Multidisciplinary Consideration of Potential Pathophysiologic Mechanisms of Paradoxical Erythema with Topical Brimonidine Therapy

Rosacea is a chronic inflammatory disease with transient and non-transient redness as key characteristics. Brimonidine is a selective α2-adrenergic receptor (AR) agonist approved for persistent facial erythema of rosacea based on significant efficacy and good safety data. The majority of patients treated with brimonidine report a benefit; however, there have been sporadic reports of worsening erythema after the initial response. A group of dermatologists, receptor physiology, and neuroimmunology scientists met to explore potential mechanisms contributing to side effects as well as differences in efficacy. We propose the following could contribute to erythema after application: (1) local inflammation and perivascular inflammatory cells with abnormally functioning ARs may lead to vasodilatation; (2) abnormal saturation and cells expressing different AR subtypes with varying ligand affinity; (3) barrier dysfunction and increased skin concentrations of brimonidine with increased actions at endothelial and presynaptic receptors, resulting in increased vasodilation; and (4) genetic predisposition and receptor polymorphism(s) leading to different smooth muscle responses. Approximately 80% of patients treated with brimonidine experience a significant improvement without erythema worsening as an adverse event. Attention to optimizing skin barrier function, setting patient expectations, and strategies to minimize potential problems may possibly reduce further the number of patients who experience side effects. Funding: Galderma International S.A.S., Paris, France

The influence of direct funding, indirect funding, and institutional design policies on industrial research and development

During the last decade there have been fundamental changes in Research and Development (R&D) policies and the mechanisms used to implement those policies. Before 1960, although direct funding mechanisms were prevalent, there were only modest tax mechanisms, and a minuscule number of cooperative mechanisms. Interaction between government, university, and industrial labs was uncommon. In the past ten years that situation has changed tremendously. Policy complexity has replaced relative simplicity but the real impact of these changes has not yet been ascertained. The mechanisms used for policy intervention with industrial R&D can be classified into three groups: direct government support mechanisms, indirect government support mechanisms, and institutional design mechanisms. Direct mechanisms are grants, loans, appropriations, or government contracts. Indirect mechanisms are various tax law provisions allowing firms to recoup costs on R&D. Institutional design mechanisms concentrate on the creation of new institutions amenable to higher levels of R&D performance. A great variety of such institutions exist, including research and development limited partnerships, joint ventures, and multiple forms of government, industry, and university interaction. Current policy consists of all three types of government involvement with industrial R&D. The relative influence of each mechanism is a source of great concern. Too often, the debate focuses only on the desired outcome of policy mechanisms--the policy-push --to the exclusion of the characteristics or environment of the laboratory the-- lab-pull . What best explains the differential utilization of the policy mechanisms by industrial R&D laboratories: policy-push or lab-pull? This study attempts to lend some insights into this question by examining policy-push and lab-pull explanations for policy mechanism utilization. To provide the foundation for the empirical portions of the study, several chapters deal with the justifications for and evolution of the various policy mechanisms. The interaction between internal laboratory structures and policy mechanism utilization is considered using data collected as part of the National Comparative Research and Development project (NCRDP). An assessment of the overall influence of the policy mechanisms, drawing from both the detailed policy discussion and the NCRDP data, is given