It is commonly thought that bacterial endotoxin such as lipopolysaccharide (LPS) causes sepsis. A... more It is commonly thought that bacterial endotoxin such as lipopolysaccharide (LPS) causes sepsis. Authors argue that LPS is merely a disease marker. The real mechanism of sepsis lies in the Toll-like receptors that suppress sepsis caused by tissue injury or endotoxin. When Toll-like receptors' initial suppression role is overwhelmed, sepsis ensues.
The purpose of this study was to evaluate nifedipine oral and topical compounding formulas and pr... more The purpose of this study was to evaluate nifedipine oral and topical compounding formulas and procedures. Topical preparations were compounded in Plastibase 50 W, using combinations of two drug sources and four types of light exposure. Oral preparations were compounded using combinations of two drug sources, two types of light exposure, and four suspending vehicles. Drug sources consisted of the contents of commercial nifedipine soft-gelatin capsules and nifedipine powder USP. Light exposures were ambient, red-shaded, gold-shaded fluorescent light. Topical formulations were assessed for potency, uniformity, and usability characteristics such as acceptable look and feel of the preparation. Oral formulations were assessed for potency, uniformity, and usability characteristics, such as acceptable look and taste of the preparation. Preparations which were compounded, in entirety, under gold-shaded fluorescent light with nifedipine powder USP as the drug source resulted in a potency of 90% to 110% of intended value. Preparations that were exposed to ambient or red-shaded fluorescent light at any time in the compounding procedure resulted in sub potent preparations. Nifedipine is sensitive to certain wavelengths of light resulting in rapid degradation. When exposed to fluorescent room light, significant degradation may occur in a time frame less than what may be required to compound a preparation, necessitating the need for compounding to take place under a spectrum of light that will not degrade the drug. Gold fluorescent lighting appears to prevent nifedipine degradation during compounding procedures. Concerning the drug source, the use of commercial nifedipine soft-gelatin capsules was problematic, while nifedipine powder USP is a suitable choice for the active pharmaceutical ingredient.
Advances in Experimental Medicine and Biology, 1994
Stimulation of resting, G0-phase T lymphocytes with antigenic peptides presented in the context o... more Stimulation of resting, G0-phase T lymphocytes with antigenic peptides presented in the context of self-MHC triggers a pleiotropic activation program that culminates in cell-cycle entry and the expression of high-affinity receptors for T-cell-derived growth factors. The principal growth and differentiation factor for antigen-activated T lymphocytes is the T-cell-derived cytokine, interleukin-2 (IL-2). Binding of IL-2 to the high-affinity IL-2 receptor (IL-2R) drives the progression of activated, G1-phase T cells into S-phase and, ultimately, mitosis. The intracellular pathways through which IL-2R occupancy provokes this cell-cycle progression response remains an area of intense interest in the field of T-cell biology.
Toll-like receptors activate innate and adaptive immune systems in mammals. This ancient family o... more Toll-like receptors activate innate and adaptive immune systems in mammals. This ancient family of receptors has been evolving since before the taxonomic split between the plant and animal kingdoms. The discovery of the mammalian Toll-like receptors was heralded as confirmation of a predicted biological system explicitly designed to detect exogenous molecules from micro-organisms. However, there is accumulating evidence that Toll-like receptors also detect endogenous agonists, such as the degradation products of macromolecules, products of proteolytic cascades, intracellular components of ruptured cells, and products of genes that are activated by inflammation. Here we review endogenous models of Toll-like receptor activation, a subject of extensive debate. Endogenous activation of mammalian Toll-like receptors may provide key insights for the treatment of multiple conditions, from atherosclerosis to transplant rejection.
The macrolide rapamycin (RAP) is a potent inhibitor of interleukin-2 (IL-2)-induced T-cell prolif... more The macrolide rapamycin (RAP) is a potent inhibitor of interleukin-2 (IL-2)-induced T-cell proliferation. Current models suggest that RAP, when complexed to its intracellular receptor, FK506-binding protein, interferes with an IL-2 receptor-coupled signaling pathway required for cell-cycle progression from G1- to S-phase. Here we show that RAP treatment inhibits the growth of an IL-2-dependent cytotoxic T-cell line, CTLL-2, in late G1-phase, just prior to entry of the cells into S-phase. In contrast, RAP-treated CTLL-2 cells retained the ability to respond to IL-2 with enhanced cytolytic activity, indicating that RAP was not a general suppressant of cellular responsiveness to IL-2. Subsequent studies revealed that IL-2 stimulation triggered a delayed activation of the p34cdc2 kinase, the timing of which correlated with the G1- to S-phase transition. The IL-2-dependent increase in p34cdc2 kinase activity was blocked by RAP. The RAP sensitivity of the p34cdc2 activation mechanism implicates this signaling pathway in the control of S-phase commitment in IL-2-stimulated T-cells.
