Recent Patents on Endocrine, Metabolic & Immune Drug Discovery - Volume 5, Issue 1, 2011

Ghrelin, a peptide hormone predominantly produced by the stomach, is a potent stimulator of growth hormone release, food intake and weight gain. Besides its functions in regulating energy homeostasis, ghrelin has pronounced cardioprotective effects and was shown to improve cardiac performance in chronic heart failure (CHF). The multifunctional nature of ghrelin makes it an interesting pharmacological target for various diseases. Inhibition of ghrelin could be a promising approach in obesity-related disorders, while an enhancement of the ghrelin response is considered beneficial in several pathologic conditions marked by malnutrition, wasting and cachexia, including CHF, cancer, chronic pulmonary disease or chronic infections. In particular, patients suffering from CHF could possibly benefit from ghrelinbased compounds that do not only help to reverse cardiac cachexia - by inducing a positive energy balance - but also enhance the direct cardioprotective effects of ghrelin. This review highlights the role of ghrelin in the regulation of energy balance and cardiovascular function and summarizes the most recent patents, developments and strategies in ghrelin-based pharmacotherapy for the treatment of pathologic conditions associated with obesity, cachexia or cardiovascular dysfunction.

Entamoeba histolytica in culture produces a pentapeptide (MQCNS). This oligopeptide inhibits the in vitro and in vivo locomotion of human monocytes, hence its denomination Monocyte Locomotion Inhibitory Factor (MLIF). The original isolated peptide and its synthetic construct display similar effects, among others, being inhibition of the respiratory burst in monocytes and neutrophils, decrease of Dinitrochlorobenzene (DNCB) skin hypersensitivity in guinea pigs and gerbils, and delay of mononuclear leukocytes in human Rebuck skin windows with inhibition of vascular cell Very late antigen (VLA)-4 and Vascular adhesion molecules (VCAM) in endothelia and monocytes. The MLIF molecular mechanism of action is unknown, but data reveal its implication in Nuclear factor-kappa B (NF-ΚB) and Mitogenactivated protein kinase (MAPK) pathways. This could explain MLIF multiplicity of biological effects. On the other hand, the amebic peptide has been useful in treating experimental amebiasis of the liver. The amebic peptide is effective in reducing inflammation induced by carragenin and arthritis in a Collagen-induced arthritis (CIA) model. Microarray data from experimental arthritis revealed an MLIF gene expression profile that includes genes that are involved in apoptosis, cell adhesion, extracellular matrix, and inflammation/chemotaxis. MLIF could be involved in unsuspected biological factions because there is increasing data on the peptide effect on several cell activities. This review also presents uses of MLIF as described in patents.

G Protein-coupled receptors (GPCRs) are cell membrane proteins that recognize specific chemical signals such as drugs and hormones and transduce these signals into cellular responses by activating G-proteins. As is the case for all newly synthesized proteins, GPCRs are subjected to conformational scrutiny at the endoplasmic reticulum prior to processing and trafficking to the cell surface membrane. Because of this stringent quality control screening mechanism, mutations that result in protein misfolding frequently lead to retention in the endoplasmic reticulum, aggregation or other misrouting and, eventually, to disease. This article reviews some patents and new therapeutic opportunities based on the misfolding and retention of otherwise functional GPCRs that represent promising approaches to correct conformational abnormalities leading to distinct disease states.

Type 2 diabetes is a complex, multifactorial disease resulting from insulin resistance in target tissues and the impairment of insulin secretion from the pancreas. One of the key metabolic actions of insulin is to control blood sugar levels by promoting glucose uptake into adipocyte and muscle cells. This is achieved by activation of a complex signal transduction cascade that stimulates the trafficking of the insulin responsive glucose transporter protein, GLUT4, from specific intracellular sites to the plasma membrane. This review is divided into two major sections. The first section gives an overview of GLUT4 trafficking and the second section focuses on the patents that have been acquired for GLUT4 associated proteins and which demonstrate potential as therapeutic targets for the treatment of diabetes. Inventions in this area include methods and agents to translocate GLUT4 to the plasma membrane independent of insulin and methods to increase the level of GLUT4 in insulin responsive cells.

