Adjuvant-dependent modulation of Th1 and Th2 responses to immunization with beta-amyloid

The role of adjuvant on the T(h)1 and T(h)2 immune responses to Abeta-immunotherapy (Abeta(42 )peptide) was examined in wild-type mice. Fine epitope analysis with overlapping oligomers of the Abeta(42) sequence identified the 1-15 region as a dominant B cell epitope. The 6-20 peptide was recognized only weakly by antisera from mice administrated with Abeta(42) peptide formulated in complete Freund's adjuvant (CFA), alum or TiterMax Gold (TMG). However, mice immunized with Abeta(42) mixed with QS21 induced a significant antibody response to the 6-20 peptide. The only T cell epitope found was within the 6-28 sequence of Abeta(42). QS21 and CFA induced the strongest humoral response to Abeta, alum was intermediate, and TMG the weakest adjuvant. Analysis of antibody isotypes specific for Abeta indicates that alum induces primarily T(h)2-type immune response, whereas TMG, CFA and QS21 shift the immune responses toward a T(h)1 phenotype. Stimulation of splenocytes from Abeta-immunized mice with Abeta(40) peptide induced strikingly different cytokine expression profiles. QS21 and CFA induced significant IFN-gamma, IL-4 and tumor necrosis factor-alpha expression, whereas alum induced primarily IL-4 production. As T(h)1-type immune responses have been implicated in many autoimmune disorders, whereas T(h)2-type responses have been shown to inhibit autoimmune disease, the choice of adjuvant may be critical for the design of a safe and effective immunotherapy for Alzheimer's disease.     

FDA evaluations using in vitro metabolism to predict and interpret in vivo metabolic drug-drug interactions: impact on labeling.

Recent advances in in vitro metabolism methods have led to an improved ability to predict clinically relevant metabolic drug-drug interactions. To address the relationships of in vitro metabolism data and in vivo metabolism outcomes, the Office of Clinical Pharmacology and Biopharmaceutics in the Center for Drug Evaluation and Research, Food and Drug Administration, evaluated a number of recently approved new drug applications. The goal of these evaluations was to determine the contribution of in vitro metabolism data in (1) predicting in vivo drug-drug interactions, (2) determining the need to conduct an in vivo drug-drug interaction study, and (3) incorporating findings into drug product labeling. Ten cases are presented in this article. They fall into two major groups: (1) in vitro data were predictive of in vivo results, and (2) in vitro data were not predictive of in vivo results. Discussion of these cases highlights factors limiting predictability of in vivo metabolic interactions from in vitro metabolism data. The integration of these findings into drug product labeling is also discussed.     

Do athletes have a right to access data in their Athlete Biological Passport?

The Athlete Biological Passport (ABP) refers to the collection of data related to an individual athlete. The ABP contains the Haematological Module and the Steroidal Module, which are used for the longitudinal monitoring of variables in blood and urine, respectively. Based on changes in these variables, a statistical model detects outliers which indicate doping use and guide further targeted testing of the athlete. Presently, athletes can access their data of the Haematological Module in the Anti‐Doping Administration and Management System (ADAMS). However, granting athletes access to this data has been a matter of debate within the anti‐doping community. This article investigates whether an athlete has a right to access the contents of their ABP profile. We approached this discussion by comparing the nature of ABP data with that of forensic and medical data and touched on important concerns with ABP data disclosure to athletes such as potentially allowing for the development of alternative doping techniques to circumvent detection; and making athletes vulnerable to pressure by the media to publicly release their data. Furthermore, given that ABP data may contain medically relevant information that can be used to diagnose disease, athletes may over‐interpret its medical significance and wrongly see it as a free health check. We argue that safeguarding the integrity of the ABP system must be seen as the most essential element and thus a departure from immediate data disclosure is necessary. Two different strategies for delayed data disclosure are proposed which diminish the chances of ABP data being misused to refine doping techniques.