Pegunigalsidase alfa, a PEGylated α-galactosidase A enzyme replacement therapy (ERT) for Fabry disease, has a longer plasma half-life than other ERTs administered intravenously every 2 weeks (E2W). BRIGHT (NCT03180840) was a phase III, open-label study in adults with Fabry disease, previously treated with agalsidase alfa or beta E2W for ≥3 years, who switched to 2 mg/kg pegunigalsidase alfa every 4 weeks (E4W) for 52 weeks. Primary objective assessed safety, including number of treatment-emergent adverse events (TEAEs). Thirty patients were enrolled (24 males); 23 previously received agalsidase beta. Pegunigalsidase alfa plasma concentrations remained above the lower limit of quantification throughout the 4-week dosing interval. Thirty-three of 182 TEAEs (in 9 patients) were considered treatment-related; all were mild/moderate. No patients developed de novo anti-drug antibodies (ADAs). In the efficacy analysis (n = 29), median (inter-quartile range) eGFR change from baseline over 52 weeks was -1.9 (-5.9; 1.8) mL/min/1.73 m2 (n = 28; males [n = 22]: -2.4 [-5.2; 3.2]; females [n = 6]: -0.7 [-9.2; 2.0]). Overall, median eGFR slope was -1.9 (-8.3; 1.9) mL/min/1.73 m2/year (ADA-negative [n = 20]: -1.2 [-6.4; 2.6]; ADA-positive [n = 9]: -8.4 [-11.6; -1.0]). Lyso-Gb3 concentrations were low and stable in females, with a slight increase in males (9/24 ADA-positive). The BRIGHT study results suggest that 2 mg/kg pegunigalsidase alfa E4W is tolerated well in stable adult patients with Fabry disease. Due to the low number of patients in this study, more research is needed to demonstrate the effects of pegunigalsidase alfa given E4W. Further evidence, outside of this clinical trial, should be factored in for physicians to prolong the biweekly ERT intervals to E4W. TAKE-HOME MESSAGE: Treatment with 2 mg/kg pegunigalsidase alfa every 4 weeks could offer a new treatment option for patients with Fabry disease.
- MeSH
- alfa-galaktosidasa * aplikace a dávkování terapeutické užití MeSH
- dospělí MeSH
- enzymová substituční terapie * metody MeSH
- Fabryho nemoc * farmakoterapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- polyethylenglykoly aplikace a dávkování MeSH
- rekombinantní proteiny * aplikace a dávkování terapeutické užití MeSH
- rozvrh dávkování léků MeSH
- senioři MeSH
- sfingolipidy krev MeSH
- trihexosylceramidy krev MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
The utilization of 3D printing- digital light processing (DLP) technique, for the direct fabrication of microneedles encounters the problem of drug solubility in printing resin, especially if it is predominantly composed of water. The possible solution how to ensure ideal belonging of drug and water-based printing resin is its pre-formulation in nanosuspension such as nanocrystals. This study investigates the feasibility of this approach on a resin containing nanocrystals of imiquimod (IMQ), an active used in (pre)cancerous skin conditions, well known for its problematic solubility and bioavailability. The resin blend of polyethylene glycol diacrylate and N-vinylpyrrolidone, and lithium phenyl-2,4,6-trimethylbenzoylphosphinate as a photoinitiator, was used, mixed with IMQ nanocrystals in water. The final microneedle-patches had 36 cylindrical microneedles arranged in a square grid, measuring approximately 600 μm in height and 500 μm in diameter. They contained 5wt% IMQ, which is equivalent to a commercially available cream. The homogeneity of IMQ distribution in the matrix was higher for nanocrystals compared to usual crystalline form. The release of IMQ from the patches was determined ex vivo in natural skin and revealed a 48% increase in efficacy for nanocrystal formulations compared to the crystalline form of IMQ.
