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Prague Medical Report 2019Tyrosine kinase inhibitors have recently become an essential tool in management of chronic myeloid leukaemia (CML). Dasatinib, a representative of those drugs, acts by... (Review)
Review
Tyrosine kinase inhibitors have recently become an essential tool in management of chronic myeloid leukaemia (CML). Dasatinib, a representative of those drugs, acts by inhibiting key proteins included in CML development, predominantly Bcr-Abl and Src. Its advantage is that it shows activity in many cases where other agents bring no improvement due to resistance. Pharmacokinetics of dasatinib has specific characteristics that may play an important role in achieving sufficient exposure in patients. Therefore, the key pharmacokinetic properties are summarized in this report. For example, dasatinib absorption is significantly influenced by gastric pH and its modulation can be a source of serious interactions, as well as simultaneous administration of drugs affecting cytochrome P450.
Topics: Cytochrome P-450 Enzyme System; Dasatinib; Drug Resistance, Neoplasm; Gastric Acid; Humans; Hydrogen-Ion Concentration; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors
PubMed: 31586504
DOI: 10.14712/23362936.2019.10 -
Clinical Lymphoma, Myeloma & Leukemia Feb 2017Dasatinib has demonstrated durable clinical responses in patients, both as first-line and subsequent lines of therapy. Dasatinib use can result in pleural effusion in... (Review)
Review
Dasatinib has demonstrated durable clinical responses in patients, both as first-line and subsequent lines of therapy. Dasatinib use can result in pleural effusion in some patients, occurring any time during treatment and commonly characterized as mild to moderate in severity. Early identification of symptoms is essential in the proper management of pleural effusion. Prompt confirmation of diagnosis and management of pleural effusion can minimize morbidity and maximize the ability to preserve long-term clinical benefits with dasatinib. Here, we provide guidance on early identification and management of dasatinib-related pleural effusion.
Topics: Antineoplastic Agents; Dasatinib; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Pleural Effusion
PubMed: 28082112
DOI: 10.1016/j.clml.2016.09.012 -
British Journal of Clinical Pharmacology May 2018Drug-induced (group 1) pulmonary hypertension (PH) is an important subgroup of PH involving dasatinib as a likely related agent, which is a second-generation tyrosine... (Review)
Review
Drug-induced (group 1) pulmonary hypertension (PH) is an important subgroup of PH involving dasatinib as a likely related agent, which is a second-generation tyrosine kinase inhibitor (TKI) used in the treatment of chronic myeloid leukaemia (CML). The mechanism of dasatinib-induced pulmonary arterial hypertension (PAH) is unclear. However, the occurrence of PAH with late onset in CML patients suggests a chronic pathological mechanism with an insidious onset rather than an acute inflammatory or cardiac aetiology. Dasatinib has a broader effect than other TKIs; the major known difference between dasatinib and other TKIs is the additional inhibition of Src family kinases. Therefore, Src inhibition was thought to play a role in the development of dasatinib-induced PAH. However, recently, it was also speculated that chronic dasatinib therapy may cause pulmonary endothelial damage, attenuate hypoxic pulmonary vasoconstriction responses and increase susceptibility to PAH independently of the Src family kinase-induced mechanism. Dasatinib-induced PAH usually seems to be reversible with the cessation of the drug, and sometimes with PAH-specific treatment strategies. Transthoracic echocardiography can be recommended as a routine screening prior to dasatinib initiation, and this non-invasive procedure can be utilized in patients having signs and symptoms attributable to PAH during dasatinib treatment.
Topics: Dasatinib; Echocardiography; Humans; Hypertension, Pulmonary; Protein Kinase Inhibitors
PubMed: 29334406
DOI: 10.1111/bcp.13508 -
The Gulf Journal of Oncology Sep 2022Dasatinib is a potent second-generation tyrosine kinase inhibitor (TKI) used in the first- and second-line treatment of chronic myeloid leukemia (CML). Chylothorax is a... (Review)
Review
Dasatinib is a potent second-generation tyrosine kinase inhibitor (TKI) used in the first- and second-line treatment of chronic myeloid leukemia (CML). Chylothorax is a rare presentation that results in chyle leakage from the lymphatic system into the pleural space as a consequence of thoracic duct damage. Pleural effusion has been reported frequently in patients treated with Dasatinib however chylothorax has been rarely reported. Here we report an 18year old female presenting with chylothorax after 63 months of Dasatinib intake along with a review of the relevant literature. Currently there are no standard guidelines regarding the approach to chylothorax management after the initial discontinuation of Dasatinib. Since the TKI options after stopping Dasatinib are limited, and most patients would have already failed the trial of first generation TKI, we suggest implementing a complete treatment strategy for this patient population. Key words: chronic myeloid leukemia, Dasatinib, Pleural effusion, Chylothorax.
