Drug news & perspectives最新文献

GPR119 is a G protein-coupled receptor that is expressed on only a limited number of tissues, including pancreatic β-cells and enteroendocrine cells in the small intestine, and that appears to be involved in the regulation of metabolic homeostasis. The protein was originally defined as an orphan receptor, but it has subsequently been shown to bind a variety of lipid-derived ligands, as well as a range of small synthetic molecules. There is still debate as to the identity of its principal endogenous ligand, but certain lysophospholipids species, various fatty acyl-ethanolamides and N-oleoyldopamine have all been proposed as potential agonists. GPR119 is coupled to the signal transducer Gαs and activation of the receptor leads to increased adenylate cyclase activity via Gαs and a rise in intracellular cAMP. This then potentiates glucose-induced insulin secretion or promotes the release of intestinal incretin hormones, according to cell type. Both mechanisms ultimately lead to a rise in insulin secretion (either directly or indirectly) and improved glucose control. Thus, GPR119 may represent an important new therapeutic target for the design of insulin secretagogues able to promote improvements in blood glucose control in patients with type 2 diabetes. Accordingly, a range of lead compounds are in development as potential therapeutic agents.

Specific drug therapy has created paradigm changes in the cure and control of many common and important diseases. However, the benefits of specific therapy have not been shared equally, and children have been especially disadvantaged. In addition to many drugs lacking pediatric-specific information on drug safety and efficacy, there is often a lack of child-friendly formulations. Practical challenges include issues of stability and palatability, while other issues include variations in drug metabolism and excretion in different populations of children and policy issues related to the fact that the largest number of children live in the developing world. Innovations in drug formulations offer the potential for addressing the practical issues, while changes in public policy offer the potential for all the world's children to share more equally in the benefits of pharmacotherapy.

Exploiting the RNA interference (RNAi) pathway to inhibit viral gene expression has become an active field of research. The approach has potential for therapeutic application and several viruses are susceptible to RNAi-mediated knockdown. Differences in the characteristics of individual viruses require that viral gene silencing be tailored to specific infections. Important considerations are viral tissue tropism, acute or chronic nature of the infection and the efficiency with which antiviral sequences can be delivered to affected tissue. Both synthetic short interfering RNAs (siRNAs) and expressed RNAi activators are being developed for viral therapy. The sustained silencing of expressed antiviral sequences is useful for countering chronic viral infection. siRNAs, which may be chemically modified to improve specificity and stability, are being developed for knockdown of viruses that cause acute or chronic infections. Preventing viral escape from silencing is important and overcoming this problem using combinatorial RNAi or through silencing of host dependency factors is promising. Although improving delivery efficiency and limiting off-target effects remain obstacles, rapid progress continues to be made in the field and it is likely that the goal of achieving licensed RNAi-based viral therapies will soon be realized.

Recent GABA(A) receptor drug discovery efforts have culminated in the development of transgenic mice and subtype-selective pharmacological tools, enhancing our understanding of the major inhibitory neural system in the central nervous system. Notably, subtype-selective tools have demonstrated in both preclinical studies and, to some extent, in man that it is possible to develop drugs that share the clinical benefits of benzodiazepines (e.g., anxiolysis) while obviating some adverse effects of these clinically important drugs. Here, we highlight chronic pain as another therapeutic area in which subtype-selective GABA(A) receptor drugs might have clinical utility. Specifically, based on research in animal models of inflammatory/neuropathic pain, we suggest that subtype-selective positive modulators of GABA(A) alpha(2/3) receptors might reverse a loss of postsynaptic GABA(A) receptor-mediated inhibitory function in spinal cord, leading to analgesia. However, alteration of presynaptic inhibitory neural transmission in chronic pain suggests that drugs that negatively modulate GABA(A) receptors might also be effective analgesics. For example, the non-selective negative allosteric modulator FG-7142 reverses allodynia in an animal model of neuropathic pain. Importantly, these two mechanisms are not mutually exclusive. Further clinical exploration in pain of available positive and negative subtype-selective modulators that have been administered to humans would considerably aid back translation, allowing for improved therapeutic development.

Despite advances in surgical techniques, improvement in radiation treatments and chemotherapy, and the addition of new biological agents to the armamentarium, the median survival of patients with high-grade malignant glioma has changed little over recent decades. However, advances in the fundamental understanding of brain tumor biology suggest that targeting molecular pathways underlying carcinogenesis may provide alternative or additional approaches to glioma treatment. Viruses, particularly adenoviruses, have been critical in the application and development of these molecular approaches. Adenoviruses have been engineered to function as vectors for delivering therapeutic genes for gene therapy, and as direct cytotoxic agents for oncolytic viral therapy. The purpose of this review is to provide a prospective on the use of adenoviruses in high-grade malignant glioma therapy.

Asthma is a common disorder of the airways which exhibit variable obstruction associated with hyperresponsiveness linked to altered smooth muscle. Although environmental factors are important in the origins and progression of asthma, it is a disorder with high heritability. The identification of ADAM33 (ADAM metallopeptidase domain 33, a disintegrin and metalloproteinase domain 33) as the first novel asthma gene has implications for the mechanisms of airway hyper-responsiveness and airway wall remodeling. This review discusses the molecular regulation of ADAM33, its link to asthma and chronic obstructive pulmonary disease and newly identified functions. These all point to ADAM33 being a key molecule in the development and progression of asthma by contributing to smooth muscle and vascular modeling and remodeling.

Since the discovery of nerve growth factor (NGF) in the 1950s, scientists have had great expectations for NGF in the treatment of neurodegenerative diseases. The main obstacle to overcome was the blood-brain barrier, which NGF does not cross when administered systemically. Our research group has recently demonstrated that topically instilled NGF eye drops are effective in treating several ocular diseases such as neurotrophic and autoimmune corneal ulcers. Pharmacodynamic studies have also shown that NGF eye drops have the ability to target the optic nerve and brain, thus finally opening-up avenues of research in pursuit of a novel drug for neurodegenerative diseases. In this review, clinical trials of systemically and topically administered NGF are discussed, as well as recent progress in the production of biologically active recombinant human NGF and innovative delivery routes. The pharmacological activity of NGF eye drops in ocular surface, retina and optic nerve diseases are also discussed.

The kinetic isotope effect has long been exploited by physical organic chemists to study reaction mechanisms due to its effect on reaction rates when cleavage of a C-isotope bond is rate determining. Medicinal chemists have also used the deuterium kinetic isotope effect to slow the cytochrome P450 metabolism of the deuterated versions of drug candidates, with the first in vitro microsome studies of deuterated morphine appearing in the literature in the 1960s, and a deuterated alanine compound from Merck going all the way to phase IIb in the 1970s. The recent emergence of companies such as Concert Pharmaceuticals and Auspex Pharmaceuticals, based solely on the idea of deuterium-for-hydrogen versions of existing drugs, has reinvigorated the backers of the deuterium camp, and established the strategy as a viable low-risk approach to drug development. A history of the deuterium kinetic isotope effect is presented, along with examples of deuterated drugs that span 50 years, from 1960 to present day. Specific examples of compounds from the Concert and Auspex pipelines are also analyzed and the pros and cons of their approach are discussed.