Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents) - Volume 10, Issue 2, 2010

Obesity, hypertension and obesity-related hypertension are growing health problems. Hypertension is an important risk factor for cardiovascular disease (CVD), particularly in patients with obesity, diabetes, metabolic disease, or end-organ damage. Obese subjects are frequently associated with diabetes, metabolic disease, and end-organ damage (i.e. end-stage renal damage). An integrated cardiovascular risk management approach is being adopted: aggressive blood pressure (BP) control is important in patients with high CVD risk, and well-tolerated antihypertensive agents with protective benefits beyond BP lowering are advantageous. The identification and management of these risk factors is an important part of the overall management of hypertensive patients. Because obese hypertensive patients are more predisposed to target organ damage, stringent targets for blood pressure control have been set in clinical guidelines, however clinical trial and real-life evidence suggest that these targets are difficult to achieve. In order to attain optimally reduction in the risk for cardiovascular events in patients with obesity-related hypertension, optimal blood pressure control along with comprehensive lifestyle modification for weight loss is required. The most important and difficult aspect in controlling obesity, however, is avoiding weight regain. Anti-obesity pharmacological treatments may help to lose weight and maintain weight loss. It is widely recognized that stimulation of the renin-angiotensin system (RAS), heightened sympathetic nerve activity and insulin resistance (or hyperinsulinemia) relate to obesity-related hypertension. Recently, many clinical and epidemiological studies have shown that angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) are highly efficacious, persistent, well-tolerated antihypertensive agents, with additional benefits in obesity-related hypertension, cardiovascular pathogenesis, end-organ damage, and in diabetes, or metabolic syndrome due to those cardio- and renalprotective effects. Most patients with obesity-related hypertension are very resistant to the control of hypertension and frequently require two or more types of medications to achieve their BP goals. Therefore, other antihypertensive drug classes, such as the centrally acting imidazolin receptor agonists, which inhibit sympathetic overflow from the brain, and calcium channel blockers, are frequently used to control resistant hypertension. The purpose of this article is to provide the current findings on pharmacological anti-obesity treatments and antihypertensive treatments in obesity, obesity-related hypertension.

Obesity is a major risk factor for hypertension, cardiovascular disease development and diabetes mellitus, and represents a growing worldwide health problem. Several epidemiological studies have shown a high prevalence of cardiovascular complications and mortality in obesity and metabolic syndrome, type-2 diabetes or hypertension. For at “risk populations” predisposed to target organ damage, stringent targets for blood pressure control, dyslipidaemia, and glycaemia have been set in clinical guidelines, however clinical trial and real-life evidence suggest that these targets are difficult to achieve and sustain. The first line of treatment for hypertension, metabolic syndrome and diabetes associated with obesity is weight loss with lifestyle modification, such as a low caloric diet and exercise. An alternative for those with higher BMI or comorbidities is bariatric surgery. Perhaps the most important, difficult aspect in controlling obesity, however, is avoiding weight regain. Recently, anti-obesity drugs (Orlistat, Sibutramine, and Rimonabant) have been developed to help a weight loss program and also for maintenance of weight loss, but the precise effects on blood pressure and neurohormonal parameters have not been fully clarified and side effects, particularly with rimonabant and sibutramine, have led to their use being curtailed. The purpose of this article is to discuss the current findings on pharmacological anti-obesity pharmacological treatments.

Obesity is an escalating global health problem and established cardiovascular risk factor for the development of cardiovascular and metabolic diseases. Leptin derived from the adipose tissue acts centrally to suppress appetite and increase energy expenditure, therefore leptin resistance is considered as an important mechanism for the onset and maintenance of obesity; Leptin analogues as well as leptin receptor blockers have been candidates for the treatment of obesity, however clinical trials in obese populations have yielded variable results. Given specific circumstances in obese subjects could optimize the beneficial actions of the hormone and minimize its deleterious effects. In this review, human recombinant leptin (pegylated polyethylene glycol recombinant human leptin (PEG-OB) and recombinant methionyl human leptin (r-metHuLeptin) is developed to control resistant and morbid obesity will be discussed.

Multiple abnormalities in hemodynamics, endocrine factors and adipocytokines are involved in pressor mechanisms of obesity-related hypertension. These abnormalities induce insulin resistance, which plays a central role in the mechanism leading to blood pressure elevation. Thus, in addition to body weight control, selection of pharmacological agents that improve insulin resistance is important for treatment of patients with obesity and hypertension. Although angiotensin receptor antagonists (ARBs), angiotensin-converting enzyme inhibitors (ACEIs), α-adrenoceptor blockers, and Ca2+-channel antagonists have been shown to improve insulin sensitivity in hypertensives, ARBs and ACEIs are mainly selected for this purpose. Beneficial effects of ARBs in obesity-related hypertension have recently been confirmed in Japanese subjects by the CASE-J trial.

