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Journal of Biomolecular Structure &... May 2023Nowadays, a nanostructure-based drug delivery system is one of the most noticeable topics to be studied, and in this regard, boron nitride nanoclusters are promising...
Nowadays, a nanostructure-based drug delivery system is one of the most noticeable topics to be studied, and in this regard, boron nitride nanoclusters are promising drug carriers for targeted drug delivery systems. In this article, the interaction mechanism of Anagrelide (AG) drug with B12N12 and Al- and Ga-doped B12N12 nanocages have been investigated using DFT with B3LYP/6-31 G (d, p) method in both gas and water media. All our studied complexes are thermodynamically stable, and doped nanocage complexes have higher negative adsorption energy (E and negative solvation energy than AG/B12N12 complexes which correspond to the stability of these systems in both media. The negative highest E value is 64.98 kcal/mol (63.17 kcal/mol) and 65.69 kcal/mol (65.11 kcal/mol) in gas (water) media for complex F (AG/AlB11N12) and complex I (AG/GaB11N12) respectively, which refers to the highest stability of these systems. The enhanced values of dipole moment (from 12.40 (12.65) Debye to 17.21 (17.69) Debye in complex F (complex I)) also confirm their stability. The QTAIM and RDG analysis endorse the strong adsorption nature of the AG drug onto the AlB11N12, and GaB11N12 nanocages, which is consistent with the adsorption energy as chemisorption occurs for these complexes. According to the electronic properties, doped nanocages show high sensitivity that infers their promising nature for drug delivery purposes. Thus, complex F and complex I are promising drug delivery systems, and doped nanocages (AlB11N12 and GaB11N12) are better carriers than pristine nanocages for the AG drug delivery system.Communicated by Ramaswamy H. Sarma.
Topics: Quinazolines; Boron Compounds; Nanostructures; Drug Carriers; Adsorption; Density Functional Theory; Quantum Theory
PubMed: 35272575
DOI: 10.1080/07391102.2022.2049369 -
Turkish Journal of Haematology :... Dec 2021
Topics: Humans; Leg Ulcer; Quinazolines
PubMed: 34445859
DOI: 10.4274/tjh.galenos.2021.2021.0399 -
Case Reports in Hematology 2023VEXAS syndrome stands for vacuoles, E1 enzyme, -linked, autoinflammatory, somatic syndrome. The syndrome is a combined hematological and rheumatological condition caused...
VEXAS syndrome stands for vacuoles, E1 enzyme, -linked, autoinflammatory, somatic syndrome. The syndrome is a combined hematological and rheumatological condition caused by a somatic mutation in the . There is an association between VEXAS and hematological conditions such as myelodysplastic syndrome (MDS), monoclonal gammopathies of uncertain conditions (MGUS), multiple myeloma (MM), and monoclonal B-cell lymphoproliferative conditions. There are not many descriptions of patients having VEXAS in combination with myeloproliferative neoplasm (MPN). With this article, we want to present a case history of a man in his sixties with a V617F mutated essential thrombocythemia (ET) developing VEXAS syndrome. The inflammatory symptoms occurred three and a half years after the ET diagnosis. He started to experience symptoms of autoinflammation and an overall worsening of his health, and blood work showed high inflammatory markers, leading to repeated hospitalizations. His major complaint was stiffness and pain, and high dosages of prednisolone were necessary to obtain pain relief. He subsequently developed anemia and significantly variable levels of thrombocytes, which previously were at a steady level. To evaluate his ET, we made a bone marrow smear demonstrating vacuolated myeloid and erythroid cells. Having VEXAS syndrome in mind, genetic testing identifying the gene mutation was performed, thus confirming our suspicion. The work-up with myeloid panel on his bone marrow identified genetic mutation in the too. After developing VEXAS syndrome, he experienced thromboembolic events with both cerebral infarction and pulmonary embolism. Thromboembolic events are also common in mutated patients, but in his case, they presented first after VEXAS had developed. Throughout the course of his condition, several attempts with prednisolone tapering and steroid sparing drugs were tried. He could not get pain relief unless the combination of medications included a relatively high dose of prednisolone. Currently, the patient uses prednisolone, anagrelide, and ruxolitinib, with partial remission and fewer hospitalizations and more stabilized hemoglobin and thrombocytes.
PubMed: 36879894
DOI: 10.1155/2023/6551544 -
Frontiers in Genetics 2022Glioma is the most malignant cancer of the central nervous system. There are various therapies for treating gliomas, but their outcomes are not satisfactory. Therefore,...
