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Internal Medicine (Tokyo, Japan) Nov 2022Anagrelide is used worldwide to treat essential thrombocythemia (ET) by reducing platelet counts. Cardiomyopathy and heart failure (HF) are rare but serious... (Review)
Review
Anagrelide is used worldwide to treat essential thrombocythemia (ET) by reducing platelet counts. Cardiomyopathy and heart failure (HF) are rare but serious complications associated with anagrelide use, although no cases were reported during Japanese Phase I to III studies. A 46-year-old, otherwise healthy, Japanese ET patient developed HF with reduced ejection fraction after 18 months of treatment with 1.0-3.5 mg of anagrelide daily. HF was stabilized with anagrelide withdrawal and guideline-directed HF therapy. The cardiac function returned to normal after six months. This case suggests that anagrelide can cause cardiomyopathy and HF in ET patients, regardless of nationality, comorbid cardiovascular conditions, or therapy duration.
Topics: Humans; Middle Aged; Thrombocythemia, Essential; Platelet Aggregation Inhibitors; Cardiomyopathies; Heart Failure
PubMed: 35342135
DOI: 10.2169/internalmedicine.9090-21 -
Biomolecules Mar 2022Cell adhesion molecule L1 is a cell surface glycoprotein that promotes neuronal cell migration, fosters regeneration after spinal cord injury and ameliorates the...
Cell adhesion molecule L1 is a cell surface glycoprotein that promotes neuronal cell migration, fosters regeneration after spinal cord injury and ameliorates the consequences of neuronal degeneration in mouse and zebrafish models. Counter-indicative features of L1 were found in tumor progression: the more L1 is expressed, the more tumor cells migrate and increase their metastatic potential. L1's metastatic potential is further evidenced by its promotion of epithelial-mesenchymal transition, endothelial cell transcytosis and resistance to chemo- and radiotherapy. These unfortunate features are indicated by observations that cells that normally do not express L1 are induced to express it when becoming malignant. With the aim to ameliorate the devastating functions of L1 in tumors, we designed an alternative approach to counteract tumor cell migration. Libraries of small organic compounds were screened using the ELISA competition approach similar to the one that we used for identifying L1 agonistic mimetics. Whereas in the former approach, a function-triggering monoclonal antibody was used for screening libraries, we here used the function-inhibiting monoclonal antibody 324 that reduces the migration of neurons. We now show that the L1 antagonistic mimetics anagrelide, 2-hydroxy-5-fluoropyrimidine and mestranol inhibit the migration of cultured tumor cells in an L1-dependent manner, raising hopes for therapy.
Topics: Animals; Antibodies, Monoclonal; Cell Adhesion; Cell Movement; Glioblastoma; Mice; Neural Cell Adhesion Molecule L1; Zebrafish
PubMed: 35327631
DOI: 10.3390/biom12030439 -
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 -
South Dakota Medicine : the Journal of... Nov 2021Anagrelide is a drug used for treatment of essential thrombocytosis especially when conventional therapy is insufficient. Adverse effects associated with anagrelide are...
BACKGROUND
Anagrelide is a drug used for treatment of essential thrombocytosis especially when conventional therapy is insufficient. Adverse effects associated with anagrelide are palpitation, liver toxicity, renal failure and in few cases pericardial effusion. We here report a rare case of anagrelide induced pericardial effusion.
CASE PRESENTATION
A 76-year-old male with past medical history of hypertension, hyperlipidemia, chronic obstructive pulmonary disease, and myeloproliferative disorder presented to the emergency department with dyspnea on rest and exertion. He was initially treated with hydroxyurea for thrombocytosis but was later switched to anagrelide. On examination patient had muffled heart sounds. Lab investigations identified hyperkalemia and transaminitis. Transthoracic echocardiogram identified a moderate sized pericardial effusion. The pericardial effusion and transaminitis were attributed to anagrelide toxicity as other causes were ruled out. Pericardiocentesis was performed and anagrelide was discontinued. Patient was discharged in a well-compensated state with outpatient follow-up in two to three weeks.
CONCLUSION
Anagrelide is considered to be very effective treatment for essential thrombocytosis. It is, however, associated with serious adverse effects such as pericardial effusion, liver toxicity and palpitations. The mechanisms of these adverse drug reactions are still not completely understood. We suggest that patient taking anagrelide presenting with shortness of breath should have a transthoracic echocardiogram performed to rule out pericardial effusion. Liver enzymes should also be monitored closely and anagrelide discontinued immediately if the above-mentioned adverse events are noted.