Topics: Female; Humans; Chylothorax; Dasatinib; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Pleural Effusion; Adolescent
PubMed: 36448074
DOI: No ID Found -
Blood Advances Apr 2023Novel treatment strategies are needed for the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in older patients. This trial...
Novel treatment strategies are needed for the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in older patients. This trial evaluated the feasibility and outcomes with the anti-CD19 bispecific T-cell-engaging antibody, blinatumomab, in combination with dasatinib and steroids. Patients 65 years of age or older with Ph+ or Ph-like ALL (with dasatinib-sensitive fusions/mutations) were eligible and could be newly diagnosed or relapsed/refractory. Induction therapy consisted of dasatinib/prednisone. Patients not achieving response by day 56 proceeded to blinatumomab reinduction therapy. Patients achieving response with induction or reinduction therapy proceeded to blinatumomab/dasatinib postremission therapy for 3 cycles followed by dasatinib/prednisone maintenance. All patients received central nervous system prophylaxis with intrathecal methotrexate for a total of 8 doses. Response was assessed at days 28, 56, and 84 and at additional time points based on response parameters. Measurable residual disease was assessed centrally by 8-color flow cytometry at day 28. A total of 24 eligible patients with newly diagnosed Ph+ ALL were enrolled with a median age of 73 years (range, 65-87 years). This combination was safe and feasible. With a median of 2.7 years of follow-up, 3-year overall survival and disease-free survival were 87% (95% confidence interval [CI], 64-96) and 77% (95% CI, 54-90), respectively. Although longer follow-up is needed, these results are encouraging, and future trials are building on this backbone regimen. This trial was registered at www.clinicaltrials.gov as #NCT02143414.
Topics: Humans; Aged; Aged, 80 and over; Dasatinib; Prednisone; Treatment Outcome; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 36322825
DOI: 10.1182/bloodadvances.2022008216 -
EBioMedicine Sep 2019Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing and at...
BACKGROUND
Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing and at etiological sites in multiple chronic diseases. Senolytics, including the combination of Dasatinib and Quercetin (D + Q), selectively eliminate senescent cells by transiently disabling pro-survival networks that defend them against their own apoptotic environment. In the first clinical trial of senolytics, D + Q improved physical function in patients with idiopathic pulmonary fibrosis (IPF), a fatal senescence-associated disease, but to date, no peer-reviewed study has directly demonstrated that senolytics decrease senescent cells in humans.
METHODS
In an open label Phase 1 pilot study, we administered 3 days of oral D 100 mg and Q 1000 mg to subjects with diabetic kidney disease (N = 9; 68·7 ± 3·1 years old; 2 female; BMI:33·9 ± 2·3 kg/m; eGFR:27·0 ± 2·1 mL/min/1·73m). Adipose tissue, skin biopsies, and blood were collected before and 11 days after completing senolytic treatment. Senescent cell and macrophage/Langerhans cell markers and circulating SASP factors were assayed.
FINDINGS
D + Q reduced adipose tissue senescent cell burden within 11 days, with decreases in p16-and p21-expressing cells, cells with senescence-associated β-galactosidase activity, and adipocyte progenitors with limited replicative potential. Adipose tissue macrophages, which are attracted, anchored, and activated by senescent cells, and crown-like structures were decreased. Skin epidermal p16 and p21 cells were reduced, as were circulating SASP factors, including IL-1α, IL-6, and MMPs-9 and -12.
INTERPRETATION
"Hit-and-run" treatment with senolytics, which in the case of D + Q have elimination half-lives <11 h, significantly decreases senescent cell burden in humans. FUND: NIH and Foundations. ClinicalTrials.gov Identifier: NCT02848131. Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents.
Topics: Adipocytes; Adipose Tissue; Aged; Biomarkers; Biopsy; Cellular Senescence; Clinical Trials, Phase I as Topic; Dasatinib; Diabetic Nephropathies; Drug Therapy, Combination; Female; Humans; Immunohistochemistry; Kidney Function Tests; Macrophages; Male; Middle Aged; Quercetin
PubMed: 31542391
DOI: 10.1016/j.ebiom.2019.08.069 -
Medical Oncology (Northwood, London,... May 2023Dasatinib is the 2nd generation TKI (Tyrosine Kinase Inhibitor) having the potential to treat numerous forms of leukemic and cancer patients and it is 300 times more... (Review)
Review
Dasatinib is the 2nd generation TKI (Tyrosine Kinase Inhibitor) having the potential to treat numerous forms of leukemic and cancer patients and it is 300 times more potent than imatinib. Cancer is the major cause of death globally and need to enumerate novel strategies to coping with it. Various novel therapeutics introduced into the market for ease in treating various forms of cancer. We reviewed and evaluated all the related aspects of dasatinib, which can enhance the knowledge about dasatinib therapeutics methodology, pharmacodynamic and pharmacokinetics, side effects, advantages, disadvantages, various kinds of interactions and its novel formulations as well.
