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The Korean Journal of Internal Medicine Nov 2023Although rituximab, an antiCD20 monoclonal antibody, has dramatically improved the clinical outcomes of diffuse large B-cell lymphoma, rituximab resistance remains a...
BACKGROUND/AIMS
Although rituximab, an antiCD20 monoclonal antibody, has dramatically improved the clinical outcomes of diffuse large B-cell lymphoma, rituximab resistance remains a challenge.
METHODS
We developed a rituximab-resistant cell line (RRCL) by sequential exposure to gradually increasing concentrations of rituximab in a rituximab-sensitive cell line (RSCL). When the same dose of rituximab was administered, RRCL showed a smaller decrease in cell viability and apoptosis than RSCL. To determine the differences in gene expression between RSCL and RRCL, we performed next-generation sequencing.
RESULTS
In total, 1,879 differentially expressed genes were identified, and in the over-representation analysis of Consensus-PathDB, mitogen-activated protein kinase (MAPK) signaling pathway showed statistical significance. MAPK13, which encodes the p38δ protein, was expressed more than four-fold in RRCL. Western blot analysis revealed that phosphop38 expression mainwas increased in RRCL, and when p38 inhibitor was administered, phosphop38 expression was significantly decreased. Therefore, we hypothesized that p38 MAPK activation was associated with rituximab resistance. Previous studies have suggested that p38 is associated with NF-κB activation. Deferasirox has been reported to inhibit NF-κB activity and suppress phosphorylation of the MAPK pathway. Furthermore, it also has cytotoxic effects on various cancers and synergistic effects in overcoming drug resistance. In this study, we confirmed that deferasirox induced dose-dependent cytotoxicity in both RSCL and RRCL, and the combination of deferasirox and rituximab showed a synergistic effect in RRCL at all combination concentrations.
CONCLUSION
We suggest that p38 MAPK, especially p38δ, activation is associated with rituximab resistance, and deferasirox may be a candidate to overcome rituximab resistance.
Topics: Humans; Rituximab; Deferasirox; Mitogen-Activated Protein Kinase 13; NF-kappa B; Antibodies, Monoclonal, Murine-Derived; Drug Resistance, Neoplasm; Lymphoma, Large B-Cell, Diffuse; Apoptosis; High-Throughput Nucleotide Sequencing; Cell Line, Tumor; p38 Mitogen-Activated Protein Kinases
PubMed: 37599392
DOI: 10.3904/kjim.2023.134 -
Molecules (Basel, Switzerland) Aug 2021Deferasirox is an orally active, lipophilic iron chelating drug used on thousands of patients worldwide for the treatment of transfusional iron overload. The essential... (Comparative Study)
Comparative Study
Deferasirox is an orally active, lipophilic iron chelating drug used on thousands of patients worldwide for the treatment of transfusional iron overload. The essential transition metals iron and copper are the primary catalysts of reactive oxygen species and oxidative damage in biological systems. The redox effects of deferasirox and its metal complexes with iron, copper and other metals are of pharmacological, toxicological, biological and physiological importance. Several molecular model systems of oxidative damage caused by iron and copper catalysis including the oxidation of ascorbic acid, the peroxidation of linoleic acid micelles and the oxidation of dihydropyridine have been investigated in the presence of deferasirox using UV-visible and NMR spectroscopy. Deferasirox has shown antioxidant activity in all three model systems, causing substantial reduction in the rate of oxidation and oxidative damage. Deferasirox showed the greatest antioxidant activity in the oxidation of ascorbic acid with the participation of iron ions and reduced the reaction rate by about a 100 times. Overall, deferasirox appears to have lower affinity for copper in comparison to iron. Comparative studies of the antioxidant activity of deferasirox and the hydrophilic oral iron chelating drug deferiprone in the peroxidation of linoleic acid micelles showed lower efficiency of deferasirox in comparison to deferiprone.