Obesity, hypertension and obesity-related hypertension are growing health problems. Indeed, hypertension is an important risk factor for cardiovascular disease development, particularly in patients with obesity, diabetes, and metabolic disease. Obese subjects frequently present with hypertension, diabetes mellitus, metabolic disease, and end-organ damage (i.e. end-stage renal damage). In such patients, an integrated cardiovascular risk management approach should be adopted with aggressive blood pressure control being important in patients at high cardiovascular risk. The use of welltolerated antihypertensive agents with protective benefits beyond blood pressure lowering is advantageous. The identification and management of these cardiovascular risk factors are an important part of the overall management of hypertensive patients. Given that patients with obesity or metabolic syndrome are more predisposed to target organ damage, stringent targets for blood pressure control have been set in clinical guidelines; however clinical trial and real-life evidence suggest that these targets are difficult to achieve. The first line of treatment of obesity and metabolic syndrome is weight loss with a lifestyle modification, such as low caloric diet and exercise; however it is difficult to achieve and maintain weight loss. In severe cases, bariatric surgery may be an option, although whether surgery is associated with long term significantly sustained blood pressure reduction is problematic. Sympathetic nervous system activation and insulin resistance are recognized as being important in the pathogenesis of blood pressure elevation in essential hypertension, obesity and the metabolic syndrome. Angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs), which are known of the favorable effects on insulin resistance have therefore been widely used. Recently, several clinical and epidemiological studies have shown that the centrally acting imidazolin receptor agonists which inhibit sympathetic overflow from the brainstem, are highly efficacious, persistent, and well-tolerated antihypertensive agents. Additionally, imidazoline receptor agonists, such as moxonidine or rilmenidine, have been shown to exert beneficial effects not only on blood pressure, but also lipid (reducing free fatty acids) and carbohydrate metabolism (improving glucose tolerance), and neurohormonal parameters (norepinephrine, leptin). Given these additional benefits imidazolin receptor agonists may be a preferable treatment for obesity-related elevation in blood pressure and exert beneficial effects on metabolic and cardiovascular pathogenesis and end-organ damage. The topic of this chapter is central sympathetic nervous inhibition as a treatment for obesity-related hypertension with a particular focus on the possible use of “imidazoline receptor agonists”.

Overweight and obesity are growing global health problems. The prevalence of hypertension and diabetes mellitus, frequently coexisting with obesity is increasing drastically, with all three (obesity, hypertension and diabetes) being strong risk factors for cardiovascular morbidity and mortality. In order to optimally reduce the risk for cardiovascular events in patients with obesity-related hypertension, optimal blood pressure control along with comprehensive lifestyle modification is required. Obesity and hypertension are characterized by elevated sympathetic activity as well as insulin resistance and the reninangiotensin- aldosterone system (RAAS) for the onset and development. Importantly, these characteristics, themselves, are one of the cardiovascular risks. Therefore, pharmacological treatments should be selected from favourable effects on elevated sympathetic nervous system activity, insulin resistance and stimulated RAAS. Current data suggests that angiotensin- converting enzyme inhibitors (ACE inhibitors) or angiotensin receptor blockers (ARB) with or without a diuretic are recommended, because of their cardio- and renal-protective effects and favourable effects on insulin resistance and elevated sympathetic nervous activity. Most patients with obesity-related hypertension, however, are very resistant to control hypertension and frequently require two or more types of medications to achieve blood pressure goals. Several epidemiological (i.e. V-Heft III, ACCOMPLISH study, PRAISE study, PRAISE-2 study) and clinical studies have shown that calcium channel blockers (CCBs) are favourable for cardiac risk with neutral or ameliorative effects on insulin resistance and elevated sympathetic nervous activity.

The metabolic syndrome is characterized by visceral obesity, insulin resistance, Type 2 diabetes, dyslipidemia and hypertension. All these disturbances are also typically associated with cortisol hyperactivity, such as Cushing s syndrome. Therefore, it seems worthwhile to consider increased cortisol activity in the metabolic syndrome, despite normal circulating levels, to be an important pathogenetic mechanism. Thirty women, 49-65 yr old, with visceral obesity, insulin resistance and Type 2 diabetes were treated with ketoconazole 400 mg daily, in order to down-regulate cortisol activity, in a 3-month randomized, double-blind, placebo-controlled trial. The insulin resistance was evaluated with an euglycemic, hyperinsulinemic glucose clamp. Body fat was assessed from total body potassium. During the study, insulin resistance improved in the ketoconazole-treated group as compared to the placebo-treated one (p<0.05). Total cholesterol (p<0.05), fasting glucose (p<0.05) and HbA1c (p<0.05) levels decreased, whereas serum triglyceride levels and insulin concentrations were unaffected by the ketoconazole treatment. Systolic (p<0.05) and diastolic (p<0.05) blood pressure decreased in the ketoconazole treated group. Body fat was unchanged in both groups. Furthermore, liver AST (p<0.05), ALT (p<0.05) and ALP (p<0.05) decreased in response to ketoconazole treatment. This study has demonstrated that a down-regulation of cortisol secretion can favorably affect most of the multiple risk factors associated with the metabolic syndrome. This includes improvement in insulin resistance, glucose homeostasis, total cholesterol, blood pressure and hepatic steatosis.