Glioma is the most malignant cancer of the central nervous system. There are various therapies for treating gliomas, but their outcomes are not satisfactory. Therefore, new targets for glioma treatment are needed. This study examined the cadherin-6 (CDH6) expression in gliomas using The Cancer Genome Atlas and Chinese Glioma Genome Atlas datasets. CDH6 expression positively correlated with the World Health Organization (WHO) tumor grade and negatively correlated with patient prognosis. A significant decrease in CDH6 promoter methylation was identified with an increase in the WHO grade severity. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses suggested that CDH6 might be involved in cell-cell interactions and immune processes in the glioma microenvironment. Weighted gene co-expression network analysis revealed a correlation between CDH6 and cell adhesion molecules, focal adhesions, phosphatidylinositol 3-kinase-protein kinase B signaling pathways, nuclear division, chromosome segregation, mitotic nuclear division, and immune-related pathways. CDH6 strongly correlated with immunosuppressive cells, including regulatory T cells, monocytes, macrophages, tumor-associated macrophages, and myeloid-derived suppressor cells. It also showed correlations with immune-active cells such as B cells, CD8 T cells, and dendritic cells. Single-cell analysis showed that CDH6 was expressed mainly in astrocyte (AC)-like malignant cells. Differentially expressed genes of AC-like malignant cells were found to be associated with stress response, membranous processes, viral infections, and several types of cancers. Potential drugs associated with high CDH6 expression were also predicted, including AMG-22, rutin, CCT128930, deforolimus, bis(maltolato)oxovanadium, anagrelide, vemurafenib, CHIR-98014, and AZD5582. Thus, this study showed that CDH6 correlates with glioma immune infiltration, it is expressed mainly in AC-like malignant cells, and it may act as a new target for glioma therapy.
PubMed: 35938030
DOI: 10.3389/fgene.2022.949552 -
Thrombosis and Haemostasis May 2021Hemorrhage is a well-known complication of essential thrombocythemia (ET) and polycythemia vera (PV), but evidence-based data on its management and prevention are... (Review)
Review
Hemorrhage is a well-known complication of essential thrombocythemia (ET) and polycythemia vera (PV), but evidence-based data on its management and prevention are lacking to help inform clinicians. In this review, appropriate published data from the past 15 years regarding bleeding epidemiology, classification, location, and risk factors are presented and discussed. Research was conducted using the Medline database. The bleeding classifications were heterogeneous among the collected studies. The median incidences of bleeding and major bleeding were 4.6 and 0.79% patients/year, in ET patients and 6.5 and 1.05% patients/year in PV patients, respectively. The most frequent location was the gastrointestinal tract. Bleeding accounted for up to 13.7% of deaths, and cerebral bleeding was the main cause of lethal hemorrhage. Thirty-nine potential risk factors were analyzed at least once, but the results were discrepant. Among them, age >60 years, bleeding history, splenomegaly, myeloproliferative neoplasm subtype, and platelet count should deserve more attention in future studies. Among the treatments, aspirin seemed to be problematic for young patients with ET (especially -mutated ET patients) and anagrelide was also identified as a bleeding inducer, especially when associated with aspirin. Future studies should analyze bleeding risk factors in more homogeneous populations and with common bleeding classifications. More tools are needed to help clinicians manage the increased risk of potentially lethal bleeding events in these diseases.
Topics: Age Factors; Hemorrhage; Humans; Platelet Count; Polycythemia Vera; Risk Factors; Thrombocythemia, Essential
PubMed: 33186994
DOI: 10.1055/s-0040-1720979 -
Cureus Sep 2022Essential thrombocythemia (ET) is a myeloproliferative neoplasm involving the clonal proliferation of platelets. It is Philadelphia negative and is associated with...
