Recent advances of biotechnology have laid the groundwork for potent and specific molecular-targeting therapies including RNA interference. The largest remaining hurdle for widespread use of this ...technology in skin is an effective delivery system. Here, we demonstrate an effective topical delivery system using a cream formulation containing a small-interfering RNA (siRNA) that specifically targets osteopontin (OPN). OPN is a validated target in numerous inflammatory diseases, including rheumatoid arthritis (RA). The siRNA targeting OPN was incorporated into a cream formulation GeneCream that penetrates the stratum corneum, depositing siRNA in the epidermis, dermis, and to a lesser extent, subcutaneous tissue. In addition, when the OPN siRNA cream was topically applied to the skin of a collagen antibody-induced RA mouse model, the siRNA cream prevented the occurrence of severe, irreversible damage to bone and cartilage. Thus, the siRNA cream provides effective delivery of active OPN siRNA, suggesting this formulation may represent a platform technology for delivery of siRNAs for treating various disorders including RA.
This study aimed to evaluate the efficacy and safety of an extended-release tablet formulation of pramipexole (PPX-ER) given once daily when switched from an immediate-release tablet formulation ...(PPX-IR) given 3 times daily. This open-label study included 29 patients with idiopathic Parkinson's disease (PD) who were followed for 8 weeks. Primary endpoints were Unified Parkinson's Disease Rating Scale (UPDRS) part III score, a physician evaluation of motor symptoms; nocturnal and early morning symptoms (NEMS) score, based on the results for 4 items in the Parkinson's Disease Sleep Scale and the Movement Disorder Society - sponsored revision of the UPDRS; and patients' formulation preference, determined through questionnaires. Secondary endpoints were nocturnal sleep disturbance, evaluated using the revised version of the Parkinson's Disease Sleep Scale (PDSS-2); quality of life, evaluated using the 39-item Parkinson's Disease Questionnaire (PDQ-39); Clinical Global Impression-Improvement (CGI-I) score; Patient Global Impression-Improvement (PGI-I) score; and caregiver formulation preference. UPDRS part III score (mean ± SD) was significantly decreased after 4 weeks (13.9 ± 7.3; P=0.030) and 8 weeks (12.2 ± 7.3; P<0.001) from baseline (15.3 ± 7.0). However, no significant change was found in NEMS scale, PDSS-2 or PDQ-39 scores. After 8 weeks, the responder rates based on CGI-I and PGI-I scores were 27.6% and 20.7%, respectively. As a result of the questionnaire, 63.0% of patients and 58.8% of their caregivers preferred PPX-ER. A non-serious drug-related adverse event (diarrhea) was observed in one patient. In conclusion, PPX-ER can be considered as a useful treatment option when PPX-IR needs to be switched to other dopamine agonists.This study is registered with UMIN-CTR (UMIN000006521).
summary Recently, evidence implicating the roles of the anti‐human leucocyte antigen (HLA) class II antibody in the development of transfusion‐related acute lung injury (TRALI), which is one of the ...most serious possible side effects of transfusion, has been accumulating. The aim of this study is to clarify the roles of the anti‐HLA DR alloantibody in TRALI development. Cultured human lung microvascular endothelial (LME) cells were incubated with either HLA‐DR15‐positive or HLA‐DR15‐negative monocytes together with serum from a single multiparous donor previously implicated in a clinical case of TRALI and known to contain anti‐HLA DR15 antibody. Production of soluble leukotriene B4 (LTB4) was measured in the supernatant and found to be markedly increased in the presence of HLA‐DR15‐positive monocytes but not with the HLA‐DR15‐negative monocytes or in the absence of LME cells. The vascular cell adhesion molecule‐1 expression in LME cells and leucocyte‐function‐associated molecule‐1 (LFA‐1) expression in HLA‐DR15‐positive monocytes were notably enhanced after combined culture of LME cells, HLA‐DR15‐positive monocytes and TRALI‐inducing anti‐HLA DR15 antibody‐positive serum. In conclusion, anti‐HLA DR alloantibodies may be implicated in LME dysfunction that leads to TRALI, in a monocyte‐dependent manner.
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