Cleaning validation for blister packaging machines in hospital-supplying pharmacies.

OBJECTIVE: To ensure quality-assured care for patients, validation of a cleaning process for blister machines is essential. Due to the high operating costs of maintaining high-performance liquid chromatography (HPLC) which is mainly used for this type of analysis, a new, quick and cost-effective analysis method using UV-Vis spectroscopy has been developed. METHOD: Marker substances (metamizole (dipyrone) and paracetamol tablets) were packed in blisters. Afterwards test tablets were packaged before and after cleaning the blister machine and examined for contamination using UV-Vis spectroscopy. RESULTS: UV-Vis spectroscopy has been shown to be superior to HPLC analysis for cleaning validation of blister machines, as it is much faster and cheaper, requires less equipment and personnel effort, while maintaining the same reliability and sensitivity. CONCLUSION: Unit-dose blistering is becoming increasingly popular in the daily routine of hospital pharmacies worldwide due to a variety of advantages. Therefore, cleaning validation of blistering machines has become a mandatory duty of care. The UV-Vis spectroscopic method presented here is the first innovative method suitable for the cleaning validation of blister machines to date.

Automated Non-Sterile Pharmacy Compounding: A Multi-Site Study in European Hospital and Community Pharmacies with Pediatric Immediate Release Propranolol Hydrochloride Tablets.

Pharmacy compounding, the art and science of preparing customized medications to meet individual patient needs, is on the verge of transformation. Traditional methods of compounding often involve manual and time-consuming processes, presenting challenges in terms of consistency, dosage accuracy, quality control, contamination, and scalability. However, the emergence of cutting-edge technologies has paved a way for a new era for pharmacy compounding, promising to redefine the way medications are prepared and delivered as pharmacy-tailored personalized medicines. In this multi-site study, more than 30 hospitals and community pharmacies from eight countries in Europe utilized a novel automated dosing approach inspired by 3D printing for the compounding of non-sterile propranolol hydrochloride tablets. CuraBlend® excipient base, a GMP-manufactured excipient base (pharma-ink) intended for automated compounding applications, was used. A standardized study protocol to test the automated dosing of tablets with variable weights was performed in all participating pharmacies in four different iterative phases. Integrated quality control was performed with an in-process scale and NIR spectroscopy supported by HPLC content uniformity measurements. In total, 6088 propranolol tablets were produced at different locations during this study. It was shown that the dosing accuracy of the process increased from about 90% to 100% from Phase 1 to Phase 4 by making improvements to the formulation and the hardware solutions. The results indicate that through this automated and quality controlled compounding approach, extemporaneous pharmacy manufacturing can take a giant leap forward towards automation and digital manufacture of dosage forms in hospital pharmacies and compounding pharmacies.

Introduction of Unit-Dose Care in the 1,125 Bed Teaching Hospital: Practical Experience and Time Saving on Wards.

Purpose: The shortage of nursing staff as well as the slow progress in the German health care system's digitalisation has gained much attention due to COVID-19. Patient-specific medication management using the unit-dose dispensing system (UDDS) has the potential for a lasting and positive influence on both digitalisation and the relief of nursing staff. Methods: Nursing staff UDDS-acceptance was determined via a validated online survey. For the evaluation of stock keeping on the wards, the delivery quantities were determined for a comparative period before and after the introduction of the UDDS. The time required for on-ward medication-related processes on ward before and after the introduction of UDDS was recorded based on a survey form and the nursing relief in full-time equivalent (FTE) was calculated using the data obtained. Results: We show that nurses appreciate the UDDS and confirm a significant reduction in drug stocks on the wards. The UDDS reduces the time needed to dispense medications from 4.52 ± 0.35 min to 1.67 ± 0.15 min/day/patient. In relation to the entire medication process, this corresponds to a reduction of 50% per day and per patient. Based on 40,000 patients/year and a supply of 1,125 beds with unit-dose blisters, 7.36 FTE nursing staff can be relieved per year. In contrast, 6.5 FTE in the hospital pharmacy are required for supplying the hospitals. Conclusion: UDDS is well accepted by nurses, reduces stock levels on ward, and fulfils criteria as a nursing-relief measure.

We Ask and Listen: A Group-Wide Retrospective Survey on Satisfaction with Digital Medication Software.

Purpose: Computerized physician order entry (CPOE) and clinical decision support systems (CDSS) are used internationally since the 1980s. These systems reduce costs, enhance drug therapy safety, and improve quality of care. A few years ago, there was a growing effort to digitize the healthcare sector in Germany. Implementing such systems like CPOE-CDSS requires training for effective adoption and, more important, acceptance by the users. Potential improvements for the software and implementation process can be derived from the users' perspective. The implementation process is globally relevant and applicable across professions due to the constant advancement of digitalization. The study assessed the implementation of medication software and overall satisfaction. Methods: In an anonymous voluntary online survey, physicians and nursing staff were asked about their satisfaction with the new CPOE-CDSS. The survey comprised single-choice queries on a Likert scale, categorizing into general information, digital medication administration, drug safety, and software introduction. In addition multiple-choice questions are mentioned. Data analysis was performed using Microsoft Office Excel 2016 and GraphPad PRISM 9.5.0. Results: Nurses and physicians' satisfaction with the new software increased with usage hours. The software's performance and loading times have clearly had a negative impact, which leads to a low satisfaction of only 20% among physicians and 17% among nurses. 53% of nurses find the program's training period unsuitable for their daily use, while 57% of physicians approve the training's scope for their professional group. Both professions agree that drug-related problems are easier to detect using CPOE-CDSS, with 76% of nurses and 75% of physicians agreeing. The study provides unbiased feedback on software implementation. Conclusion: In conclusion, digitizing healthcare requires managing change, effective training, and addressing software functionality concerns to ensure improved medication safety and streamlined processes. Interfaces, performance optimization, and training remain crucial for software acceptance and effectiveness.

