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An overview of Therapeutic Advances

6th September 2002 Posted on: 24 Sep 02


This week’s TherapeuticAdvances focuses on new targets for cardiovascular disease. In particular angiotensin receptors (which also feature in our recent erectile dysfunction report) and PPAR have both emerged as candidate targets for myocardial infarction. Like PPAR ligands, a second transcription factor binding protein in the news is SREBP, which is being advanced as a hypolipidemic and an insulin sensitizer. Crossing into airway diseases we bring news of an exciting target for asthma and maybe COPD, ADAM33…and finally, "Focus on CNS Disease" reports on advances in antidepressants. In this weeks edition: Cardiovascular disease: New targets, new hopes Angiotensin II receptor antagonists have gradually been cutting into the cardiovascular market. Current global sales are around $2 million and continue to increase by about 35% per year and the identification of additional indications for this class is appealing to companies wishing to further boost sales. In our recent report "Male and female sexual dysfunction: Blockbuster indication for multiple pharmacological targets" (click here for more), we analyze the potential that angiotensin II receptor antagonists, as well as a host of other therapeutic classes more traditionally associated with cardiovascular disease may have in the treatment of sexual dysfunction. Likewise there is also considerable proof of concept to support the use of angiotensin receptor ligands as treatments of anxiety, depression and Alzheimer's disease (click here for more). In the "Focus on Cardiovascular Diseases" section of this week's TherapeuticAdvances we highlight reports that angiotensin II type 1 receptor antagonists are able to improve cardiac function and reduce cardiac hypertrophy following congestive heart failure. More than one million new and recurrent cases of coronary attack occurred in the US in 1998. Forty percent of these patients died, making coronary heart disease the single leading cause of death in America. Improved therapeutic options for the treatment of patients who have suffered myocardial infarction are therefore required ( see "Heart/Cardiovascular disease 2002" for an analysis of pharmaceutical opportunities in this area). The possibility that angiotensin II type 1 receptor antagonists may not only reduce hypertension, a key risk factor for myocardial infarction, but may also offer increased hope to victims when infarction does occur therefore represents a significant step forward in the treatment of cardiovascular disease. A second target that has recently been reported to be crossing into the field of cardiovascular therapeutics is the peroxisomal proliferator-activated receptor (PPAR). This ligand-activated transcription factor regulates gene expression in response to various mediators and has been extensively studied in relation to diabetes with the result that a number of PPAR activators are now marketed for this condition. In addition to reducing the development of insulin resistance, PPAR ligands are able to limit atherosclerosis and may therefore be of use in the prevention of myocardial infarction. Most recently a number of studies have been published reporting the ability of PPAR ligands to limit the effects of myocardial infarction. For example the PPAR-alpha agonist, fenofibrate, reduces myocardial infarction size and improves post-ischemic contractile dysfunction in a mouse model. More recently researchers from the William Harvey Research Institute have extended these findings showing that various distinct PPAR-alpha and –gamma ligands were protective in a rat model of myocardial infarction. As with angiotensin targets, this data is particularly exciting since it suggests that PPAR ligands both protect against and treat the consequences of myocardial infarction. [for further details of these and other projects log on to TherapeuticAdvances] SREBP: In the footsteps of PPAR There is a strong relationship between obesity and diabetes leading to the suggestion that this co-morbidity was related to insulin resistance, leading to the identification of the insulin resistance syndrome. It is estimated that this syndrome affects 70 to 80 million Americans and is characterized by a failure of insulin to stimulate glucose utilization and uptake into tissues. Considerable attention has been paid to the development of molecules able to reduce insulin resistance ( see our recent report "Targeting links between obesity and diabetes) culminating in the development and launch of PPAR ligands. Sterol regulatory element-binding proteins (SREBPs) represent a second class of transcription factors that are regulated by metabolites and nutrients, insulin, leptin, growth factors and inflammatory signals. GSK researchers are developing a new class of compounds that directly binds to the SREBP cleavage-activating protein (SCAP). This series is currently being developed as new class of hypolipidemic drugs. German researchers have recently proposed that SREBP-1 might play a role in the development of cellular features belonging to lipid toxicity and possibly insulin resistance, and these findings therefore support the potential of SREBP-1 modulators for the treatment of diabetes as well as hyperlipidemia. Improved treatments of depression Mental disorders affect 44.3 million Americans in a given year. According to analysts the current global CNS therapeutics market is estimated at $40-55 billion, accounting for around 15% of the total global pharmaceuticals market. From a geographical perspective, the US accounts for about two-thirds of this revenue. Affective disorders (including depression) and anxiety are amongst the 10 leading causes of disability in the US and other developed countries, affecting 9.5% and 15% of the US population respectively. Due to the size of the CNS market and the inadequacies of currently available products the pharmaceutical industry continues to place considerable emphasis on the development of new approaches to indications such as anxiety and depression ( our recent feature "CNS 2002" for a full analysis of this therapeutic area). Other than side-effects one of the major problems associated with current treatment options in speed of onset. This can be a serious problem in depressed and suicidal patients and there is therefore a clear need to develop new treatments of depression that are related to novel targets ( click here for examples) or by improving existing treatments. Spanish field-leaders have adopted the latter approach and have made progress in the improvement of 5-HT reuptake inhibitors by developing molecules that have additional affinity for the 5-HT1A receptor. These molecules are amongst the first to combine such activities, and by doing so target the very reason for the slow onset of current reuptake inhibitors. Their further development thus offers excellent therapeutic and commercial opportunities for improved treatment of depression or anxiety. ADAM, set to revolutionize airway therapeutics The airway is the focus of two highly prevalent diseases, COPD and asthma, both of which have a strong inflammatory component. Hence numerous aspects of inflammation are being investigated as possible targets for improved treatment (see for example "Therapeutic and pharmaceutical approaches to COPD" - click here for access). In the click here "Focus on Airways Disease" section of this week's TherapeuticAdvances we focus on the ADAM family of membrane-anchored proteins as one such target. This family is involved in a number of functions including the shedding of cell-surface proteins such as cytokines and cytokine receptors and may therefore be implicated in the pathophysiology of diseases such as asthma. At the beginning of 2002, Japanese researchers reported the cloning of a novel member of the ADAM family, ADAM33, and further research has shown that this protein is most highly expressed in the adult brain, heart, kidney, lung and testis. This expression profile implicates ADAM33 in airway inflammation. Most recently a collaboration of researchers at Genome Therapeutics, the University of Southampton and Schering-Plough Corporation linked ADAM33 to the pathophysiology of asthma. Although environmental factors such as allergen exposure are risk factors in the development of asthma, both twin and family studies point to a strong genetic component. To date, linkage studies have identified more than a dozen genomic regions linked to asthma. In their study these researchers identify ADAM33 as a putative asthma susceptibility gene. Thus the role of ADAM proteins in the regulation of inflammation, the expression profile of ADAM33 and its possible etiological/hereditary role in asthma all point to this particular ADAM protein as a target for airway disease. Please remember that you can learn more about the publications mentioned above by logging on to TherapeuticAdvances. This is completely free and without obligation, so why not click the link and pay us a visit.

Dr Jon Goldhill

Last updated on: 27/08/2010 11:40:18

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