Topics: Aged; Humans; Male; Myeloproliferative Disorders; Platelet Aggregation Inhibitors; Thrombocytosis; Treatment Outcome
PubMed: 35008135
DOI: No ID Found -
Dermatologic Therapy Feb 2022
Topics: Humans; Prednisolone; Quinazolines; Thrombocythemia, Essential; Toes; Ulcer
PubMed: 34846771
DOI: 10.1111/dth.15221 -
Nature Communications Oct 2021Molecular glues are a class of small molecular drugs that mediate protein-protein interactions, that induce either the degradation or stabilization of target protein. A...
Molecular glues are a class of small molecular drugs that mediate protein-protein interactions, that induce either the degradation or stabilization of target protein. A structurally diverse group of chemicals, including 17-β-estradiol (E2), anagrelide, nauclefine, and DNMDP, induces apoptosis by forming complexes with phosphodiesterase 3A (PDE3A) and Schlafen 12 protein (SLFN12). They do so by binding to the PDE3A enzymatic pocket that allows the compound-bound PDE3A to recruit and stabilize SLFN12, which in turn blocks protein translation, leading to apoptosis. In this work, we report the high-resolution cryo-electron microscopy structure of PDE3A-SLFN12 complexes isolated from cultured HeLa cells pre-treated with either anagrelide, or nauclefine, or DNMDP. The PDE3A-SLFN12 complexes exhibit a butterfly-like shape, forming a heterotetramer with these small molecules, which are packed in a shallow pocket in the catalytic domain of PDE3A. The resulting small molecule-modified interface binds to the short helix (E552-I558) of SLFN12 through hydrophobic interactions, thus "gluing" the two proteins together. Based on the complex structure, we designed and synthesized analogs of anagrelide, a known drug used for the treatment of thrombocytosis, to enhance their interactions with SLFN12, and achieved superior efficacy in inducing apoptosis in cultured cells as well as in tumor xenografts.
Topics: Animals; Antineoplastic Agents; Apoptosis; Binding Sites; Cryoelectron Microscopy; Cyclic Nucleotide Phosphodiesterases, Type 3; Drug Design; HeLa Cells; Humans; Hydrophobic and Hydrophilic Interactions; Indoles; Intracellular Signaling Peptides and Proteins; Mice; Multiprotein Complexes; Naphthyridines; Pyridazines; Quinazolines; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 34707099
DOI: 10.1038/s41467-021-26546-8 -
In Vivo (Athens, Greece) 2021This work aimed to prospectively evaluate the clinical significance of circulating microparticles (MPs) in relation to thrombotic risk factors and thrombotic...
BACKGROUND/AIM
This work aimed to prospectively evaluate the clinical significance of circulating microparticles (MPs) in relation to thrombotic risk factors and thrombotic complications in patients with BCR/ABL1-negative myeloproliferative neoplasms (MPN).
PATIENTS AND METHODS
In a cohort of 206 patients with MPN, MPs' procoagulant activity was measured by the Zymuphen functional assay in 429 samples, while platelet- and erythrocyte-MPs were enumerated by flow cytometry in 558 samples.
RESULTS
MPN patients had higher MP levels than the control group. The levels of MPs were higher in male patients, smokers, and those who were older than 60 years, and in the presence of JAK2 mutation, history of thrombosis, platelets >400×10/l, hematocrit >45%, or leukocytes >10×10/l. Cytoreductive treatment reduced MP levels, with anagrelide being associated with lower MP levels than hydroxyurea.
CONCLUSION
The relationship with thrombotic risk factors indicates a possible role of MPs in the complex thrombotic mechanism, though cytoreductive treatment seems to affect this role through reducing MP levels.
