Objectives Intravenous immunoglobulin (IVIG) therapy is effective against some autoimmune diseases. Although its efficacy on peripheral neuropathy due to eosinophilic granulomatosis with polyangiitis-one of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis (MPO-AAV)-has been established, that on other MPO-AAV remains undetermined. We examined the effects of pharmaceutical immunoglobulins on the formation of neutrophil extracellular traps (NETs) related to MPO-ANCA production and the development of MPO-AAV.Methods Peripheral blood neutrophils from healthy volunteers were pretreated with 5 mg/ml human sulfo-immunoglobulins (IVIG-S) and then exposed to 100 nM phorbol myristate acetate (PMA). Thereafter, neutrophils were stained with SYTOX Green and then subjected to flow cytometry. Next, Wistar-Kyoto rats were given oral administration of 10 mg/kg/day propylthiouracil for 28 days and intraperitoneal (i.p.) injection of 1 µg PMA on days 0 and 7. These rats were divided into two groups: Group 1 with i.p. injection of 400 mg/kg IVIG-S on days 8-12 and Group 2 with i.p. injection of vehicle similarly. ANCA titers were chronologically determined by indirect immunofluorescence. On day 28, all rats were killed to examine NET formation in the peritoneum and the development of AAV.Results IVIG-S significantly inhibited NET formation induced by PMA in vitro. NET amounts in the peritoneum in Group 1 were significantly smaller than in Group 2, and ANCA titers in Group 1 were significantly lower than in Group 2. The degree of pulmonary hemorrhage in Group 1 was also smaller than in Group 2. ConclusionPharmaceutical immunoglobulins reduce NET formation and ameliorate the development of MPO-AAV.
Skin penetration analysis of topically applied drugs or active compounds is essential in biomedical applications. Stimulated Raman scattering (SRS) microscopy is a promising label-free skin penetration analysis tool. However, conventional SRS microcopy suffers from limited signal contrast owing to strong background signals, which prevents its use in low-concentration drug imaging. Here, we present a skin penetration analysis method of topical agents using recently developed phase-modulated SRS (PM-SRS) microscopy. PM-SRS uses phase modulation and time-resolved signal detection to suppress both nonlinear background signals and Raman background signals from a tissue. A proof-of-concept experiment with a topically applied skin moisturizing agent (ectoine) in an in vitro skin tissue model revealed that PM-SRS with 1.7-ps probe delay yields a signal contrast 40 times higher than that of conventional amplitude-modulated SRS (AM-SRS). Skin penetration measurement of a topical therapeutic drug (loxoprofen sodium) showed that the mean drug concentration at the tissue surface layer after 240 min was 47.3 ± 4.8 mM. The proposed PM-SRS microscopy can be employed to monitor the spatial and temporal pharmacokinetics of small molecules in the millimolar concentration regime.
Background An assessment of the drug penetration and distribution profiles within the skin is essential in dermatology and cosmetology. Recent advances in label‐free imaging technologies have facilitated the direct detection of unlabeled compounds in tissues, with high resolution. However, it remains challenging to provide quantitative time‐course distribution maps of drugs within the complex skin tissue. The present study aims at acquiring the real‐time quantitative skin penetration profiles of topically applied caffeine, by means of a combination of pump–probe phase‐modulated stimulated Raman scattering (PM‐SRS) and confocal reflection microscopy. The recently developed PM‐SRS microscopy is a unique imaging tool that can minimize strong background signals through a pulse‐shaping technique, while providing high‐contrast images of small molecules in tissues. Materials and methods Reconstructed human skin epidermis models were used in order to analyze caffeine penetration in tissues. The penetration profiles of caffeine in an aqueous solution, an oil‐in‐water gel, and a water‐in‐oil gel were examined by combining PM‐SRS and confocal reflection microscopy. Results The characteristic Raman signal of caffeine was directly detected in the skin model using PM‐SRS. Integrating PM‐SRS and confocal reflection microscopy allowed real‐time concentration maps of caffeine to be obtained from formulation samples, within the skin model. Compared with the conventional Raman detection method, PM‐SRS lowered the background tissue‐oriented signals and supplied high‐contrast images of caffeine. Conclusion We successfully established real‐time skin penetration profiles of caffeine from different formulations. PM‐SRS microscopy proved to be a powerful, non‐invasive, and real‐time depth‐profile imaging technique for use in quantitative studies of topically applied drugs.
Signal contrasts for topically applied substances in conventional amplitude- modulated stimulated Raman scattering microscopy (SRS) are limited by tissue background scattering. Combined phase-modulated SRS and confocal reflection microscopy enables high- contrast depth-resolved imaging and robust skin-penetration analysis.
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