Essential thrombocythemia (ET) is a myeloproliferative neoplasm involving the clonal proliferation of platelets. It is Philadelphia negative and is associated with Janus kinase 2 (JAK2), calreticulin (CALR), or myeloproliferative leukemia virus oncogene (MPL) mutations. The resultant platelets have quantitative and qualitative defects, making them more sticky and prone to thromboembolism. However, ET does not only affect platelet survival, it also has a low leukemogenic potential. It's more common in the elderly, 60 years or more, but can be seen in all age groups, including children. Patients with ET have an increased risk of vascular events like hemorrhage and thromboses like cerebrovascular events, myocardial infarction, superficial thrombophlebitis, deep vein thrombosis, and pulmonary embolism. Cardiovascular risk factors like hypertension, diabetes, and smoking can lead to increased thromboembolism and atherosclerosis. The management of ET focuses primarily on the prevention of thrombosis and hemorrhage. It involves cardiovascular risk management and antiplatelet and cytoreductive therapy according to the risk stratification. Low-risk ET patients are treated with low-dose aspirin, and high-risk ET patients are treated with cytoreductive therapy with hydroxyurea. Interferon (IFN) and anagrelide are reserved for young patients or pregnant women. This case report discusses a 40-year-old male, a known smoker presenting with myocardial infarction and left anterior descending artery (LAD) blockage without any prior history. His high platelets and the relative absence of cardiovascular risk factors helped reach the diagnosis, and bone marrow analysis and mutation analysis confirmed the diagnosis. The patient was started on hydroxyurea, which decreased the total platelet count.
PubMed: 36225436
DOI: 10.7759/cureus.28883 -
Journal of Pharmaceutical and... May 2023Anagrelide (ANG) is a widely used drug for the treatment of essential thrombocytosis and myeloproliferative neoplasms. Recently, a new oxidative degradant was identified...
Anagrelide (ANG) is a widely used drug for the treatment of essential thrombocytosis and myeloproliferative neoplasms. Recently, a new oxidative degradant was identified when the drug product capsule underwent stress testing. Full structural characterization of this previously unidentified degradant was conducted. Preliminary LC-MS analysis indicated the targeted degradant as a mono-oxygenated product of ANG. For the purpose of facile isolation and purification, various forced degradation conditions were screened to enrich the desired degradant, among which, pyridinium chlorochromate (PCC)-treatment effectively afforded a yield of 55 % unknown degradant. Following isolation by prep-HPLC, 1D and 2D NMR studies and HRMS characterization assigned the products as a pair of 5-hydroxy-Anagrelide (5-OH-ANG) enantiomers. A plausible mechanism of formation is proposed.
Topics: Chromatography, High Pressure Liquid; Chromatography, Liquid; Mass Spectrometry; Quinazolines
PubMed: 36989665
DOI: 10.1016/j.jpba.2023.115352 -
Neurological Research Dec 2023In polycythemia vera (PV) patients undergoing phlebotomy, iron deficiency (ID) may develop. ID has been linked to restless legs syndrome (RLS), and in one study, 29.6%...
INTRODUCTION
In polycythemia vera (PV) patients undergoing phlebotomy, iron deficiency (ID) may develop. ID has been linked to restless legs syndrome (RLS), and in one study, 29.6% of PV patients had RLS. We aimed to evaluate the frequency of RLS in PV and to evaluate factors that might play a role in RLS development among PV and essential thrombocythemia (ET) patients.
METHODS
We consecutively included PV cases as the patient group, and ET and ID patients and healthy subjects (HSs) were included as controls. Those with conditions that could lead to RLS were excluded. All subjects were questioned according to the diagnostic criteria of the International Restless Legs Syndrome Study Group.
RESULTS
Twenty-seven PV, 23 ET, and 22 ID patients and 23 HSs were included. RLS was detected in 25.9%, 34.8%, and 45.5% of PV, ET, and ID patients, respectively. None of the HSs had RLS. In univariate analysis, interferon-α and anagrelide use, magnesium levels, and the Leeds assessment of neuropathic symptoms and signs (LANSS) scores had a significant impact on RLS in PV and ET patients ( = 0.014, = 0.032, = 0.036, and = 0.003, respectively).
CONCLUSION
RLS was more common among PV and ET patients than HSs, which was irrespective to the iron status. RLS was more frequent in ET patients than that observed in PV cases, indicating that ID may not be the only causative factor for RLS development in PV. Further prospective studies are needed to determine the prevalence and risk factors of RLS developing in PV and ET.
Topics: Humans; Polycythemia Vera; Cross-Sectional Studies; Restless Legs Syndrome; Iron Deficiencies; Prevalence
PubMed: 37736879
DOI: 10.1080/01616412.2023.2257443 -
Pharmacology 2021When choosing a cytoreduction method for patients suffering from essential thrombocythemia (ET), it is important to know the safety profile of the medicine used. Few...
BACKGROUND AND PURPOSE
When choosing a cytoreduction method for patients suffering from essential thrombocythemia (ET), it is important to know the safety profile of the medicine used. Few articles have been published about the effects of hydroxycarbamide (hydroxyurea, HU) and anagrelide (ANA) on renal function in ET patients. This study is the largest analysis of nephrotoxicity of cytoreductive drugs used in ET therapy so far, which additionally includes risk factors for the progression of kidney disease and coexisting genetic mutation.
