IUPHAR-DB: the IUPHAR database of G protein-coupled receptors and ion channels.

The IUPHAR database (IUPHAR-DB) integrates peer-reviewed pharmacological, chemical, genetic, functional and anatomical information on the 354 nonsensory G protein-coupled receptors (GPCRs), 71 ligand-gated ion channel subunits and 141 voltage-gated-like ion channel subunits encoded by the human, rat and mouse genomes. These genes represent the targets of approximately one-third of currently approved drugs and are a major focus of drug discovery and development programs in the pharmaceutical industry. IUPHAR-DB provides a comprehensive description of the genes and their functions, with information on protein structure and interactions, ligands, expression patterns, signaling mechanisms, functional assays and biologically important receptor variants (e.g. single nucleotide polymorphisms and splice variants). In addition, the phenotypes resulting from altered gene expression (e.g. in genetically altered animals or in human genetic disorders) are described. The content of the database is peer reviewed by members of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR); the data are provided through manual curation of the primary literature by a network of over 60 subcommittees of NC-IUPHAR. Links to other bioinformatics resources, such as NCBI, Uniprot, HGNC and the rat and mouse genome databases are provided. IUPHAR-DB is freely available at http://www.iuphar-db.org.

Missing steps in the STAIR case: a Translational Medicine perspective on the development of NXY-059 for treatment of acute ischemic stroke.

The continued failure in approving new drugs for treatment of acute stroke has been recently set back by the failure of the NXY-059 (Stroke-Acute Ischemic NXY Treatment (SAINT) II) trial. The disappointment was heightened by the latter study being viewed as a most promising compound for stroke drug development program based on the preclinical data. Since the SAINT I/II development program included many of the STAIR (Stroke Therapy Academic Industry Round table) guidelines, yet have still failed to achieve the expected efficacy, there is a clear need to continue and analyze the path forward for stroke drug discovery. To this end, this review calls for a consortium approach including academia, government (FDA/NIH), and pharmaceutical industry partnerships to define this path. It is also imperative that more attention is given to the evolving discipline of Translational Medicine. A key issue in this respect is the need to devote more attention to the characteristics of the drug candidate nature-target interaction, and its relationship to pharmacodynamic treatment end points. It is equally important that efforts are spent to prove that phenotypic outcomes are linked to the purported mechanism of action of the compound. Development of technologies that allows a better assessment of these parameters, especially in in vivo models are paramount. Finally, rational patient selection and new outcome scales tailored in an adaptive design model must be evaluated.

Discontinued drugs in 2006: cardiovascular drugs translational medicine perspective.

This perspective on discontinued cardiovascular drugs is the first in a series of papers on drugs dropped from clinical development in 2006. The compounds described in this perspective have been removed from development in various stages and for different reasons. This paper hereby provides a translational medicine perspective on these compounds based on information available through the Pharmaprojects pipeline database. In particular, potential gaps in the pipeline, due to a lack of biomarkers and translational medicine perspectives are emphasized.

Why has R&D productivity declined in the pharmaceutical industry?

Productivity in pharmaceutical R&D has been on the decline for the past several years, and much has been written on the subject. The causes for the decline in productivity are many and complex. Some of the causes are external to R&D and therefore difficult to address, such as growing regulatory conservatism and lack of international regulatory harmonisation. However, a number of the causes for the decline in productivity are internal to R&D groups and can be addressed by R&D managers, such as cost-containment and maximum use of resources. This article focuses on some of the major issues that have caused productivity to decline, and some of the areas where those who manage large R&D organisations may focus to improve R&D productivity.

Carvedilol case history: the discovery and development of the first ß-blocker for the treatment of congestive heart failure.

Carvedilol is a multiple action drug that blocks ß1-, ß2- and α1- adrenoceptors, and has potent antioxidant properties. Carvedilol is the first drug of its kind to be approved for the treatment of congestive heart failure, and is now the standard of care for this devastating disease. The discovery and development of carvedilol encountered an adverse regulatory climate, skepticism by the cardiology community and hesitance by the company, and in the early 1990s, the fate of the drug was uncertain. Nonetheless, in the largest heart failure study conducted up until that point, carvedilol produced marked reductions in morbidity and mortality, and has given new hope to patients afflicted with congestive heart failure. The story behind carvedilol contains important observations and lessons for scientists, regulators and physicians.