- MeSH
- 3D tisk * MeSH
- aplikace kožní MeSH
- imichimod * chemie aplikace a dávkování MeSH
- jehly * MeSH
- kožní absorpce MeSH
- kůže metabolismus MeSH
- lékové transportní systémy přístrojové vybavení MeSH
- mikroinjekce přístrojové vybavení MeSH
- nanočástice * chemie aplikace a dávkování MeSH
- polyethylenglykoly chemie aplikace a dávkování MeSH
- povidon chemie MeSH
- rozpustnost * MeSH
- uvolňování léčiv MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Free radical polymerization technique was used to formulate Poloxamer-188 based hydrogels for controlled delivery. A total of seven formulations were formulated with varying concentrations of polymer, monomer ad cross linker. In order to assess the structural properties of the formulated hydrogels, Fourier Transform Infrared Spectroscopy (FTIR), Thermogravimetric analysis (TGA), Differential Scanning Calorimetry (DSC), Scanning electron microscopy (SEM), and X-ray diffraction (XRD) were carried out. To assess the effect of pH on the release of the drug from the polymeric system, drug release studies were carried in pH 1.2 and 7.4 and it was found that release of the drug was significant in pH 7.4 as compared to that of pH 1.2 which confirmed the pH responsiveness of the system. Different kinetic models were also applied to the drug release to evaluate the mechanism of the drug release from the system. To determine the safety and biocompatibility of the system, toxicity study was also carried out for which healthy rabbits were selected and formulated hydrogels were orally administered to the rabbits. The results obtained suggested that the formulated poloxamer-188 hydrogels are biocompatible with biological system and have the potential to serve as controlled drug delivery vehicles.
- MeSH
- akrylové pryskyřice * chemie MeSH
- diferenciální skenovací kalorimetrie MeSH
- difrakce rentgenového záření MeSH
- hydrogely * chemie MeSH
- koncentrace vodíkových iontů MeSH
- králíci MeSH
- lékové transportní systémy MeSH
- léky s prodlouženým účinkem chemie farmakokinetika MeSH
- mikroskopie elektronová rastrovací MeSH
- nosiče léků chemie MeSH
- poloxamer * chemie MeSH
- spektroskopie infračervená s Fourierovou transformací MeSH
- termogravimetrie MeSH
- timolol * aplikace a dávkování farmakokinetika chemie MeSH
- uvolňování léčiv MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: The AIEOP-BFM ALL 2009 protocol included, at the end of the induction phase, a randomized study of patients with high-risk (HR) ALL to investigate if an intensive exposure to pegylated L-asparaginase (PEG-ASNASE, 2,500 IU/sqm once a week × 4) on top of BFM consolidation phase IB allowed us to decrease minimal residual disease (MRD) and improve outcome. PATIENTS AND METHODS: A total of 1,097 patients presented, from June 2010 to February 2017, with one or more of the following HR criteria: KMT2A::AFF1 rearrangement, hypodiploidy, prednisone poor response, poor bone marrow response at day 15 (Flow MRD ≥10%), or no complete remission (CR) at the end of induction. Of them, 809 (85.1%) were randomly assigned to receive (404) or not receive (405) four weekly doses of PEG-ASNASE. RESULTS: By intention to treat (ITT) analysis, there was no significant difference in the proportion of patients with polimerase chain reaction MRD ≥5 × 10-4 at the end of phase IB in the experimental versus control arm (13.9% v 17.0%, P = .25). The 5-year event-free survival (median follow-up 6.3 years) by ITT in the experimental and control arms was 70.4% (2.3) versus 75.0% (2.2; P = .18), and the 5-year overall survival was 81.5% (2.0) versus 84.0% (1.9; P = .25), respectively. The corresponding 5-year cumulative incidence of death in CR was 9.5% (1.5) versus 5.7% (1.2; P = .08), and that of relapse was 17.7% (1.9) versus 17.2% (1.9), respectively (P = .94). Adverse reactions in phase IB occurred in 22.2% and 8.9% of patients in the experimental and control arm, respectively (P < .001). CONCLUSION: Additional PEG-ASNASE in phase IB did not translate into a benefit for decreasing relapse incidence but was associated with higher toxicity. Further improvements with conventional chemotherapy might be difficult in the context of intensive treatment protocols.