EXPERIMENTAL APPROACH
The retrospective study included 310 patients diagnosed with ET. Demographic data, comorbidities, Cr, and estimated glomerular filtration rate (eGFR) were all taken into account prior to diagnosis and after 6 months of HU and ANA treatment.
KEY RESULTS
A statistically significant difference was found between Cr and eGFR levels at baseline and after 6 months of treatment (p < 0.001). The applied treatment (HU and ANA) had the greatest impact on kidney function. ANA significantly increased the risk of worsening renal function in contrary to hydroxycarbamide after 6 months of treatment (eGFR change: median +1 mL/min/1.73 m2 [interquartile range (IQR) (-4)-(+7)] in the HU group vss. median -13 mL/min/1.73 m2 [IQR (-18)-(-6)] in the ANA group, odds ratio [OR] 7.92 95% confidence interval [95% CI] [4.17-15.08], p < 0.001). Lowering of eGFR <60 mL/min/1.73 m2 occurred in 31 patients (31.0%) from the ANA group and 10 people (4.8%) treated with HU (p = 0.000). In 1 patient from the ANA group, >50% decrease in eGFR was observed. The chance for an increase in Cr levels was higher in people with pre-existing arterial hypertension (OR 1.92 CI = 95% [1.21-3.05], p = 0.006). Sex, type of mutation found (JAK2 V617F or CALR), and previous renal impairment did not affect renal function after 6 months of treatment. In addition, there was no difference in the efficacy of ET treatment between HU and ANA (p = 0.998).
CONCLUSIONS AND IMPLICATIONS
The observations indicate that ANA should be used in patients with ET with great caution and taking into account the risk of worsened kidney function.
Topics: Aged; Calreticulin; Creatinine; Disease Progression; Female; Humans; Hydroxyurea; Janus Kinase 2; Kidney Diseases; Male; Middle Aged; Mutation; Platelet Aggregation Inhibitors; Quinazolines; Retrospective Studies; Risk Factors; Thrombocythemia, Essential; Treatment Outcome
PubMed: 33691325
DOI: 10.1159/000513377 -
Cardiovascular Toxicology Mar 2021Essential thrombocythaemia (ET) is a rare myeloproliferative neoplasm. This multicentre, Phase 3b, randomised, open-label, non-inferiority study investigated the cardiac... (Comparative Study)
Comparative Study
Essential thrombocythaemia (ET) is a rare myeloproliferative neoplasm. This multicentre, Phase 3b, randomised, open-label, non-inferiority study investigated the cardiac safety, efficacy and tolerability of first-line treatment with anagrelide or hydroxyurea in high-risk ET patients for up to 3 years. Eligible patients aged ≥ 18 years with a diagnosis of high-risk ET confirmed by bone marrow biopsy within 6 months of randomisation received anagrelide (n = 75) or hydroxyurea (n = 74), administered twice daily. Treatment dose for either compound was titrated to the lowest dose needed to achieve a response. Planned primary outcome measures were change in left ventricular ejection fraction from baseline over time and platelet count at Month 6. Planned secondary outcome measures were platelet count change from baseline at Months 3 and 36; percentage of patients with complete or partial response; time to complete or partial response; number of patients with thrombohaemorrhagic events; and changes in white blood cell count or red blood cell count over time. Neither treatment altered cardiac function. There were no significant differences in adverse events between treatment groups, and no reports of malignant transformation. The incidence of disease-related thrombotic or haemorrhagic events was numerically higher in anagrelide-treated patients. Both treatments controlled platelet counts at 6 months, with the majority of patients experiencing complete or partial responses. In conclusion, these results suggest that long-term treatment with anagrelide is not associated with adverse effects on cardiac function. This is one of the few studies using left ventricular ejection fraction assessment and central biopsy reading to confirm the diagnosis of ET.Trial registration number: Clinicaltrials.gov NCT00202644.
Topics: Adolescent; Adult; Aged; Biopsy; Blood Platelets; Bone Marrow Examination; Echocardiography; Europe; Female; Humans; Hydroxyurea; Male; Middle Aged; Platelet Count; Quinazolines; Stroke Volume; Thrombocythemia, Essential; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left; Young Adult
PubMed: 33123978
DOI: 10.1007/s12012-020-09615-0