Recent Patents on Endocrine, Metabolic & Immune Drug Discovery (Discontinued) - Volume 2, Issue 2, 2008

Hyperglycemia activates several signaling pathways associated with vascular complications in diabetes. Hyperfunction of the diacylglycerol - protein kinase C (DAG-PKC) pathway can lead to enhanced vascular permeability, endothelial cell activation and expression of leukocyte adhesion molecules, altered blood flow and abnormal growth factor signaling. One of the most important approaches aimed at modulating these adverse effects involves the inhibition of PKC, and several inhibitory compounds have been proposed including ruboxistaurin (Eli Lilly & Co.), PKC412 and PKC412-A (Novartis Pharmaceuticals). Other patents with similar function has also been proposed such as substituted pyrrolines kinases inhibitors (US200698710B2; US2006020576A1; WOO4094422A1; US2006987110) modulation of angiogenesis (W007035782A2; US20070141040A1). This present approach intends to modulate of angiogensis by the inhibition of PKC beta as an monotherapy or in combination with other antioangiogenic compounds. Some of these compounds are currently tested in a clinical trial while other are on intensive investigation. This brief review considers therapeutic strategies with new drugs and/or new approaches using PKC inhibitors to treat diabetic complications.

Endothelial dysfunction represents an important pathway thereby cardiovascular risk factors promote the development and progression of atherosclerosis. Hypothyroidism is associated with an increased cardiovascular risk, and the assessment of endothelium function is recognised an effective tool for the detection of evidence of preclinical cardiovascular alterations. Both vascular smooth muscle cells and endothelium play pivotal roles in modulating vascular tone and both are potential targets of thyroid hormone action. The pathogenesis of the association between endothelial dysfunction and hypothyroidism is complex and still not well established. The presence of traditional and emerging risk factors may contribute to the development of endothelium impairment, generating a chronic state of injury that triggers abnormal endothelial response. Levothyroxine replacement therapy is currently used for restoring euthyroidism and improving cardiovascular risk of hypothyroid patients. The decision to treat patients with subclinical hypothyroidism should depend on the presence of risk factors, rather than on a TSH threshold. However, the actual effectiveness of thyroid hormone substitution in reducing the risk of cardiovascular events, especially in subclinically hypothyroid patients, remains to be elucidated. Large multicenter, placebo-controlled prospective trials are necessary to address the issue. The article also discusses recent patents in this field.

Metabolism is one of the most important physiological functions. Resting energy expenditure, physical activity and diet are the main factors of total metabolism but the contribution of these components to total energy expenditure may be significantly changed with chronic inflammatory diseases such as rheumatoid arthritis (RA). RA is a disease that alters normal metabolism due to the overproduction of pro-inflammatory cytokines and may lead to rheumatoid cachexia. This review focuses on the individual components of total energy expenditure and discusses how physical activity and diet may influence resting metabolism both in the healthy population as well as patients with RA. Moreover, information is provided regarding the available patents (i.e. equipment and prediction equations) that may be used in order to predict metabolism in the normal population and RA patients.

Obesity is a disease with an acknowledged high metabolic and cardiovascular risk, however, only recent studies demonstrated that the dietary treatment of obesity consisting of lifestyle modification programs may be successful in the long run. As for any therapeutic procedure, the dietary hypocaloric treatment of obesity has results and objectives to be verified and surveillance is needed as far as it concerns safety and tolerability. The epidemic of obesity is spreading to impressive levels in the western world; therefore, the treatment of obesity must be cost-effective in order to reach as much people is possible, even for the aspects relative to the follow-up. Unfortunately, there are not significant official guidelines at this regard. In this article, we report the procedures of follow-up as presented in the recent long-term clinical trials that demonstrated the efficacy of the treatment of obesity. Recent patent related to the field are also discussed.

Vitamin A is an important fat soluble vitamin with multiple physiological functions such as vision, growth, reproduction and gene regulation. Vitamin A exists in three physiologically active forms known as vitamers. These are retinol (alcohol), retinal (aldehyde) and retinoic acid (acid). The retinol and retinaldehyde (RALD) perform all the functions, whereas retinoic acid (RA) can perform all the functions of vitamin A except vision. Retinoids are a broad group of small vitamin A-derived natural and synthetic compounds with varied physiological functions. Vitamers of vitamin A and retinoids exert their action through the activation of transcription factors belonging to the retinoic acid receptors (RAR) and retinoid X receptors (RXR). Each of these receptors have three sub families namely α, β & γ, whose expressions vary in different tissues. Of late, RA is shown to play a role in adipocyte differentiation (adipogenesis) as well as adipose tissue loss through apoptosis, thereby determining adiposity in mammals. The importance of retinoids is mainly because of their therapeutic usage in several dermatological disorders and cancers. The most common side effect of this treatment is dyslipidemia. Hence, the purpose of this review is to bring about the molecular mechanisms involved in the regulation of adiposity/obesity, specifically by vitamin A (retinol & its metabolites) in normal and genetically obese rodent models and associated changes in lipid and lipoprotein metabolism by vitamin A and retinoids and also highlighting some of the important patents aimed at containing the problem of abnormal lipid metabolism.

Gestational diabetes mellitus is a common disorder which is defined as any degree of glucose intolerance with onset at, or first recognized during pregnancy. Women with gestational diabetes are at greater risk for many adverse pregnancy outcomes and maternal or fetal mortality. We tried to conduct the cumulative experience regarding the management of the disease, especially emphasizing the novel therapeutic approaches like new types of insulin preparations, oral hypoglycemic agents and herbal drugs or supplements. In this review important recent patents are also discussed.

One of the causes of failure to achieve target HbA1C in type 2 diabetes mellitus is delay in starting insulin .The standard insulin fails in large number because soluble insulin used for postprandial glucose control does not have a fast enough onset of action ; it needs to be given 30 and 45 minutes before meals ,and has an inappropriately prolonged duration of action, while the longer-acting zinc formulations do not have the long duration of action required of a basal insulin , even with biphasic human insulin. Biphasic insulin analogs allows delivery of both basal and prandial insulin in 1 injection that can be administered closer to mealtime, and produce greater reductions in the magnitude of postprandial glucose excursions than biphasic human insulin with less incidence of major hypoglycemia. The data in this review discuss related recent patents and highlights the importance of biphasic insulin analogs in the management of type 2 diabetes mellitus.

Parkinson's disease (PD) is an age associated neurodegenerative disease clinically characterized as a movement disorder. Till date there have been several treatment options for PD involving either surgical or pharmacological approaches. Levodopa (L-dopa) therapy has been the most popular pharmacological treatment for PD. But the development of motor fluctuations and dyskinesias in chronic L-dopa therapy has prompted the utilization of alternative drugs including dopamine receptor agonists, anti-cholinergic medications, monoamine oxidase-B inhibitors, catechol-Omethyl transferase inhibitors and amantadine which constitute the “L-dopa-sparing strategies”. Recently, there have been proposals regarding the utilization of coenzyme Q10, creatine and minocycline as pharmacological options. Although, most of the existing therapies are intended to provide symptomatic relief, their neuroprotective ability has not been completely substantiated in humans. In this review, the existing therapies of PD with their shortcomings are discussed and some of the recent patents that could open up newer options for PD therapy are highlighted.

Full text available