Recent Patents on Endocrine, Metabolic & Immune Drug Discovery - Volume 3, Issue 2, 2009

Deregulation of apoptosis is responsible for diseases that involve defects in the death pathway, such as neoplasias, or in its inhibition, like degenerative processes. Among apoptosis- regulating molecules, a role is emerging for BAG3, a member of the BAG proteins family (BAG1L, BAG1, BAG2, BAG3, BAG4. BAG5 and BAG6) involved in cochaperoning of heat shock proteins. Through its BAG, WW and prolix-rich domains, BAG3 protein can interact with a variety of molecular partners, including Hsc70/Hsp70, phospholipase C-γ and others. It has been recently shown that, in human primary lymphoid and myeloblastic leukemias, thyroid carcinoma and other human tumors, BAG3 expression sustains cell survival and impairs cell response to therapy. This review discusses two patents concerning, respectively, BAG3 and other Hsc70/Hsp70 co-chaperones, namely HspBP-1 and HspBP-2.

Dysfunction of the hypothalamo-pituitary gonadal (HPG) axis may result in a variety of disorders, ranging from precocious puberty to infertility. Current therapies for such disorders have varying degrees of success, and are associated with adverse effects and / or practical limitations. The recent identification of Kisspeptin as a critical regulator of reproduction, may offer a new avenue for therapeutically manipulating the HPG axis. This article provides a synopsis of the role of Kisspeptin and the Kisspeptin receptor in reproduction, with an emphasis on potential areas of its exploitation as a therapeutic or diagnostic tool. This article also reviews some of the recent patents related to the field.

The prevalence of childhood obesity as well as of the obesity-related complications is rapidly increasing worldwide in the paediatric age. Insulin resistance (IR) is a common feature of childhood obesity and a key component of its metabolic and cardiovascular complications which are already present in this age group. NAFLD is the most common cause of hepatic steatosis disease in obese children and adolescents and is a spectrum of liver diseases ranging from simple fatty infiltration of the liver (hepatic steatosis) to steato-hepatitis and fibrosis. The pathophysiology of NAFLD has been described on the basis of a “two-hit model”. The “first hit” is characterized by the effect of IR and subsequent increase of fatty acids in the hepatocytes. The “second hit” is due to the contribution of increased oxidative stress, which promotes hepatic inflammation and fibrosis. On the basis of the continuous progresses in understanding the pathogenesis of NALD, new potentially applicable therapeutic strategies are being developed. Although, at the moment the standard treatment is based on the lifestyle changes, including diet and increased physical activity, several authors postulated the adoption of drugs, which can improve IR and oxidative stress. Pharmacotherapy includes lipid lowering agents, ursodeoxycholic acid, antioxidants and molecules able to improve insulin sensitivity. However, in literature no consensus on the treatment of NAFLD is available, especially in children and adolescents. The aim of this review is to summarize recent patent and what is known about paediatric NAFLD in terms of treatment.

The growing worldwide prevalence of obesity needs urgent attention because the potential morbidity, mortality, and economic tolls have to be avoided. Despite obesity is known as a healthcare issue on an epidemic scale, it remains largely an unsolved medical problem. The successful management of obesity is theoretically possible through lifestyle changes, with diet modifications and increasing physical activity. However, low results by traditional treatments have inevitably prompted interest in the development of effective therapies, including pharmacological interventions and gastrointestinal surgery. As our knowledge of the physiological systems regulating food intake and body weight has considerably increased over the past decade, many studies have underlined the scientific and clinical relevance of potential treatments based on peripheral hormones or central neuropeptides signals. Here we have summarized the complex pattern of the appetite regulation, divided into central and peripheral mechanisms. In the second part of this paper, we have reviewed the currently approved and putative obesity therapies. Up to now only two drugs, sibutramine and orlistat have been approved by the Food and Drug Administration for long term use, but several other medications are currently used to cure severe obesity and many other are developing. Thus, in the last part, we have analyzed recent literature and patents describing new and upcoming molecules. The new anti-obesity drugs under clinical development include agents affecting peripheral and central mechanisms. Further investigations are needed to approve these upcoming therapeutic agents for the treatment of obesity.