It is commonly thought that bacterial endotoxin such as lipopolysaccharide (LPS) causes sepsis. A... more It is commonly thought that bacterial endotoxin such as lipopolysaccharide (LPS) causes sepsis. Authors argue that LPS is merely a disease marker. The real mechanism of sepsis lies in the Toll-like receptors that suppress sepsis caused by tissue injury or endotoxin. When Toll-like receptors' initial suppression role is overwhelmed, sepsis ensues.
The purpose of this study was to evaluate nifedipine oral and topical compounding formulas and pr... more The purpose of this study was to evaluate nifedipine oral and topical compounding formulas and procedures. Topical preparations were compounded in Plastibase 50 W, using combinations of two drug sources and four types of light exposure. Oral preparations were compounded using combinations of two drug sources, two types of light exposure, and four suspending vehicles. Drug sources consisted of the contents of commercial nifedipine soft-gelatin capsules and nifedipine powder USP. Light exposures were ambient, red-shaded, gold-shaded fluorescent light. Topical formulations were assessed for potency, uniformity, and usability characteristics such as acceptable look and feel of the preparation. Oral formulations were assessed for potency, uniformity, and usability characteristics, such as acceptable look and taste of the preparation. Preparations which were compounded, in entirety, under gold-shaded fluorescent light with nifedipine powder USP as the drug source resulted in a potency of 90% to 110% of intended value. Preparations that were exposed to ambient or red-shaded fluorescent light at any time in the compounding procedure resulted in sub potent preparations. Nifedipine is sensitive to certain wavelengths of light resulting in rapid degradation. When exposed to fluorescent room light, significant degradation may occur in a time frame less than what may be required to compound a preparation, necessitating the need for compounding to take place under a spectrum of light that will not degrade the drug. Gold fluorescent lighting appears to prevent nifedipine degradation during compounding procedures. Concerning the drug source, the use of commercial nifedipine soft-gelatin capsules was problematic, while nifedipine powder USP is a suitable choice for the active pharmaceutical ingredient.
Advances in Experimental Medicine and Biology, 1994
Stimulation of resting, G0-phase T lymphocytes with antigenic peptides presented in the context o... more Stimulation of resting, G0-phase T lymphocytes with antigenic peptides presented in the context of self-MHC triggers a pleiotropic activation program that culminates in cell-cycle entry and the expression of high-affinity receptors for T-cell-derived growth factors. The principal growth and differentiation factor for antigen-activated T lymphocytes is the T-cell-derived cytokine, interleukin-2 (IL-2). Binding of IL-2 to the high-affinity IL-2 receptor (IL-2R) drives the progression of activated, G1-phase T cells into S-phase and, ultimately, mitosis. The intracellular pathways through which IL-2R occupancy provokes this cell-cycle progression response remains an area of intense interest in the field of T-cell biology.
Toll-like receptors activate innate and adaptive immune systems in mammals. This ancient family o... more Toll-like receptors activate innate and adaptive immune systems in mammals. This ancient family of receptors has been evolving since before the taxonomic split between the plant and animal kingdoms. The discovery of the mammalian Toll-like receptors was heralded as confirmation of a predicted biological system explicitly designed to detect exogenous molecules from micro-organisms. However, there is accumulating evidence that Toll-like receptors also detect endogenous agonists, such as the degradation products of macromolecules, products of proteolytic cascades, intracellular components of ruptured cells, and products of genes that are activated by inflammation. Here we review endogenous models of Toll-like receptor activation, a subject of extensive debate. Endogenous activation of mammalian Toll-like receptors may provide key insights for the treatment of multiple conditions, from atherosclerosis to transplant rejection.
The macrolide rapamycin (RAP) is a potent inhibitor of interleukin-2 (IL-2)-induced T-cell prolif... more The macrolide rapamycin (RAP) is a potent inhibitor of interleukin-2 (IL-2)-induced T-cell proliferation. Current models suggest that RAP, when complexed to its intracellular receptor, FK506-binding protein, interferes with an IL-2 receptor-coupled signaling pathway required for cell-cycle progression from G1- to S-phase. Here we show that RAP treatment inhibits the growth of an IL-2-dependent cytotoxic T-cell line, CTLL-2, in late G1-phase, just prior to entry of the cells into S-phase. In contrast, RAP-treated CTLL-2 cells retained the ability to respond to IL-2 with enhanced cytolytic activity, indicating that RAP was not a general suppressant of cellular responsiveness to IL-2. Subsequent studies revealed that IL-2 stimulation triggered a delayed activation of the p34cdc2 kinase, the timing of which correlated with the G1- to S-phase transition. The IL-2-dependent increase in p34cdc2 kinase activity was blocked by RAP. The RAP sensitivity of the p34cdc2 activation mechanism implicates this signaling pathway in the control of S-phase commitment in IL-2-stimulated T-cells.
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Papers by Gregory Brunn