Enzymatically hydrolyzed low-density lipoprotein modulates inflammatory responses in endothelial cells.

There is evidence that low-density lipoprotein (LDL) is modified by hydrolytic enzymes, and that the product (E-LDL) induces selective production of interleukin 8 (IL-8) in endothelial cells. Since nuclear factor-kappaB (NF-kappaB) is a major regulator of IL-8 transcription, we studied its activation in endothelial cells treated with E-LDL. Unexpectedly, the modified lipoprotein not only failed to activate NF-kappaB, but completely blocked its activation by tumour necrosis factor-alpha (TNF-alpha) in EA.hy926-cells, as assessed by electrophoretic mobility shift assays and immunofluorescence. Inhibition occurred upstream of NF-kappaB translocation, as inhibitor of NF-kappaB- (IkappaB)-phosphorylation was suppressed by E-LDL. In contrast to NF-kappaB, transcription factor activator protein-1 (AP-1) proved to be activated. Removal of free fatty acids present in E-LDL obliterated both activation of AP-1 and inhibition of NF-kappaB. Chromatin immunoprecipitation revealed that phosphorylated c-jun, but not NF-kappaBp65 bound to the natural IL-8 promoter. Production of endothelial IL-8 and simultaneous modulation of NF-kappaB in response to hydrolyzed LDL might serve to protect the vessel wall and promote silent removal of the insudated lipoprotein.

Enzymatically modified LDL induces cathepsin H in human monocytes: potential relevance in early atherogenesis.

OBJECTIVE: Modification with proteases and cholesterylesterase transforms LDL to a moiety that resembles lipoproteins isolated from atherosclerotic lesions and possesses atherogenic properties. To identify changes in monocyte-derived foam cells laden with enzymatically modified LDL (E-LDL), we compared patterns of the most abundant transcripts in these cells after incubation with LDL or E-LDL. METHODS AND RESULTS: Serial analyses of gene expression (SAGE) libraries were constructed from human monocytes after treatment with LDL or E-LDL. Several tags were differentially expressed in LDL-treated versus E-LDL-treated cells, whereby marked selective induction by E-LDL of cathepsin H was conspicuous. We show that cathepsin H is expressed in atherosclerotic lesions in colocalization with E-LDL. Furthermore, we demonstrate that LDL modified with cathepsin H and cholesterylesterase can confer onto LDL the capacity to induce macrophage foam cell formation and to induce cathepsin H. CONCLUSIONS: Cathepsin H could contribute to the transformation of LDL to an atherogenic moiety; the process might involve a self-sustaining amplifying circle.

Enzymatically modified nonoxidized low-density lipoprotein induces interleukin-8 in human endothelial cells: role of free fatty acids.

BACKGROUND: Treatment of low-density lipoprotein (LDL) with a protease and cholesterolesterase transforms the lipoprotein to an entity that resembles lipoprotein particles in atherosclerotic lesions, which have a high content of free cholesterol, reflecting extensive de-esterification in the intima. Because de-esterification would occur beneath the endothelium, we examined the effects of enzymatically modified LDL (E-LDL) on cultured endothelial cells. METHODS AND RESULTS: Incubation of endothelial cells with E-LDL provoked selective accumulation of interleukin (IL)-8 mRNA and production of the cytokine. Chemical analyses and depletion experiments indicated that the effect was caused by the presence of free fatty acids in the altered lipoprotein. Reconstitution studies demonstrated that the oleic and linoleic acids associated with E-LDL are particularly effective IL-8 inducers. The effects of E-LDL on endothelial cells could be abrogated with albumin. CONCLUSION: IL-8 is required for rolling monocytes to adhere firmly to the endothelium; thus, the findings reveal a link between subendothelial entrapment of LDL, cleavage of cholesterol esters, and monocyte recruitment into the lesion.

Resealing of large transmembrane pores produced by streptolysin O in nucleated cells is accompanied by NF-kappaB activation and downstream events.

Streptolysin O (SLO), archetype of a cholesterol-binding bacterial cytolysin, forms large pores in the plasma membrane of mammalian cells. We have recently reported that when a limited number of pores are generated in a cell, they can be sealed in a Ca++-dependent process. Here, we show that resealing is followed by the release of IL-6 and IL-8 from keratinocytes and from endothelial cells, both relevant targets for SLO attack. Production of cytokines by these cells was preceded by activation of transcription factor nuclear factor kappaB, which thus emerges as a common denominator of stress responses to various pore-forming agents, including alpha-toxin of Staphylococcus aureus and complement. Furthermore, we show that activation and cytokine release in response to an agent that forms a pore in the plasma membrane do not depend on paracrine effects, because supernatants of cells perforated by SLO did not activate bystander cells. The study provides definitive evidence that a transient transmembrane pore suffices to trigger productive transcriptional activation in a target cell.