Much interest has focused on the newer incretin-based therapeutic modalities for diabetes, especially GLP-1 analogues. While the comparatively older GLP-1 analogs, exenatide and liraglutide, have been discussed extensively in literature, much less is known about the newer GLP-1 analogues in the pipeline. This review focuses on the newer molecules being studied, the newer routes of administration being tried, some recent patents and potential uses for these multifaceted compounds.

Diabetes mellitus occurs when pancreatic β-cell performance is compromised, due to either loss of the β-cell mass and/or decreased β-cell function. The regeneration of β-cells in vivo is providing a novel potential therapeutic approach to replace the β-cells lost by autoimmune destruction in type 1 diabetes; or restore the β-cell mass and β-cell function damaged by the failure of compensation in type 2 diabetes. The data obtained from the rodents indicate that adult β-cells replicate primarily from pre-existing β-cells, rather than from non-β-cell precursors. Furthermore, the β-cell replication is regulated sensitively by specific cellular factors. The positive results from the combination therapy of the gastrin-based, plus biological factors are attracting more attention. The evidences have implied that this might be an important step in curing diabetes, rather than just lowering the blood glucose level by the administration of oral hypoglycemic drugs or the exogenous insulin injection for the patients with diabetes. The present review summarizes the advances and recent patents in the field of β-cell replication in vivo and the regulation of β-cell renewal.

The aim of the work was to evaluate the levels of angiogenin and VEGF in children and adolescents with longstanding diabetes mellitus type 1 (DM1) in relation to the duration of the disease. The study was performed on a group of 64 patients diagnosed with DM1. 52 healthy children and adolescents volunteered as the control group. Patients with duration of diabetes less than 5 years (group 1) were younger, but their age at the onset of the disease was older. Moreover they had lower 24 hour urine albumin excretion as well as angiogenin and VEGF serum levels with regard to the group of patients with longer, exceeding 5 years duration of the disease (group 2). Detailed statistical analysis revealed that the patients with shorter duration and no complications were characterized by a statistically significant lower serum angiogenin and VEGF levels in relation to the patients over 5 years from diagnosis and showing complications (group 2A). Statistical analysis revealed that the group 1 patients without complications were characterized by the highest levels of angiogenin and VEGF in relation to the group 2B patient. Our results suggest that evaluation of pro-angiogenic factors at early stages of diabetes may become an additional prognostic marker when assessing the risk of retinopathy development in children and adolescents with long-standing DM1. Possibly, in future, anti-angiogenic therapy will become a substantial element in prevention of diabetic retinopathy in young patients with long-standing DM1.This review article also discussed some recent patent related to the field.

In 2008, ADA provided new standards of care and recommendations including therapeutic actions favourably affecting health outcomes of patients with diabetes. In this context, Continuous Subcutaneous Insulin Infusion (CSII) becomes a great flexible therapeutic alternative, because of glucose sensors' availability, theoretical support and improved therapeutic decisions. However, there are no conclusive studies on the benefits of CSII in pregnancy. In particular, ‘80’ randomized and controlled trials describe the pregnancy outcomes of few type 1 and type 2 diabetic patients. A recent Cochrane review, including 61 pregnancies concluded that there is no sufficient evidence to support any sort of insulin administration in diabetic pregnancy. Similar conclusions were reported by another review and a meta-analysis of 6 randomized and controlled trials on 213 subjects. No better results were obtained by recent retrospective studies. Doubts exist about CSII timing (before/and or after conception). Poor results are due to the inadequate patients selection, education, and abilities. Multi -centre studies are needed to verify the real utility of insulin pump during pregnancy, considering risks, costs and benefits including quality of life, in order to outline recommendations for an appropriate use. This review article also discussed some recent patents related to the field.

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