- MeSH
- akutní lymfatická leukemie * MeSH
- asparaginasa * MeSH
- kojenec MeSH
- lidé MeSH
- lokální recidiva nádoru farmakoterapie MeSH
- polyethylenglykoly MeSH
- prednison škodlivé účinky MeSH
- přežití bez známek nemoci MeSH
- protokoly protinádorové kombinované chemoterapie škodlivé účinky MeSH
- randomizované kontrolované studie jako téma MeSH
- recidiva MeSH
- výsledek terapie MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- protokol klinické studie MeSH
BACKGROUND: Chronic lymphocytic leukemia (CLL) is a common adult leukemia characterized by the accumulation of neoplastic mature B cells in blood, bone marrow, lymph nodes, and spleen. The disease biology remains unresolved in many aspects, including the processes underlying the disease progression and relapses. However, studying CLL in vitro poses a considerable challenge due to its complexity and dependency on the microenvironment. Several approaches are utilized to overcome this issue, such as co-culture of CLL cells with other cell types, supplementing culture media with growth factors, or setting up a three-dimensional (3D) culture. Previous studies have shown that 3D cultures, compared to conventional ones, can lead to enhanced cell survival and altered gene expression. 3D cultures can also give valuable information while testing treatment response in vitro since they mimic the cell spatial organization more accurately than conventional culture. METHODS: In our study, we investigated the behavior of CLL cells in two types of material: (i) solid porous collagen scaffolds and (ii) gel composed of carboxymethyl cellulose and polyethylene glycol (CMC-PEG). We studied CLL cells' distribution, morphology, and viability in these materials by a transmitted-light and confocal microscopy. We also measured the metabolic activity of cultured cells. Additionally, the expression levels of MYC, VCAM1, MCL1, CXCR4, and CCL4 genes in CLL cells were studied by qPCR to observe whether our novel culture approaches lead to increased adhesion, lower apoptotic rates, or activation of cell signaling in relation to the enhanced contact with co-cultured cells. RESULTS: Both materials were biocompatible, translucent, and permeable, as assessed by metabolic assays, cell staining, and microscopy. While collagen scaffolds featured easy manipulation, washability, transferability, and biodegradability, CMC-PEG was advantageous for its easy preparation process and low variability in the number of accommodated cells. Both materials promoted cell-to-cell and cell-to-matrix interactions due to the scaffold structure and generation of cell aggregates. The metabolic activity of CLL cells cultured in CMC-PEG gel was similar to or higher than in conventional culture. Compared to the conventional culture, there was (i) a lower expression of VCAM1 in both materials, (ii) a higher expression of CCL4 in collagen scaffolds, and (iii) a lower expression of CXCR4 and MCL1 (transcript variant 2) in collagen scaffolds, while it was higher in a CMC-PEG gel. Hence, culture in the material can suppress the expression of a pro-apoptotic gene (MCL1 in collagen scaffolds) or replicate certain gene expression patterns attributed to CLL cells in lymphoid organs (low CXCR4, high CCL4 in collagen scaffolds) or blood (high CXCR4 in CMC-PEG).
- MeSH
- buněčné kultury metody MeSH
- chronická lymfatická leukemie * patologie metabolismus MeSH
- gely chemie MeSH
- kolagen * chemie farmakologie MeSH
- lidé MeSH
- polyethylenglykoly * chemie MeSH
- receptory CXCR4 metabolismus MeSH
- sodná sůl karboxymethylcelulosy * chemie farmakologie MeSH
- techniky 3D buněčné kultury metody MeSH
- tkáňové podpůrné struktury * chemie MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Léčivé přípravky pro intravenózní podání často obsahují kromě farmakologicky účinné látky i pomocné látky, které zajišťují rozpustnost, stabilitu a správné pH léčiva. Tradičně se předpokládá, že pomocné látky jsou biologicky inertní, avšak tento předpoklad není vždy naplněn. Některé pomocné látky mohou způsobovat hypersenzitivní reakce, indukovanou orgánovou toxicitu, diskomfort při aplikaci či vykazovat vlastní biologické účinky. Regulace těchto látek se liší podle jejich známých účinků, a tak ne vždy je kvantitativ- ní obsah těchto látek specifikován. Tento článek se zaměřuje na tři často používané pomocné látky v intravenózních lékových formách – propylenglykol, polysorbát 80 a sulfobutylether-β-cyklodextrin (SBECD). V článku analyzujeme farmakologické profily těchto látek, jejich potenciální toxicitu a možnosti prevence nežádoucích účinků, s důrazem na jejich použití u kriticky nemocných dospělých pacientů, kde intravenózní podání léků je často jedinou možností. Tento přístup je zásadní pro minimalizaci rizik spojených s použitím těchto pomocných látek v intenzivní medicíně.
