Olaparib treatment significantly improved objective response rate (primary end point) and progression-free survival versus nonplatinum chemotherapy in patients with BRCA-mutated platinum-sensitive relapsed ovarian cancer in the open-label phase III SOLO3 trial (ClinicalTrials.gov identifier: NCT02282020). We report final overall survival (OS; prespecified secondary end point), post hoc OS analysis by number of previous chemotherapy lines, and exploratory BRCA reversion mutation analysis. Two hundred sixty-six patients were randomly assigned 2:1 to olaparib tablets (300 mg twice daily; n = 178) or physician's choice of single-agent nonplatinum chemotherapy (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan; n = 88). OS was similar with olaparib versus chemotherapy (hazard ratio [HR], 1.07 [95% CI, 0.76 to 1.49]; P = .71, median 34.9 and 32.9 months, respectively, full analysis set). OS with olaparib was favorable in patients with two previous chemotherapy lines (HR, 0.83 [olaparib v chemotherapy] [95% CI, 0.51 to 1.38]; median 37.9 v 28.8 months); however, a potential detrimental effect was seen in patients with at least three previous chemotherapy lines (HR, 1.33 [95% CI, 0.84 to 2.18]; median 29.9 v 39.4 months). BRCA reversion mutations might have contributed to this finding. No patient randomly assigned to olaparib with a BRCA reversion mutation detected at baseline (6 of 170 [3.5%]) achieved an objective tumor response.
- MeSH
- Deoxycytidine analogs & derivatives administration & dosage MeSH
- Progression-Free Survival MeSH
- Adult MeSH
- Doxorubicin analogs & derivatives administration & dosage MeSH
- Phthalazines * therapeutic use adverse effects administration & dosage MeSH
- Gemcitabine MeSH
- Middle Aged MeSH
- Humans MeSH
- Neoplasm Recurrence, Local * drug therapy MeSH
- Ovarian Neoplasms * drug therapy genetics mortality pathology MeSH
- Paclitaxel administration & dosage MeSH
- Poly(ADP-ribose) Polymerase Inhibitors * therapeutic use adverse effects MeSH
- Piperazines * therapeutic use adverse effects administration & dosage MeSH
- Polyethylene Glycols administration & dosage MeSH
- BRCA1 Protein genetics MeSH
- BRCA2 Protein genetics MeSH
- Antineoplastic Combined Chemotherapy Protocols * therapeutic use adverse effects MeSH
- Aged MeSH
- Topotecan administration & dosage MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
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
- alpha-Galactosidase * administration & dosage therapeutic use MeSH
- Adult MeSH
- Enzyme Replacement Therapy * methods MeSH
- Fabry Disease * drug therapy MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Polyethylene Glycols administration & dosage MeSH
- Recombinant Proteins * administration & dosage therapeutic use MeSH
- Drug Administration Schedule MeSH
- Aged MeSH
- Sphingolipids blood MeSH
- Trihexosylceramides blood MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
Many photosensitive substances suitable for photodynamic therapy (PDT) have limited applications due to their insufficient solubility in polar solvents. Our research overcomes this challenge by means of nanotechnology in order to transform hydrophobic compounds into stable aqueous solutions, enabling them to use their full potential and unique properties in cancer therapy. In this study, the novel nano-composite cGQDs-PEG-curcumin was developed to overcome the insolubility of curcumin in water and its extraordinary efficacy in PDT was evaluated. Complex characterization was performed using high-resolution transmission electron microscopy (HR-TEM), FTIR, and UV-Vis spectroscopy. Further analysis involved fluorescence lifetime imaging (FLIM), and its cellular localization was mapped with confocal microscopy. In order to evaluate PDT effectiveness, cells treated with cGQDs-PEG-curcumin were irradiated with 5 J/cm2 of 414 nm light. After irradiation, cell viability assay, scanning electron microscopy (SEM), reactive oxygen species (ROS) detection, comet assay, and γH2AX-based DNA double-strand breaks (DSBs) detection were assessed and revealed a remarkable ability of the nano-composite to induce DNA damage after irradiation without ROS production. Our findings highlight the potential of cGQDs-PEG-curcumin as a cutting-edge PDT agent, capable of disrupting cell membrane and nucleolar integrity and impairing ribosomal synthesis, which is crucial for proliferating tumour cells.