Topics: Blood Platelets; Cell-Derived Microparticles; Humans; Male; Myeloproliferative Disorders; Neoplasms; Thrombosis
PubMed: 34697168
DOI: 10.21873/invivo.12632 -
The Lancet. Haematology Sep 2021Recommendations regarding management of essential thrombocythaemia rely on studies done before the discovery of the CALR mutation. On May 20, 2020, the European... (Review)
Review
Recommendations regarding management of essential thrombocythaemia rely on studies done before the discovery of the CALR mutation. On May 20, 2020, the European LeukemiaNet annual meeting was held with the goal to identify unmet clinical needs in myeloproliferative neoplasms. Because patients with a CALR mutation have specific clinical characteristics, treatment of CALR-mutated essential thrombocythaemia was considered an unmet clinical need by the European LeukemiaNet. The elaboration of a consensus document with recommendations according to current evidence was proposed as a solution for resolving uncertainties in the treatment of CALR-mutated essential thrombocythaemia. A steering committee comprising four European LeukemiaNet members was then formed and a panel of ten experts in the field was recruited. The experts proposed 51 potential unmet clinical needs in the management of CALR-mutated essential thrombocythaemia and were asked to score the relevance of each topic. Those topics that obtained the highest scores as relevant unmet clinical needs were identified, including antiplatelet therapy in patients at low risk, definition of extreme thrombocytosis and its management in patients at low risk, indications of cytoreduction and targets of therapy, first-line treatment of choice in young patients (<60 years), and management of pregnancy. After the steering committee revised the available evidence for each topic, a consensus on management and proposal for improving knowledge was achieved by use of an email-based, two round, Delphi approach. Consensus was achieved when 90% of the panellists agreed with a statement and included 14 recommendations and six solution proposals. Key recommendations included careful observation for asymptomatic patients with classical, low-risk, CALR-mutated essential thrombocythaemia without cardiovascular risk factors; caution in the use of antiplatelet therapy for symptomatic patients at low risk with platelet counts of 1000-1500 × 10 platelets per L, in such cases cytoreduction is an adequate option, especially if adquired Von Willebrand disease is present; cytoreduction is recommended for extreme thrombocytosis (platelet count >1500 × 10 platelets per L) with pegylated interferon alfa being the preferred option for younger patients; both hydroxycarbamide and anagrelide might be given to patients ineligible for pegylated interferon alfa; and treatment algorithms for patients with high-risk pregnancies should not be changed according to genotype. The European LeukemiaNet proposes to use these recommendations in the routine management of patients with CALR-mutated essential thrombocythaemia, and designing new clinical studies in this field might be useful.
Topics: Age Factors; Calreticulin; Female; Heparin, Low-Molecular-Weight; Humans; Platelet Aggregation Inhibitors; Platelet Count; Pregnancy; Severity of Illness Index; Thrombocythemia, Essential
PubMed: 34450103
DOI: 10.1016/S2352-3026(21)00204-0 -
Turkish Journal of Haematology :... Dec 2021
Topics: Humans; Leg Ulcer; Quinazolines
PubMed: 34445859
DOI: 10.4274/tjh.galenos.2021.2021.0399 -
Expert Review of Hematology Sep 2021Chronic myeloproliferative neoplasm (MPNs) are clonal malignant bone marrow (BM) diseases, arising from a hematopoietic stem cell. All therapies for these neoplasms... (Review)
Review
Chronic myeloproliferative neoplasm (MPNs) are clonal malignant bone marrow (BM) diseases, arising from a hematopoietic stem cell. All therapies for these neoplasms have peculiar effects on the bone marrow, but little evidence has been described in the literature. This review examines BM morphological changes following the main treatments in Philadelphia-negative MPNs. Hydroxyurea can reduce the cellularity of the erythroid and megakaryocyte lineages but has minimal impact on fibrotic evolution. There is general agreement on its dysplastic effects, with a high incidence of acute myeloid leukemia and myelodysplastic syndrome. Interferon treatment can reduce or normalize BM cellularity, improve erythropoiesis, and reduce the number and atypicality of megakaryocytes. Most data describe reduction or complete resolution of marrow fibrosis; dysplastic effects are not reported. Anagrelide may induce an increase in the number of BM megakaryocytes, especially immature megakaryocytes or precursors, and a worsening of marrow fibrosis or increased transformation of essential thrombocythemia into myelofibrosis. Ruxolitinib can improve or stabilize BM fibrosis and reduces the frequency and dense clustering of megakaryocytes. Since previous therapy can modify BM features, it is essential to obtain information on previous or current therapies and to collect complete clinical information.
Topics: Bone Marrow; Humans; Myeloproliferative Disorders; Neoplasms; Primary Myelofibrosis; Thrombocythemia, Essential
PubMed: 34384330
DOI: 10.1080/17474086.2021.1967138