Recent Patents on Endocrine, Metabolic & Immune Drug Discovery - Volume 4, Issue 3, 2010

Polysaccharides are receiving increased attention due to their clinical applications in tissue engineering, vaccine development, nutritional supplementation and antimicrobial biopolymer engineering. The most abundant polysaccharides include fungal cell wall components chitin and β-1,3-glucans. Recent evidence has shown that these polysaccharides modulate airway inflammation, making them the basis of several drug discovery platforms. Small to intermediate chitin fragments (< 70 μm) are protective in allergic inflammatory models, skewing T cell immunity towards Th1 responses, and reducing the production of Th2 cytokines. As such, chitin prevents the development of the quintessential features of asthmatic disease including chronic airway inflammation, airway hyperresponsiveness and pathological remodeling changes in mouse models of allergy. In contrast, the in vivo effects of β-glucans in animal models of airway inflammation are often contradictory, and the number of human studies is limited. β-1,3-glucans are both proand anti-inflammatory, preventing and enhancing allergic inflammation depending on the preparation, purity and species origin of the β-glucans. This review summarizes recent studies of chitin and β-glucans in models of atopy and airway inflammation and examines the possible reasons for the apparently contradictory observations. Recent relevant patents are also highlighted.

The central nervous system (CNS) barriers are composed of blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (B-CSFB). The BBB and B-CSFB are a highly specialized brain endothelial and epithelial structure of the fully differentiated neurovascular system. These barriers separate components of the circulating blood from neurons. Moreover, the BBB and B-CSFB maintain the chemical composition of the neuronal “milieu,” which is required for the proper functioning of neuronal circuits, synaptic transmission, synaptic remodelling, angiogenesis, and neurogenesis in the adult brain. Hematoencephalic barrier breakdown, due to disruption of the tight junctions, alters transport of molecules between blood and brain and vice versa, causes an aberrant angiogenesis, vessel regression, and inflammatory responses. Megalin is a multi-ligand endocytic receptor expressed in the choroid plexus epithelium and in the brain-endothelial cells, playing a central role in the clearance/entrance of many proteins from the brain or cerebrospinal fluid (CSF). Megalin cooperates with various membrane molecules and interacts with many adaptor proteins for endocytic trafficking. It has already been implicated in amyloid-β clearance and amyloidosis through the BBB and B-CSFB. Also, it is a promiscuous receptor involved in the endocytic uptake of many ligands, including many of the known carriers of amyloid-β, insulin, IGF-I, leptin, transthyretin, transferrin, ApoE and others. The knowledge of B-CSFB and its transporters in healthy and pathological situations supports the development of new therapeutic approaches for chronic diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, multiple sclerosis, brain cancer, diabetes and others. This article outlines recent patents on artificial carriers for transport of substances across of the CNS barriers, different models for the drug delivery research and future therapies for the treatment of Alzheimer's disease.

One option for treating osteoporosis is a group of medicines known as selective estrogen receptor modulators (SERMs). They can act as an estrogen receptor agonist in some tissues, whereas as an antagonist in others. In relation to this ago-antagonistic action, SERMs have a positive effect on bones, the serum lipid profile and the cardio-vascular system. Moreover they can protect against the development of some estrogen-dependent neoplasms. The first used SERM was tamoxifen, but due to its negative effect on the endometrium it is not indicated in osteoporosis. Raloxifene, which is currently in use, besides involving a reduction of risk of vertebral fractures has also a beneficial influence on the risk of endometrial and breast cancer. On the other hand, raloxifene aggravates vasomotor symptoms and its bone-protecting effect is limited. At present, new SERMs (ospemifene, lasofoxifene, bazedoxifene) are being introduced on the market or researched in clinical trials. In recent years, many interesting patents referring to these new SERMs have been submitted. The implementation of SERMs in combined therapy of osteoporosis is currently also under research. Some SERMs, such as arzoxifene or levormeloxifene have been withdrawn from the trials because of serious side effects. Many other compounds possessing estrogen activity have been identified and patented in recent years, but their clinical significance is not known. Future studies on SERMs may result in new preparations that are adjusted to patients' individual needs.