Topics: Antioxidants; Ascorbic Acid; Coordination Complexes; Deferasirox; Deferiprone; Humans; Iron; Iron Chelating Agents; Iron Overload; Linoleic Acid; Metals; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species
PubMed: 34443652
DOI: 10.3390/molecules26165064 -
Oxidative Medicine and Cellular... 2022Iron accumulates in the vital organs with aging. This is associated with oxidative stress, inflammation, and mitochondrial dysfunction leading to age-related disorders.... (Review)
Review
Iron accumulates in the vital organs with aging. This is associated with oxidative stress, inflammation, and mitochondrial dysfunction leading to age-related disorders. Abnormal iron levels are linked to neurodegenerative diseases, liver injury, cancer, and ocular diseases. Canonical Wnt signaling is an evolutionarily conserved signaling pathway that regulates many cellular functions including cell proliferation, apoptosis, cell migration, and stem cell renewal. Recent evidences indicate that iron regulates Wnt signaling, and iron chelators like deferoxamine and deferasirox can inhibit Wnt signaling and cell growth. Canonical Wnt signaling is implicated in the pathogenesis of many diseases, and there are significant efforts ongoing to develop innovative therapies targeting the aberrant Wnt signaling. This review examines how intracellular iron accumulation regulates Wnt signaling in various tissues and their potential contribution in the progression of age-related diseases.
Topics: Aging; Bone Remodeling; Eye Diseases; Humans; Iron Chelating Agents; Iron Overload; Neoplasms; Neurodegenerative Diseases; Oxidative Stress; Wnt Signaling Pathway
PubMed: 35116092
DOI: 10.1155/2022/7163326 -
Frontiers in Oncology 2021Iron chelation therapy (ICT) has become a mainstay in heavily transfused hematological patients, with the aim to reduce iron overload (IOL) and prevent organ damage.... (Review)
Review
Iron chelation therapy (ICT) has become a mainstay in heavily transfused hematological patients, with the aim to reduce iron overload (IOL) and prevent organ damage. This therapeutic approach is already widely used in thalassemic patients and in low-risk Myelodysplastic Syndrome (MDS) patients. More recently, ICT has been proposed for high-risk MDS, especially when an allogeneic bone marrow transplantation has been planned. Furthermore, other hematological and hereditary disorders, characterized by considerable transfusion support to manage anemia, could benefit from this therapy. Meanwhile, data accumulated on how iron toxicity could exacerbate anemia and other clinical comorbidities due to oxidative stress radical oxygen species (ROS) mediated by free iron species. Taking all into consideration, together with the availability of approved oral iron chelators, we envision a larger use of ICT in the near future. The aim of this review is to better identify those non-thalassemic patients who can benefit from ICT and give practical tips for management of this therapeutic strategy.
PubMed: 34692534
DOI: 10.3389/fonc.2021.752192 -
Journal of Blood Medicine 2023Chronic kidney disease (CKD) is a major global health concern, affecting millions of people worldwide. The progressive decline in kidney function often necessitates... (Review)
Review
Chronic kidney disease (CKD) is a major global health concern, affecting millions of people worldwide. The progressive decline in kidney function often necessitates renal replacement therapy, such as hemodialysis (HD) or peritoneal dialysis (PD), to maintain a patient's health. Iron overload, which is common in CKD patients on dialysis, can lead to severe complications, including cardiovascular disease and infections where most of the existing iron chelators are deemed unsuitable due to their suboptimal clearance in patients with compromised renal function, it becomes a significant challenge to effectively manage iron overload. Deferasirox (DFX), an oral iron chelator, has emerged as a promising treatment option for managing iron overload in these patients. However, the use of DFX comes with its unique set of challenges, such as its cost, potential side effects, and the need for close monitoring of patients, as well as the noticeable scarcity of comprehensive and rigorous clinical studies confirming its efficacy and safety of DFX. In this review, we delve into both the promising prospects and the emerging challenges associated with DFX use in managing CKD patients on HD or PD, striving for a comprehensive understanding that informs better clinical practice and patient care.
PubMed: 38047247
DOI: 10.2147/JBM.S415604 -
Pharmaceutics Dec 2022Microneedles are minimally invasive systems that can deliver drugs intradermally without pain and bleeding and can advantageously replace the hypodermal needles and oral...