Medicinal products for intravenous administration often contain excipients, in addition to the pharmacologically active substance, that ensure the solubility, stability and correct pH of the drug. Excipients are assumed to be biologically inert, but this assumption is not always met. Some excipients may cause hypersensitivity reactions, organ toxicity, discomfort on administration or show own biological effects The regulatory framework for these substances varies according to their known effects, thus the quantitative content of these substances is not always compulsory to be specified. This article focuses on three frequently used excipients in intravenous drug dosage forms - propylene glycol, polysorbate 80 and sulfobutyl ether-β-cyclodextrin (SBECD). In this article, we discuss the pharmacological profiles of these agents, their potential toxicity, and options for preventing adverse effects, with an emphasis on their use in critically ill adults where intravenous drug administration is often the only option. This approach is essential to minimise the risks associated with the use of these excipients in critically ill.
- Klíčová slova
- sulfobutylether-β-cyklodextrin,
- MeSH
- intravenózní podání metody MeSH
- lidé MeSH
- nežádoucí účinky léčiv * farmakoterapie klasifikace MeSH
- polysorbáty farmakologie klasifikace metabolismus MeSH
- pomocné látky * farmakologie škodlivé účinky MeSH
- propylenglykol farmakologie metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Koloskopické vyšetření je klíčová metoda pro prevenci, diagnostiku i léčbu onemocnění tlustého střeva. Součástí koloskopického vyšetření je příprava střeva před samotným zákrokem, spočívající ve vyprázdnění střeva pomocí perorálně užívaných lavážujících látek a s tím související přechodná změna diety. Tato příprava může u pacientů s diabetes mellitus vést k rozkolísání glykemie a riziku hypoglykemie. Kazuistika popisuje případ pacienta s diabetes mellitus 1. typu léčeného pomocí hybridního uzavřeného okruhu, který v rámci přípravy na koloskopické vyšetření využíval na základě dat z kontinuální monitorace glykemie sáčky s 5 gramy sacharózy k doplnění energie a stabilizaci glykemie. Glykemie se v průběhu přípravy pohybovaly
Colonoscopy is a key method for preventing, diagnosing, and treating colon diseases. The colonoscopic examination includes preparing the colon before the procedure, which involves emptying the bowel with orally administered lavage agents and the associated temporary change in diet. This preparation can lead to glycemic fluctuations and the risk of hypoglycemia in patients with diabetes mellitus. This case report describes the case of a patient with type 1 diabetes mellitus treated with a hybrid closed-loop system who used 5 grams of sucrose sachets during colonoscopic preparation to replenish energy and stabilize glucose based on continuous glucose monitoring data. Glycemia during preparation kept within recommended values 3.9-10.0 mmol/l.
- MeSH
- defekace účinky léků MeSH
- diabetes mellitus 1. typu * komplikace MeSH
- hypoglykemie prevence a kontrola MeSH
- kolonoskopie * škodlivé účinky MeSH
- kolorektální nádory prevence a kontrola MeSH
- komplikace diabetu prevence a kontrola MeSH
- krevní glukóza analýza MeSH
- lidé středního věku MeSH
- lidé MeSH
- polyethylenglykoly aplikace a dávkování MeSH
- předoperační péče metody MeSH
- regulace glykemie metody MeSH
- sacharosa aplikace a dávkování MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- Publikační typ
- kazuistiky MeSH
BACKGROUND: A comparison of fusion rates and clinical outcomes of instrumented transforaminal interbody fusion (TLIF) between polyetheretherketone (PEEK) and titanium-coated PEEK (Ti-PEEK) cages is not well documented. METHODS: A single-centre, prospective, randomised study included patients who underwent one-level TLIF between L3-S1 segments. Patients were randomised into one of two groups: TLIF surgery with the PEEK cage and TLIF surgery with the Ti-PEEK cage. Clinical results were measured. All patients were assessed by repeated X-rays and 3D CT scans. Cage integration was assessed using a modified Bridwell classification. The impact of obesity and smoking on fusion quality was also analysed. Patients in both groups were followed up for 2 years. RESULTS: Altogether 87 patients were included in the study: of these 87 patients, 81 (93.1%) completed the 2-year follow-up. A significant improvement in clinical outcome was found in the two measurements scales in both groups (RM: p = 0.257, VAS: p = 0.229). There was an increase in CobbS and CobbL angle in both groups (p = 0.172 for CobbS and p = 0.403for CobbL). Bony fusion was achieved in 37 of 40 (92.5%) patients in the TiPEEK group and 35 of 41 (85.4%) in the PEEK group (p = 0.157). Cage subsided in 2 of 40 patients (5%) in the TiPEEK group and 11 of 41 (26.8%) in the PEEK group (p = 0.007). Body mass index > 30 and smoking were not predictive factors of bony fusion achievement. CONCLUSION: There is no significant advantage of TiPEEK cages over PEEK cages in clinical outcome and fusion rate 2 years after surgery.
