Diabetic foot ulceration stands as one of the most costly and debilitating complications of diabetes and remains the leading cause of nontraumatic lower extremity amputation in the United States. Traditionally, ischemia, neuropathy, trauma, and infection were considered the culprits of the recurring chronic wound and treatment revolved largely around wound debridement and revascularization. However, recent investigations have uncovered an impaired cutaneous wound healing process in diabetes caused by cellular and molecular alterations in the diabetic microenvironment and have subsequently identified an array of potential molecular targets for intervention. Here, we review recent patents describing upcoming molecular technologies at various stages of development for treating foot ulceration in the diabetic patient. Target classes reviewed include immunomodulators, neuropeptides, and growth factors, and targets reviewed include lactoferrin, thymosin beta 4, T cell immune response cDNA 7, substance P, neuropeptide Y, vascular endothelial growth factor, fibroblast growth factor, nerve growth factor, connective tissue growth factor, hepatocyte growth factor, homeobox genes, and treprostinil. In the course of this presentation, the biology of wound healing and the pathobiology of impaired wound healing in diabetes are emphasized to illustrate how these future molecular therapeutics are intended to counteract disease pathology and promote normal wound repair.
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP-1) are the 2 major incretin hormones released after meals to enhance glucose-stimulated insulin secretion. In patients with type 2 diabetes, a loss of activity of GIP for insulinotropic function and a reduced secretion of GLP-1 exist in response to oral glucose while GLP-1 action is preserved. GLP-1 is therefore an attractive avenue for treating type 2 diabetes. Due to the short circulating half-life of GLP-1, which is degraded by dipeptidyl peptidase IV (DPP-IV), 2 approaches have been undertaken. One is to develop long-acting GLP-1 analogs, such as exendin-4 that is resistant to degradation. Here we review another approach for developing DPP-IV inhibitors. This group of potential drugs covers several major chemical classes and their derivatives, such as amino acid amide, carbocyclic, alkylamine, and heterocyclic compounds. More than 100 patents have been issued for DPP-IV inhibitors to be used either as a monotherapy or in combination with other antidiabetic agents for the treatment of type 2 diabetes, as well as metabolic syndrome, osteoporosis, and arthritis. Structure-based drug design is currently under intensive investigation for future development of more selective therapeutic agents.
The goal of all drug delivery systems is to deploy medications intact to specifically targeted parts of the body through a medium that can control the therapys administration by means of either a physiological or chemical trigger. The polypeptide insulin is the primary hormone responsible for controlling the transport, utilization and storage of glucose in the body. Due to the inconvenience of insulin injections, various approaches have been attempted to formulate insulin for administration by non-injectable routes. Different approaches to deliver insulin including transdermal, transmucosal, pulmonary route using dry aerosols and inhalers, smart hydrogels, nasal delivery, oral delivery, and treatment of diabetes with synthetic beta cells, has resulted in recent developments in treatment of diabetes. Among the latest patent approaches are delivering into the subject a genetic construct comprising a coding sequence for a human proinsulin operably connected a promoter functional in the host cells. Polypeptides having activity of human neurogenin3 (hNgn3), and nucleic acid encoding such polypeptide are among the other inventions that use of islet transcription factors such as hNgn3 to facilitate production of pancreatic islet cells from progenitor cells, and to facilitate insulin delivery by production of islet cells so produced.
Hyperprolactinemia is an endocrine pathology resulting from over-production of prolactin (PRL) by pituitary adenomas, and leading to various reproductive disorders. In addition, there is increasing evidence that PRL acts as a growth-promoter of breast and prostate tumors. Classical drugs blocking pituitary PRL production are not necessarily efficient in these pathological situations, which has encouraged the search for alternative ways of inhibiting the undesirable actions of PRL. Prolactin receptor (PRLR) antagonists, acting at the level of receptor activation rather than PRL production, are the most promising strategy. Based on the protein core of human (h)PRL or growth hormone (hGH), the other natural hPRLR ligand, a series of new variants have been engineered within the past couple of years, leading to various patent applications. Modifications of amino acid sequences involve single/multiple substitutions, truncations, or generation of fusion proteins. Three mechanisms of action have been reported for these PRLR antagonists: 1) inhibition of PRLR signaling by competition with endogenous PRL for receptor binding, 2) activation of specific PRLR signalling pathways resulting in actions opposite to those of wild-type hPRL, and 3) engineering of chimeric ligands targeting more than one receptor/cell type, in order to improve tumor-growth inhibition. Since none of these patented molecules is yet in clinical trials, their efficacy to treat PRL-dependent pathologies remains to be demonstrated in humans.
Recent data has demonstrated that fatty acid metabolism plays a critical role in the hypothalamic regulation of food intake and the evidence is as follows. Circulating long chain fatty acids act as nutrient surplus signals in the hypothalamus. On addition, fatty acid synthesis pathway enzymes, such as fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) and its upstream regulator, AMP-activated protein kinase (AMPK) are regulated by nutritional and hormonal stimuli. Very importantly, current evidence also indicates that fatty acid metabolism pathway may be a potential target for obesity treatment. In this sense, it has been demonstrated that pharmacological inhibition of FAS results in profound decrease in food intake and body weight in rodents. These anorectic actions are mediated by the modulation of hypothalamic neuropeptide systems, through a malonyl-CoA dependent mechanism. In this review, we recapitulate what is known about hypothalamic fatty acid metabolism and the regulation of feeding, with particular interest in a specific FAS inhibitor, C75, which has been recently patented as a potential drug for adipose mass reduction.
Many are the diseases which course with free radical formation. These disorders cover a great range of fields such as neurodegenerative, immune, inflammatory and mitochondrial-related diseases. Melatonin is the main pineal gland product and it functions as “time-giver” in the regulation of circadian rhythms, among others. But the actions of melatonin are not only restricted to the neuroendocrine physiology. In fact, it has been known as a radical scavenger, a role that has been deeply studied in all those conditions where free radicals are generated. Furthermore, melatonin has been shown to act as an indirect antioxidant, since it is able to increase the activity and expression of the main antioxidant enzymes, the machinery for the glutathione synthesis, and many others direct or indirectly implicated in the free radical removal. Melatonin can also diminish the activity or expression of enzymes or factors that are considered as prooxidants. Thus, researchers have paid attention to the possible actions of melatonin in the attenuation of those processes where free radical overproduction is implicated. This review summarizes some of the proposed melatonin mechanisms for different free radical-dependent pathological situations, as well as some patents on melatonin significance recently reported for the treatment of attention deficit, hyperactivity disorders, stress-related diseases, Chronic fatigue syndrome, diabetes, Parkinsons disease. Alzheimers disease, age associated cognitive dysfunction and cancer.
As is frequently found in the living body, many vital functions are regulated by pulsed or triggered release of bioactive substances at a specific site and time. Thus it is important to develop new drug delivery devices to achieve pulsed delivery of a certain amount of drugs in order to mimic the function of the living systems to minimize the undesired side effects. The pulsed or triggered delivery systems are designed to alter their rate of drug delivery in response to stimuli such as changes in a specific molecule, a magnetic or electric field, temperature, light or mechanical forces. Such systems are suitable for the release of therapeutics that benefit from non-constant plasma concentrations. In this article, several types of drug delivery systems which cause the pulsed or triggered release of bioactive compounds due to certain external stimuli, mostly focuses on thermally-, electrically- and magnetically- induced release are described in detail. The recent patents on various delivery systems which release the active compounds only with the external stimuli are described in detail.