Microneedles are minimally invasive systems that can deliver drugs intradermally without pain and bleeding and can advantageously replace the hypodermal needles and oral routes of delivery. Deferasirox (DFS) is an iron chelator employed in several ailments where iron overload plays an important role in disease manifestation. In this study, DFS was formulated into a nanosuspension (NSs) through wet media milling employing PVA as a stabilizer and successfully loaded in polymeric dissolving microneedles (DMNs). The release studies for DFS-NS clearly showed a threefold increased dissolution rate compared to pure DFS. The mechanical characterization of DFS-NS-DMNs revealed that the system was sufficiently strong for efficacious skin penetration. Optical coherence tomography images confirmed an insertion of up to 378 µm into full-thickness porcine skin layers. The skin deposition studies showed 60% drug deposition from NS-DMN, which was much higher than from the DFS-NS transdermal patch (DFS-NS-TP) (without needles) or pure DFS-DMNs. Moreover, DFS-NS without DMNs did not deposit well inside the skin, indicating that DMNs played an important role in effectively delivering drugs inside the skin. Therefore, it is evident from the findings that loading DFS-NS into novel DMN devices can effectively deliver DFS transdermally.
PubMed: 36559310
DOI: 10.3390/pharmaceutics14122817 -
British Journal of Clinical Pharmacology Aug 2022To develop a drug-disease model describing iron overload and its effect on ferritin response in patients affected by transfusion-dependent haemoglobinopathies and...
AIMS
To develop a drug-disease model describing iron overload and its effect on ferritin response in patients affected by transfusion-dependent haemoglobinopathies and investigate the contribution of interindividual differences in demographic and clinical factors on chelation therapy with deferiprone or deferasirox.
METHODS
Individual and mean serum ferritin data were retrieved from 13 published studies in patients affected by haemoglobinopathies receiving deferiprone or deferasirox. A nonlinear mixed effects modelling approach was used to characterise iron homeostasis and serum ferritin production taking into account annual blood consumption, baseline demographic and clinical characteristics. The effect of chelation therapy was parameterised as an increase in the iron elimination rate. Internal and external validation procedures were used to assess model performance across different study populations.
RESULTS
An indirect response model was identified, including baseline ferritin concentrations and annual blood consumption as covariates. The effect of chelation on iron elimination rate was characterised by a linear function, with different slopes for each drug (0.0109 [90% CI: 0.0079-0.0131] vs. 0.0013 [90% CI: 0.0008-0.0018] L/mg mo). In addition to drug-specific differences in the magnitude of the ferritin response, simulation scenarios indicate that ferritin elimination rates depend on ferritin concentrations at baseline.
CONCLUSION
Modelling of serum ferritin following chronic blood transfusion enabled the evaluation of drug-induced changes in iron elimination rate and ferritin production. The use of a semi-mechanistic parameterisation allowed us to disentangle disease-specific factors from drug-specific properties. Despite comparable chelation mechanisms, deferiprone appears to have a significantly larger effect on the iron elimination rate than deferasirox.
Topics: Benzoates; Chelation Therapy; Deferasirox; Deferiprone; Deferoxamine; Ferritins; Hemoglobinopathies; Humans; Iron; Iron Chelating Agents; Pyridones; Triazoles
PubMed: 35199367
DOI: 10.1111/bcp.15290 -
Antibiotics (Basel, Switzerland) Jan 2022Due to the rapid mutation of pathogenic microorganisms, drug-resistant superbugs have evolved. Antimicrobial-resistant germs may share their resistance genes with other...
Due to the rapid mutation of pathogenic microorganisms, drug-resistant superbugs have evolved. Antimicrobial-resistant germs may share their resistance genes with other germs, making them untreatable. The search for more combative antibiotic compounds has led researchers to explore metal-based strategies centered on perturbing the bioavailability of essential metals in microbes and examining the therapeutic potential of metal complexes. Given the limited knowledge on the application of titanium(IV), in this work, eight Ti(IV) complexes and some of their corresponding ligands were screened by the Community for Open Antimicrobial Drug Discovery for antimicrobial activity. The compounds were selected for evaluation because of their low cytotoxic/antiproliferative behavior against a human non-cancer cell line. At pH 7.4, these compounds vary in terms of their solution stability and ligand exchange lability; therefore, an assessment of their solution behavior provides some insight regarding the importance of the identity of the metal compound to the antimicrobial therapeutic potential. Only one compound, Ti(deferasirox), exhibited promising inhibitory activity against the Gram-positive bacteria methicillin-resistant and minimal toxicity against human cells. The ability of this compound to undergo transmetalation with labile Fe(III) sources and, as a consequence, inhibit Fe bioavailability and ribonucleotide reductase is evaluated as a possible mechanism for its antibiotic effect.