- MeSH
- bederní obratle chirurgie MeSH
- benzofenony * MeSH
- fúze páteře * metody MeSH
- ketony MeSH
- lidé MeSH
- polyethylenglykoly MeSH
- polymery * MeSH
- prospektivní studie MeSH
- titan * MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
Restoring the structures and functions of tissues along with organs in human bodies is a topic gathering attention nowadays. These issues are widely discussed in the context of regenerative medicine. Excipients/delivery systems play a key role in this topic, guaranteeing a positive impact on the effectiveness of the drugs or therapeutic substances supplied. Advances in materials engineering, particularly in the development of hydrogel biomaterials, have influenced the idea of creating an innovative material that could serve as a carrier for active substances while ensuring biocompatibility and meeting all the stringent requirements imposed on medical materials. This work presents the preparation of a natural polymeric material based on pullulan modified with silymarin, which belongs to the group of flavonoids and derives from a plant called Silybum marianum. Under UV light, matrices with a previously prepared composition were crosslinked. Before proceeding to the next stage of the research, the purity of the composition of the matrices was checked using Fourier-transform infrared (FT-IR) spectroscopy. Incubation tests lasting 19 days were carried out using incubation fluids such as simulated body fluid (SBF), Ringer's solution, and artificial saliva. Changes in pH, electrolytic conductivity, and weight were observed and then used to determine the sorption capacity. During incubation, SBF proved to be the most stable fluid, with a pH level of 7.6-7.8. Sorption tests showed a high sorption capacity of samples incubated in both Ringer's solution and artificial saliva (approximately 350%) and SBF (approximately 300%). After incubation, the surface morphology was analyzed using an optical microscope for samples demonstrating the greatest changes over time. The active substance, silymarin, was released using a water bath, and then the antioxidant capacity was determined using the Folin-Ciocâlteu test. The tests carried out proved that the material produced is active and harmless, which was shown by the incubation analysis. The continuous release of the active ingredient increases the biological value of the biomaterial. The material requires further research, including a more detailed assessment of its balance; however, it demonstrates promising potential for further experiments.
- MeSH
- glukany * chemie MeSH
- koncentrace vodíkových iontů MeSH
- lékové transportní systémy metody MeSH
- lidé MeSH
- nosiče léků * chemie MeSH
- polyethylenglykoly * chemie MeSH
- silymarin * chemie MeSH
- spektroskopie infračervená s Fourierovou transformací MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Lipid nanoparticle (LNP)-mRNA complexes are transforming medicine. However, the medical applications of LNPs are limited by their low endosomal disruption rates, high toxicity and long tissue persistence times. LNPs that rapidly hydrolyse in endosomes (RD-LNPs) could solve the problems limiting LNP-based therapeutics and dramatically expand their applications but have been challenging to synthesize. Here we present an acid-degradable linker termed 'azido-acetal' that hydrolyses in endosomes within minutes and enables the production of RD-LNPs. Acid-degradable lipids composed of polyethylene glycol lipids, anionic lipids and cationic lipids were synthesized with the azido-acetal linker and used to generate RD-LNPs, which significantly improved the performance of LNP-mRNA complexes in vitro and in vivo. Collectively, RD-LNPs delivered mRNA more efficiently to the liver, lung, spleen and brains of mice and to haematopoietic stem and progenitor cells in vitro than conventional LNPs. These experiments demonstrate that engineering LNP hydrolysis rates in vivo has great potential for expanding the medical applications of LNPs.
