shown to reduce LDL-C in patients with familial hypercholesterolaemia already treated with statins or healthy normocholesterolaemic controls. Expert opinion: PCSK-9 inhibition is a potentially interesting novel addition to the armamentarium of LDL-C reducing drugs. Its effects in reducing LDL-C will need to be confirmed to reduce CVD events in large-scale clinical trials. © 2012 Informa UK, Ltd. Source

Viljoen A.,Lister Hospital | Wierzbicki A.S.,Guys and St. Thomas Hospital
Expert Review of Cardiovascular Therapy | Year: 2012

Severe hypertriglyceridemia is associated with acute pancreatitis and can be a manifestation of lipoprotein lipase (LPL) deficiency. It is associated with a spectrum of disorders, ranging from heterozygous LPL deficiency allied with environmental factors to rare severe cases of homozygous LPL deficiency. The genes associated with reduced LPL activity include LPL, its cofactor apoC-2, a controlling protein apoA-5 and the LPL receptor GPI-HBP1. The effects of mutations are exacerbated by environmental factors such as diet, pregnancy and insulin resistance. Treatment of clinical LPL deficiency is by ultra-low-fat diet along with the use of fibrates, omega-3 fatty acids, niacin, statins and insulin-sensitizing therapies, depending on the extent of residual LPL activity. Novel therapies that target lipoprotein particle assembly through the antisense oligonucleotides or by interference with triglyceride-loading microsomal transport protein inhibitors offer new potential options for treating hypertriglyceridemia. © 2012 Expert Reviews Ltd. Source

Wierzbicki A.S.,Guys and St. Thomas Hospitals | Viljoen A.,Lister Hospital
Drug Safety | Year: 2010

Atherosclerosis begins in childhood with the formation of fatty streaks. Early plaques can be found in adolescence and early coronary disease can be found in young adults. It has been suggested that early treatment may lead to great benefits in later life. This article is a narrative review of the role of lipid-lowering drug therapy in paediatric practice.Increased rates of atherosclerosis are known to occur in children with familial hypercholesterolaemia (FH), especially in homozygotes. There is evidence for the efficacy and safety of lipid-lowering therapies in children, particularly with respect to the effects of HMG-CoA reductase inhibitors (statins) on lipids and, to a limited extent, on other surrogate measures of atherosclerosis in patients with FH. Diagnosis of FH and its early treatment are recommended in all guidelines. Lipid-lowering drug therapy is recommended for the treatment of homozygous FH at all ages and from as young as 10 years of age for the treatment of heterozygous FH when there is a family history of very premature coronary heart disease (occurring at age <40 years).Controversy exists about other possible indications. Increased rates of atherosclerosis are seen in autoimmune disorders, including type 1 diabetes mellitus, systemic lupus erythematosus and Kawasakis disease, and in transplant recipients. All evidence in these areas is derived by extrapolation from studies in adults. These disorders can be divided into those for which percutaneous coronary intervention is performed early andor for which drugs used to treat the primary disorder increase the rate of atherosclerosis, and those for which this is not the case. In both cardiac transplantation and Kawasakis disease, increased atherosclerosis can occur as a result of (i) disease-related vasculopathy; or (ii) increased restenosis secondary to interventions. Statins have a good evidence base for reducing rates of re-occlusion following coronary artery procedures, and this justifies their use in these settings. In renal transplantation, statins may have a role to play in patients with persistent dyslipidaemia and additional cardiovascular risk factors. In other disorders, such as type 1 diabetes, the disease process is atherogenic and thus statins may be justified in patients with a long history of disease (>10 years), poor control, and evidence of vascular or endothelial damage or additional cardiovascular risk factors.There is a role for lipid-lowering therapies in children at high risk of atherosclerosis, but the evidence base outside of FH is weak. Lipid-lowering therapy should be prescribed to all children with homozygous or severe heterozygous FH. Based on adult evidence, statin therapy should be considered in patients who have undergone coronary artery procedures or received cardiac transplants, in whom their primary role is to prevent vascular re-occlusion. In diseases associated with a chronic increased atherogenic risk, such as type 1 diabetes, statins should be considered in high-risk cases where additional cardiovascular risk factors are present.At present, the most important need is for trials to be performed in children using accepted surrogate endpoints to define whether lipid-lowering drug therapy is beneficial in this group. © 2010 Adis Data Information BV. All rights reserved. Source

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