It has been envisaged that in this century, disorders of the central nervous system will have a significant bearing on the healthcare concerns of the human population worldwide. Such neurological and psychiatric disorders are generally associated with loss of memory, cognitive deficits, impaired mental function etc. Due to the multi-factorial nature of these diseases, modern medicine based psychoactive drugs have met with limited success. Therefore, there is a growing demand for novel products that could target multiple pathways and improve the mental capabilities either independently or in combination with conventional drugs. In the recent times, herbal products based on traditional knowledge have been increasingly used both in developed and developing countries. According to “Ayurveda”, the Indian traditional system of medicine, “medhyarasayanas” represent herbal therapeutics that boost memory, restore cognitive deficits and improve mental function. The current review deals with the components and application of such a traditional herb “Brahmi” that corresponds to two plants, Bacopa monnieri and Centella asiatica. Research evidences clearly indicate that both plants possess neuroprotective properties, have nootropic activity with therapeutic implications for patients with memory loss. The field has witnessed exciting patent activity with most inventions aiming at either (i) improving the methods of herbal extraction or (ii) enrichment and purification of novel compounds from brahmi or (iii) providing novel synergistic formulations for therapeutics in various human ailments. In this review, clinical trials related to the therapeutic properties of brahmi and current patents relevant to the preparation, composition and application have also been included.

The influence of thyroid dysfunction on haemostasis is complex and still not very well understood. Both bleeding tendency and hypercoagulable states have been reported. In this article, we attempt to discuss the possible relationship between thyroid dysfunction and secondary haemostasis and fibrinolysis. After the analysis of the recent literature, we conclude that thyroid dysfunction is associated with alterations in fibrin generation and fibrinolysis. Most of the evidence suggests that hyperthyroidism is associated with impaired fibrinolysis and enhanced coagulation. Although, former studies proposed that there was an increase in fibrinolytic activity in hypothyroidism, increasing number of recent reports advocated the opposite. We believe that further prospective comprehensive clinical studies involving large numbers of patients either with overt or subclinical thyroid dysfunctions should be performed to clarify the effect of thyroid dysfunction on secondary haemostasis and fibrinolysis. Recent important patents focusing on coagulation and thyroid dysfunction are also discussed in this review.

Male patient 24 years old with a pituitary microadenoma and mental and behavioural disorders due to multiple drug use and use of other psychoactive substances (cocaine, cannabis and alcohol) were treated with haloperidol (dopamine receptor blocker) 10 mg daily. In the last control, the patient presented mammary hypertrophy; laboratory testing and brain magnetic resonance imaging (MRI) was performed, reporting the presence of a pituitary microadenoma syndrome with hormonal alteration (Prolactin levels 28.4 ng/ml). Haloperidol, carbamazepine and levomepromazine were then discontinued. He was started on aripiprazole 15 mg po daily for 4 days; the dosage was then increased to 30 mg po daily, with Valproic Acid 500 mg po tid. After 3 weeks on aripiprazole, the mammary hypertrophy that had increased in the patient had resolved. After 10 weeks follow up of prolactin revealed a normal level, at 4.33 ng/ml. Insomnia, aggressiveness, irritability, visual, tactile and auditory hallucinations remained absent after treatment with aripiprazole which is not a first line drug in multiple drug use patient with psychosis. We also consider the correlation of drug use in patient with psychosis, haloperidol treatment, pituitary microadenoma syndrome, hyperprolactinemia, and dopamine D2- receptor partial agonist aripiprazole treatment. This article also summarizes some relevant patents.

This paper reviews recent patents and development related to bromocriptine and other dopaminergic agents, being used or suggested for use in the management of diabetes. The article discusses the contribution of dopaminergic pathways to glucose, energy and weight homeostasis. The mechanism of action of bromocriptine, its pharmacological properties, efficacy, safety and tolerability are assessed. The article also covers recent patents which may be utilized to improve the efficiency and tolerability of dopamine-based therapy in diabetes mellitus.

Type 2 diabetes is increasing in prevalence and causes a significant health care burden due to associated microvascular and macrovascular complications. Type 2 diabetes is diagnosed by clinical findings of hyperglycemia and laboratory confirmation of elevated plasma glucose. Initial therapy includes diet and exercise, followed by the use of oral hypoglycemic agents and potentially subcutaneous insulin injections. Of the oral hypoglycemic agents currently available, metformin is the first-line choice. Recently, new adjunct therapies have been introduced that can improve glycemic control, although the long term effects on modifying the disease outcome in terms of diabetes complications remain to be seen. A review of the mechanism of action of current, non-insulin therapies will be presented. This review article will also discuss recent patents related to the field.