Albumin as a versatile platform for drug half-life extension.

BACKGROUND: Albumin is the most abundant plasma protein, is highly soluble, very stable and has an extraordinarily long circulatory half-life as a direct result of its size and interaction with the FcRn mediated recycling pathway. In contrast, many therapeutic molecules are smaller than the renal filtration threshold and are rapidly lost from the circulation thereby limiting their therapeutic potential. Albumin can be used in a variety of ways to increase the circulatory half-life of such molecules. SCOPE OF REVIEW: This article will review the mechanisms which underpin albumin's extraordinarily long circulatory half-life and how the understanding of these processes are currently being employed to extend the circulatory half-life of drugs which can be engineered to bind to albumin, or are conjugated to, or genetically fused to, albumin. MAJOR CONCLUSIONS: The recent and growing understanding of the pivotal role of FcRn in maintaining the extended circulatory half-life of albumin will necessitate a greater and more thorough investigation of suitable pre-clinical model systems for assessing the pharmacokinetic profiles of drugs associated, conjugated or fused to albumin. GENERAL SIGNIFICANCE: Association, conjugation or fusion of therapeutic drugs to albumin is a well-accepted and established half-life extension technology. The manipulation of the albumin-FcRn interaction will facilitate the modulation of the circulatory half-life of albumin-enabled drugs, leading to superior pharmacokinetics tailored to the disease state and increased patient compliance. This article is part of a Special Issue entitled Serum Albumin.

Collection of family health history for assessment of chronic disease risk in primary care.

BACKGROUND: Family health history can predict a patient's risk for common complex diseases. This project assessed the completeness of family health history data in medical charts and evaluated the utility of these data for performing risk assessments in primary care. METHODS: Family health history data were collected and analyzed to determine the presence of quality indicators that are necessary for effective and accurate assessment of disease risk. RESULTS: More than 99% of the 390 paper charts analyzed contained information about family health history, which was usually scattered throughout the chart. Information on the health of the patient's parents was collected more often than information on the health of other relatives. Key information that was often not collected included age of disease onset, affected side of the family, and second-degree relatives affected. Less than 4% of patient charts included family health histories that were informative enough to accurately assess risk for common complex diseases. LIMITATIONS: Limitations of this study include the small number of charts reviewed per provider, the fact that the sample consisted of primary care providers in a single geographic location, and the inability to assess ethnicity, consanguinity, and other indicators of the informativeness of family health history. CONCLUSIONS: The family health histories collected in primary care are usually not complete enough to assess the patient's risk for common complex diseases. This situation could be improved with use of tools that analyze the family health history information collected and provide risk-stratified decision support recommendations for primary care.

Monocarboxylate transporter MCT1 is a target for immunosuppression.

Current immunosuppressive therapies act on T lymphocytes by modulation of cytokine production, modulation of signaling pathways or by inhibition of the enzymes of nucleotide biosynthesis. We have identified a previously unknown series of immunomodulatory compounds that potently inhibit human and rat T lymphocyte proliferation in vitro and in vivo in immune-mediated animal models of disease, acting by a novel mechanism. Here we identify the target of these compounds, the monocarboxylate transporter MCT1 (SLC16A1), using a strategy of photoaffinity labeling and proteomic characterization. We show that inhibition of MCT1 during T lymphocyte activation results in selective and profound inhibition of the extremely rapid phase of T cell division essential for an effective immune response. MCT1 activity, however, is not required for many stages of lymphocyte activation, such as cytokine production, or for most normal physiological functions. By pursuing a chemistry-led target identification strategy, we have discovered that MCT1 is a previously unknown target for immunosuppressive therapy and have uncovered an unsuspected role for MCT1 in immune biology.