PubMed: 35203761
DOI: 10.3390/antibiotics11020158 -
Clinical and Translational Science Mar 2024Administration of oral medicinal products as crushed tablets or open capsules is an important delivery option for patients suffering from dysphagia. To obtain full... (Review)
Review
Administration of oral medicinal products as crushed tablets or open capsules is an important delivery option for patients suffering from dysphagia. To obtain full interchangeability of generics with the original products, demonstration of bioequivalence (BE) between both products administered as crushed tablets/open capsules was required for poorly soluble product by European Medicines Agency (EMA) at the time of development of our rivaroxaban and deferasirox generic products. We present the results of two BE studies with modified administration of these products, which compared relative bioavailability between generic and reference products. In the rivaroxaban study, the test product was administered as a capsule sprinkled on and mixed with applesauce, whereas the reference tablet was crushed and administered with applesauce under fed conditions. In the deferasirox study, both treatments were administered as crushed tablets under fasting conditions. Both studies applied a two-way crossover design and were conducted after a single-dose in healthy volunteers. The 90% confidence interval of the geometric mean ratio area under the analyte concentration versus time curve, from time zero to the time of the last measurable analyte concentration and maximum measured analyte concentration over the sampling period of the test to reference ratio were 103.36-110.37% and 97.98-108.45% for rivaroxaban, respectively, and 96.69-107.29% and 94.19-109.45% for deferasirox, respectively. Thus, the BE criteria (80.00-125.00%) were met in both studies which demonstrated that bioavailability was not affected when the test and reference products were administered in the form of crushed tablet/open capsule. These results support the argument of redundancy of crushed product studies for poorly soluble drugs, which is in line with the currently revised position of the EMA on this topic.
Topics: Humans; Therapeutic Equivalency; Rivaroxaban; Deferasirox; Administration, Oral; Tablets; Drugs, Generic
PubMed: 38511529
DOI: 10.1111/cts.13752 -
Pharmacogenomics and Personalized... 2023Sickle cell disease (SCD) is a genetic disease influenced by ethnicity and regional differences in its clinical course. Recent advances in the management of SCD with... (Review)
Review
UNLABELLED
Sickle cell disease (SCD) is a genetic disease influenced by ethnicity and regional differences in its clinical course. Recent advances in the management of SCD with newer therapies are being introduced to the Western population. However, many of these treatments are yet to be used in the Arabic SCD population. Understanding the genetic variations of SCD regionally is essential to anticipate the utilization of new treatments. This systematic review's main objective is to pool the available data on the genetic composition of SCD in the Arabic population. Data for 44,034 patients was extracted from 184 studies (11 case reports, 8 case series, 56 retrospectives, 107 prospective observational studies, and 2 clinical trials) using PubMed, Scopus, and Google Scholar. Male (49%) and female (51%) patients were equally reported wherever gender was available (N=13105). Various SCD genotypes were reported in a total of 14,257 patients, including Hb SS (77%) Hb Sβ0 (9.9%), and Hb Sβ+ (7.2%), while the rest of the genotypes, including HbSC, HbSD, HbSE, HbSO Arab, Hb S/α-Thal, Hb Sβ0 + α-Thal, and HBS Oman were individually reported in <4% of the cases. Major SCD complications in the Arab population included pain crises (48.25%) followed by neurological complications (33.46%), hepatobiliary complications (25.53%), musculoskeletal complications (24.73%), and hemolytic anemia (23.57%). The treatments reported for SCD included hydroxyurea (20%), blood transfusion (14.32%), and Deferasirox (3.03%). We did not find the use of stem cell transplantation or newer treatments such as L-Glutamine, Voxelotor, Crizanlizumab, or gene therapy reported in any of the studies included in our review. This review highlights the genetic makeup of SCD in Arab countries and its common phenotypic manifestations and will help direct further research on SCD in this region, especially concerning genetic therapy.
SYSTEMATIC REVIEW REGISTRATION
The protocol has been registered in the International Prospective Register of Systematic Reviews(PROSPERO):CRD42020218,666. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=218666.
PubMed: 36851992
DOI: 10.2147/PGPM.S391394