Animal models, heart disease

Animal models of disease that might be considered for use in SP shonld be dictated by whether or not they improve predictive value of adverse reactions in patients, bnt of course they may also be valuable/preferred in studies on mechanism of action and efficacy. Scientists may be guided by selection of specific models that are well known to manifest increased sensitivity for adverse reactions in the clinic (e.g., obesity, senility, heart failure, hypertrophy, diabetes). Clinicians already know, and consider in design of clinical trials, many features of subjects (e.g., age, geographical location, sex, somatotype, strain) that inflnence the outcome of smdies. It is likely that diversity of subjects in preclinical smdies is as important as diversity of snbjects in clinical studies. My suspicion is that smdies conducted on one mouse, one rat, one rabbit, one gninea pig, one dog, and one monkey per each of four groups (vehicle, low dose, mid... 

Animal models of diseases, as well as studies in patients with congestive heart failure, liver cirrhosis or renal insufficiency, have shown that prostanoids contribute to normal renal function by regulating vascular tone and normal blood flow (Harris, 2002 Parente and Perretti, 2003). PGE is involved in the regulation of sodium reabsorption, and its inhibition results in sodium retention that can manifest clinically in a variety of ways, such as peripheral edema, increased blood pressure, weight gain, and occasionally deterioration or heart failure. PGI increases potassium secretion and, since it has vasodilatory properties, it increases renal blood flow and glomerular filtration rate (Harris, 2002). 

The disturbance of balance between superoxide and nitric oxide occurs in a variety of common disease states. For example, altered endothelium-dependent vascular relaxation due to a decrease in NO formation has been shown in animal models of hypertension, diabetes, cigarette smoking, and heart failure [21]. Miller et al. [22] suggested that a chronic animal model atherosclerosis closely resembles the severity of atherosclerosis in patients. On the whole, the results obtained in humans, for example, in hypertensive patients [23] correspond well to animal experiments. It is important that endothelium-dependent vascular relaxation in patients may be improved by ascorbic acid probably through the reaction with superoxide. 

As in the case of other cardiovascular diseases, the possibility of antioxidant treatment of diabetes mellitus has been studied in both animal models and diabetic patients. The treatment of streptozotocin-induced diabetic rats with a-lipoic acid reduced superoxide production by aorta and superoxide and peroxynitrite formation by arterioles providing circulation to the region of the sciatic nerve, suppressed lipid peroxidation in serum, and improved lens glutathione level [131]. In contrast, hydroxyethyl starch desferrioxamine had no effect on the markers of oxidative stress in diabetic rats. Lipoic acid also suppressed hyperglycemia and mitochondrial superoxide generation in hearts of glucose-treated rats [132],... 

Animal models have established that infections can induce autoimmune disease. For example, coxsackievirus B3 infection of susceptible strains of mice results in inflammation in the heart that resembles the myocarditis and dilated cardiomyopathy that occurs in humans.28 44 The same disease can be induced by injecting mice with cardiac myosin mixed with adjuvant, thereby reproducing the disease in the absence of virus infection, indicating that an active viral infection is not necessary for the development of autoimmune disease.9 29 44 Likewise, a number of autoimmune diseases can be... 

The transdifferentiation of HSCs into a mature hematopoietic fate (e.g., endothelium) in the heart is less controversial [148]. In animal models of stem cell therapy in ischemic heart disease, the evidence points toward increased neovascularization (with reduced myocardial ischemia) and consequent improvement in cardiac function [149-151]. Bone marrow stem cells may directly contribute to an increase in contractility or, more likely, may passively limit infarct expansion and remodeling. Unfortunately, the limitations of the present animal models leave this question unanswered. 

Of these, omapatrilat is at the most advanced stage of clinical development. It lowers blood pressure in animal models of hypertension as well as in hypertensive patients and improves cardiac function in patients with heart failure. Unfortunately, omapatrilat causes a significant incidence of angioedema in addition to cough and dizziness. Nevertheless, combined inhibition of neutral endopeptidase NEP 24.11 and ACE with this new class of drugs may be a promising approach to treat cardiovascular disease and further clinical trials are underway. 

The antiplatelet/antithrombotic activity of dipyridamole has been demonstrated in laboratory and in animal models, and has been shown to inhibit platelet aggregation and vessel-wall thrombogenesis [9-11]. Dipyridamole has been given either alone or with aspirin in the management of myocardial infarction and stroke. For the secondary prevention of stroke or transient ischemic attack, the drug may be given as a modified-release preparation in a dose of 200 mg twice daily. Dipyridamole administered intravenously results in a marked coronary vasodilation and is used in stress testing in patients with ischemic heart disease [5]. 

There are four gel protein databases of cardiac proteins, established by three independent groups, that can be accessed via the World Wide Web (Table 16.1). These databases facilitate proteomic research into heart diseases containing information on several hundred cardiac proteins that have been identified by protein chemical methods. They all conform to the rules for federated 2-D protein databases (Appel et al., 1996). In addition, 2-D protein databases for other mammals, such as the mouse, rat (li et al., 1999), dog (Dimn et al., 1997), pig and cow, are also under construction to support work on animal models of heart disease and heart failure. 

Appropriate animal models of human heart disease are an attractive alternative for proteomic investigations as human diseased tissue samples can often be compromised by factors such as the disease stage, tissue heterogeneity, genetic variability, and the patient s medical history/therapy. Avoiding any of the above complications when working with human samples can prove to be extremely difficult... 

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