- MeSH
- Cell Nucleolus * drug effects metabolism MeSH
- DNA Breaks, Double-Stranded drug effects MeSH
- Photochemotherapy * methods MeSH
- Photosensitizing Agents * pharmacology MeSH
- Graphite * chemistry pharmacology MeSH
- Curcumin * pharmacology chemistry MeSH
- Quantum Dots * chemistry MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Neoplasms * drug therapy MeSH
- Polyethylene Glycols * chemistry pharmacology MeSH
- DNA Damage * drug effects MeSH
- Reactive Oxygen Species metabolism MeSH
- Cell Survival drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Exclusion of serum macroform presence is essential to avoid potential misdiagnosis. The aim of this study was to determine critical limits (CL) for enzymes (total and pancreatic amylase, AMY and pAMY; aminotransferases, AST and ALT; alkaline phosphatase, ALP; creatine kinase, CK; lipase, LIP; gamma-glutamyl transferase, GGT; lactate dehydrogenase, LDH) after polyethylene glycol (PEG) precipitation in children and adults. METHODS: A total of 126 sera of patients suspected for macroenzyme presence (adults or children) was matched by serum enzyme activity of controls and all these sera were precipitated by PEG. PEG-precipitable activity ( %PPA) and CLs of %PPA were calculated for adults, children, and controls. RESULTS: CLs of %PPA were substantially lower than common 60 % for ALP and CK in all subjects. Significant differences between adults and children were found for ALT and ALP (lower in children), and LIP and CK (higher in children). No meaningful correlation was found between initial enzyme activity and %PPA. CONCLUSIONS: Age specific CLs should be used for ALP, ALT, CK, and LIP. Generally accepted value of %PPA of 60 % may be used with caution for AMY, pAMY, AST, GGT, and LDH. A careful selection of CLs is needed for timely detection of macrocomplexes.
- MeSH
- Chemical Precipitation MeSH
- Child MeSH
- Adult MeSH
- Enzymes * blood MeSH
- Infant MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Polyethylene Glycols * chemistry MeSH
- Child, Preschool MeSH
- Aged MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Infant MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Child, Preschool MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Pegylované růstové faktory granulopoézy, lipegfilgrastim a pegfilgrastim, mají zásadní roli ve snížení rizika febrilní neutropenie a těžké neutropenie po chemoterapii, a pomáhají tak udržet i její dávkovou intenzitu. Lipegfilgrastim, zavedený od roku 2014, zůstává doposud dostupný v originální molekule a bez biosimilárního ekvivalentu. Data observačních studií i z reálné praxe dokládají jeho účinnost a bezpečnost.
Pegylated granulocyte colony-stimulating factors, lipegfilgrastim and pegfilgrastim, play a crucial role in reducing the risk of febrile neutropenia and severe neutropenia after chemotherapy, and thus help maintain its dose intensity. Lipegfilgrastim, introduced in 2014, remains available as the original molecule and without its biosimilar equivalent. Data from observational studies and from real practice demonstrate its effectiveness and safety.
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
- Printing, Three-Dimensional * MeSH
- Administration, Cutaneous MeSH
- Imiquimod * chemistry administration & dosage MeSH
- Needles * MeSH
- Skin Absorption MeSH
- Skin metabolism MeSH
- Drug Delivery Systems instrumentation MeSH
- Microinjections instrumentation MeSH
- Nanoparticles * chemistry administration & dosage MeSH
- Polyethylene Glycols chemistry administration & dosage MeSH
- Povidone chemistry MeSH
- Solubility * MeSH
- Drug Liberation MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article 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
- Acrylic Resins * chemistry MeSH
- Calorimetry, Differential Scanning MeSH
- X-Ray Diffraction MeSH
- Hydrogels * chemistry MeSH
- Hydrogen-Ion Concentration MeSH
- Rabbits MeSH
- Drug Delivery Systems MeSH
- Delayed-Action Preparations chemistry pharmacokinetics MeSH
- Microscopy, Electron, Scanning MeSH
- Drug Carriers chemistry MeSH
- Poloxamer * chemistry MeSH
- Spectroscopy, Fourier Transform Infrared MeSH
- Thermogravimetry MeSH
- Timolol * administration & dosage pharmacokinetics chemistry MeSH
- Drug Liberation MeSH
- Animals MeSH
- Check Tag
- Rabbits MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article 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
- Precursor Cell Lymphoblastic Leukemia-Lymphoma * MeSH
- Asparaginase * MeSH
- Infant MeSH
- Humans MeSH
- Neoplasm Recurrence, Local drug therapy MeSH
- Polyethylene Glycols MeSH
- Prednisone adverse effects MeSH
- Disease-Free Survival MeSH
- Antineoplastic Combined Chemotherapy Protocols adverse effects MeSH
- Randomized Controlled Trials as Topic MeSH
- Recurrence MeSH
- Treatment Outcome MeSH
- Check Tag
- Infant MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial Protocol 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
- Cell Culture Techniques methods MeSH
- Leukemia, Lymphocytic, Chronic, B-Cell * pathology metabolism MeSH
- Gels chemistry MeSH
- Collagen * chemistry pharmacology MeSH
- Humans MeSH
- Polyethylene Glycols * chemistry MeSH
- Receptors, CXCR4 metabolism MeSH
- Carboxymethylcellulose Sodium * chemistry pharmacology MeSH
- Cell Culture Techniques, Three Dimensional methods MeSH
- Tissue Scaffolds * chemistry MeSH
- Cell Survival drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article 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.
- Keywords
- sulfobutylether-β-cyklodextrin,
- MeSH
- Administration, Intravenous methods MeSH
- Humans MeSH
- Drug-Related Side Effects and Adverse Reactions * drug therapy classification MeSH
- Polysorbates pharmacology classification metabolism MeSH
- Excipients * pharmacology adverse effects MeSH
- Propylene Glycol pharmacology metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