Topics: Humans; Dasatinib; Tyrosine Kinase Inhibitors; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors; Imatinib Mesylate
PubMed: 37165283
DOI: 10.1007/s12032-023-02018-5 -
The Journals of Gerontology. Series A,... Oct 2021Cellular senescence contributes to age-related disorders including physical dysfunction, disabilities, and mortality caused by tissue inflammation and damage. Senescent...
Cellular senescence contributes to age-related disorders including physical dysfunction, disabilities, and mortality caused by tissue inflammation and damage. Senescent cells accumulate in multiple tissues with aging and at etiological sites of multiple chronic disorders. The senolytic drug combination, Dasatinib plus Quercetin (D+Q), is known to reduce senescent cell abundance in aged mice. However, the effects of long-term D+Q treatment on intestinal senescent cell and inflammatory burden and microbiome composition in aged mice remain unknown. Here, we examine the effect of D+Q on senescence (p16Ink4a and p21Cip1) and inflammation (Cxcl1, Il1β, Il6, Mcp1, and Tnfα) markers in small (ileum) and large (caecum and colon) intestine in aged mice (n = 10) compared to age-matched placebo-treated mice (n = 10). Additionally, we examine microbial composition along the intestinal tract in these mice. D+Q-treated mice show significantly lower senescent cell (p16 and p21 expression) and inflammatory (Cxcl1, Il1β, Il6, Mcp1, and Tnfα expression) burden in small and large intestine compared with control mice. Further, we find specific microbial signatures in ileal, cecal, colonic, and fecal regions that are distinctly modulated by D+Q, with modulation being most prominent in small intestine. Further analyses reveal specific correlation of senescence and inflammation markers with specific microbial signatures. Together, these data demonstrate that the senolytic treatment reduces intestinal senescence and inflammation while altering specific microbiota signatures and suggest that the optimized senolytic regimens might improve health via reducing intestinal senescence, inflammation, and microbial dysbiosis in older subjects.
Topics: Animals; Biomarkers; Cellular Senescence; Dasatinib; Gastrointestinal Microbiome; Inflammation; Interleukin-6; Intestines; Mice; Quercetin; Senotherapeutics; Tumor Necrosis Factor-alpha
PubMed: 33406219
DOI: 10.1093/gerona/glab002 -
Aging Cell Feb 2023Aging results in an elevated burden of senescent cells, senescence-associated secretory phenotype (SASP), and tissue infiltration of immune cells contributing to chronic...
Aging results in an elevated burden of senescent cells, senescence-associated secretory phenotype (SASP), and tissue infiltration of immune cells contributing to chronic low-grade inflammation and a host of age-related diseases. Recent evidence suggests that the clearance of senescent cells alleviates chronic inflammation and its associated dysfunction and diseases. However, the effect of this intervention on metabolic function in old age remains poorly understood. Here, we demonstrate that dasatinib and quercetin (D&Q) have senolytic effects, reducing age-related increase in senescence-associated β-galactosidase, expression of p16 and p21 gene and P16 protein in perigonadal white adipose tissue (pgWAT; all p ≤ 0.04). This treatment also suppressed age-related increase in the expression of a subset of pro-inflammatory SASP genes (mcp1, tnf-α, il-1α, il-1β, il-6, cxcl2, and cxcl10), crown-like structures, abundance of T cells and macrophages in pgWAT (all p ≤ 0.04). In the liver and skeletal muscle, we did not find a robust effect of D&Q on senescence and inflammatory SASP markers. Although we did not observe an age-related difference in glucose tolerance, D&Q treatment improved fasting blood glucose (p = 0.001) and glucose tolerance (p = 0.007) in old mice that was concomitant with lower hepatic gluconeogenesis. Additionally, D&Q improved insulin-stimulated suppression of plasma NEFAs (p = 0.01), reduced fed and fasted plasma triglycerides (both p ≤ 0.04), and improved systemic lipid tolerance (p = 0.006). Collectively, results from this study suggest that D&Q attenuates adipose tissue inflammation and improves systemic metabolic function in old age. These findings have implications for the development of therapeutic agents to combat metabolic dysfunction and diseases in old age.
Topics: Mice; Animals; Dasatinib; Cellular Senescence; Quercetin; Senotherapeutics; Adipose Tissue; Inflammation; Glucose
PubMed: 36637079
DOI: 10.1111/acel.13767 -
Internal Medicine (Tokyo, Japan) Aug 2022
Topics: Antineoplastic Agents; Dasatinib; Humans; Hypertension, Pulmonary; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors
PubMed: 35110497
DOI: 10.2169/internalmedicine.9107-21