The liver has a central role in glucose homeostasis. In turn, glucose-induced signals modulate the transcriptional regulation of genes involved in the glycolysis and lipogenesis pathways and could favour fatty acid storage in the liver. The prevalence of hepatobiliary diseases is increased in patients with diabetes mellitus. Type 1 diabetes is associated with a hepatic form of microvascular disease (diabetic hepatosclerosis), hemochromatosis and autoimmune hepatitis. Type 2 diabetes is associated with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) whose prevalence increases with multiple components of metabolic syndrome. Hepatitis C virus infection has been reported to be associated with and predispose to diabetes mellitus. Silibinin or silybin is a flavonoid derived from Silybum marianum and known to have hepatoprotective, anti-carcinogenic and anti-inflammatory effects. Silymarin is a standardised extract of four polyphenolic flavanolignans (silybin, isosilybin, silydianin and silychristin) from the seeds of Silybum marianum; it possesses a potent scavenging capacity of oxidizing free radicals whose mechanistic aspects have been extensively evaluated. This single herbal drug formulation is used for hepatoprotection although recent evidence in carbon tetrachloride- induced cirrhotic rats suggests that chronic silymarin treatment might compromise the hemodynamic endothelial nitric oxide synthase activity. In order to enhance silymarin bioavailability flavonoid molecules have been converted into lipid-compatible molecular complexes, phytosomes. A new silybin-phosphatidylcholine-Vitamin E complex, characterised by elevated oral bioavailability and lipophilicity, was effective on rat hepatic fibrosis induced by dimethylnitrosamine administration and by bile duct ligation. The complex has been suggested as a complementary approach to the treatment of patients with chronic liver damage. The manuscript provides a review of literature on this topic and discusses the potential usefulness of the complex to prevent/treats liver disease in diabetes as well as contraindications.

Decompensated cirrhosis from hepatitis C virus (HCV) genotype 1 is the leading indication for liver transplantation in the United States, accounting for nearly 50% of all liver transplants. Recurrent HCV is universal after liver transplantation in patients viremic at the time of transplantation and leads to cirrhosis in up to 30% of patients by five years. Once cirrhosis develops, the risk of hepatic decompensation is 42% per year. This has led to recurrent HCV emerging as an important yet controversial indication for liver retransplantation and a renewed interest in the role of anti-viral therapies. Since the first report of interferon for recurrent HCV treatment in 1996, there have been several reports in the literature of interferon-based therapies for this silent epidemic. However, these studies are limited by a paucity of randomized controlled trials. Despite encouraging results with pegylated interferon and ribavirin in the non-transplant HCV population, these findings have not translated to transplant recipients where viral eradication is frequently unsuccessful (<40%). Although stimulating factors are often used to treat the side effects of anti-viral therapy, they are expensive and their use remains controversial. Rejection due to anti-viral therapy, although rare, continues to be a significant concern. Despite successful HCV eradication in a small percentage of patients, progressive cryptogenic fibrosis can still develop leading to hepatic decompensation requiring retransplantation. The lack of effective therapies, severe side effects and reports of hepatic decompensation despite HCV eradication raises the question of whether recurrent HCV genotype 1 should be treated with interferon-based therapies. Clinical trials of newer antiviral medications are urgently required in these patients who are at risk of rapid development of cirrhosis.

The osteoclast is the unique bone-resorbing cell that executes its duties by tight attachment to the bone, synthesis and secretion of hydrochloric acid and powerful proteases, internalization of extracellular bone matrix degradation products, and efficient migration along the bone surface. These energy-consuming activities are carried out rapidly during its short life span. An overview of osteoclast survival and bone-resorbing activity, which are critically regulated by various intracellular signaling pathways, is provided. We also discuss about the roles of several Bcl-2 family members involved in osteoclast function. While there is certainly evidence for the involvement of Bcl-2 family proteins in cell survival, we believe that some of them play important roles in osteoclastic bone resorption. The authors' insights into the regulation of apoptosis and activity of the osteoclast will provide valuable information about therapeutic approaches for the treatment of hyper-resorptive skeletal diseases.

Mesenchymal stromal cells (MSCs) represent a cell population which displays adherent properties, be able to self-renew and have multilineage differentiation capabilities. Recently, it is found that MSCs can exert strong immunomodulatory function in numerous studies. Overall, MSCs can exert a suppressive function on nearly all the cells in the whole immune system, including T lymphocytes, B lymphocytes, natural killer cells and dendritic cells, yet they can also play a positive role in the proliferation and the differentiation of some kind of immune cells. So far there are several mechanisms considered to be responsible for the immune regulatory function of MSCs, for example, indoleamine 2, 3, - dioxygenase (IDO) -induced depletion of tryptophan from the lymphocyte environment, the secretion of prostaglandin E2 and matrix metalloproteinases (MMP), the expression of insulin-like growth factor (IGF)-binding proteins, inducible nitric oxide synthase (iNOS), human leukocyte antigen-G (HLA-G) protein and the recruitment of regulatory T cells. Thus MSCs' immunosuppressive properties encourage a possible use of these cells to therapy immune disorders. This paper will review the MSCs' impact on the generation, differentiation and function of the immune cells, as well as the underlying mechanisms