Members of the rhodopsin-like family, class A, of G-protein coupled receptors (GPCRs) are important targets for drug development and the recent better understanding of their molecular mechanisms of function is engendering new technologies for drug development. The aim of this paper is to review the patent literature covering sequence motifs and structural elements involved in the function of class-A GPCRs. One category of patents covers motifs associated with receptor signaling through G-proteins and signal termination mechanisms. In addition to the well established canonical signaling partners, many GPCRs are known to require accessory proteins for expression on the cell surface and a second category of patents covers the discovery and potential applications of accessory proteins. The pharmacological profiles of GPCRs are known to be sensitive to both homo- and heterodimerization and recent data suggest that tissue specific activities of some GPCRs are determined by the co-expression of interacting partners. Consequently, methods for identifying dimerization partners as well as bivalent ligands are likely to yield new targets and drugs with improved properties. Although the underlying mechanisms are not entirely clear, tissue specific expression of GPCRs provides an important avenue for targeted therapies and subfamilies of class A GPCRs with circumscribed tissue expression profiles, such as chemokine and melanocortin receptors, are important targets for cancer therapy. Thus, recent discoveries in the structure and mechanisms of function of GPCRs are yielding reagents with potential applications to drug development.

Dopamine is the predominant physiological inhibitory factor of prolactin release. Hyperprolactinemia is associated with potentially serious short and long-term clinical consequences. Several physiological and pathological conditions can cause elevated serum prolactin levels. Of these, in the psychiatric population, antipsychotic drugs are the most common. Because treatment of psychiatric illness often begins during adolescence and involves the long-term administration of these medications, the antipsychotic-induced hyperprolactinemia appears to be a major health concern for these patients. There are many possible management strategies of antipsychotic-induced hyperprolactinemia: estrogen/testosterone replacement, adding a dopamine agonist and introducing an alternative antipsychotic. Aripiprazole, a drug with partial agonist activity at dopamine D2 receptors, may be effective for antipsychotic-induced hyperprolactinemia. This paper reviews recent patents, mechanisms and evidences regarding the clinical action of aripiprazole on antipsychotic-induced hyperprolactinemia.

Advanced glycation end products (AGEs) are important biochemical compounds found in diabetes mellitus and are likely to be associated with an inflammatory process. Within the vessel wall, AGEs may interact with specific receptors to modulate a large number of cellular properties by activating several signaling pathways. One of these receptors is called “receptor for AGE” (RAGE). The AGE-RAGE interactions enhance transcription genes encoding for cytokines, growth factors, adhesive molecules and increased classical acute phase proteins. Potential preventive and therapeutic approaches toward diabetes and its complications include inhibition of AGE formation, breakage of preformed AGE-proteins crosslink, blockade of AGE-RAGE interactions with RAGE competitors, antibody antagonists and RAGE specific metabolic inhibition. Blockade of AGE-RAGE complex formation suppresses the levels of pro-inflammatory cytokines and growth factors and it may be considered as a target for overcoming diabetic complications. This concise review about AGE-RAGE interaction and diabetes complications discusses pathophysiological mechanisms at a glance. Patents on inhibition of AGE formation, RAGE expression and AGE-RAGE interaction are shown and discussed here.

The importance of insulin in the management of diabetes mellitus cannot be over emphasized. Newer formulations and delivery devices have improved the efficacy, safety and tolerability of insulin. All available insulins and insulin analogues, however, are administered by subcutaneous insulin. The subcutaneous route of administration is associated with a certain level of discomfort, which is not acceptable to some patients. This has led researchers to explore other methods of insulin delivery. Inhaled insulin, nasal insulin and oral insulin are some of the novel insulins which have been studied. This review highlights recent advances and patents related to oral insulin. It covers the limitations of subcutaneous insulin, the physiological rationale of administering oral insulin, and the barriers to these formulations. The review is based on a literature search, done by all authors, using the key words “oral insulin”, from 1991 to 2010, using PubMed and Google Scholar. All four authors decided the relative importance of papers on various oral insulin formulations. Focus was kept on oral preparations which are still in active development, and stand a chance of reaching the commercial market. The review studies the methods of producing oral insulin such as encapsulation, protease inhibitor use, PEGylation, permeation enhancer use and liposomal administration. It highlights recent patents and studies for all these methods.

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