Pattern of Use and Long-Term Safety of Tyrosine Kinase Inhibitors: A Decade of Real-World Management of Chronic Myeloid Leukemia

Bettiol, Alessandra; Marconi, Ettore; Lombardi, Niccolò; Crescioli, Giada; Gherlinzoni, Filíppo; Walley, Thomas; Chinellato, Alessandro; Giusti, Pietro

doi:10.1007/s40261-018-0676-7

Cited by 9 publications

(15 citation statements)

References 28 publications

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“…Only approximately 14% of the patients changed TKI in their first year of treatment but there were discontinuations in 23% of the cases and almost 52% of interruptions. These results are consistent with studies that investigate treatment patterns with protein kinase inhibitors among patients with CML (35)(36)(37)(38). Reasons for switching or discontinuation could be adverse effects or intolerance to TKI (38,39).…”

Section: Patterns Of Tki Treatment and Healthcare Resources Consumptionsupporting

confidence: 88%

Patterns of Tyrosine Kinase Inhibitor Utilization in Newly Treated Patients With Chronic Myeloid Leukemia: An Exhaustive Population-Based Study in France

et al. 2021

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We analyzed demographic characteristics, comorbidities and patterns of treatment with tyrosine kinase inhibitors (TKIs) in a cohort of 3,633 incident cases of chronic myeloid leukemia (CML) identified across France from 1 January 2011 to 31 December 2014. Patients were identified through a specific algorithm in the French Healthcare Data System and were followed up 12 months after inclusion in the cohort. The estimated incidence rate of CML for this period in France was 1.37 per 100,000 person-years (95% Confidence Interval 1.36-1.38) and was higher in men, with a peak at age 75-79 years. At baseline, the median age of the cohort was 60 years (Inter Quartile Range 47-71), the Male/Female ratio was 1.2, and 25% presented with another comorbidity. Imatinib was the first-line TKI for 77.6% of the patients, followed by nilotinib (18.3%) and dasatinib (4.1%). Twelve months after initiation, 86% of the patients remained on the same TKI, 13% switched to another TKI and 1% received subsequently three different TKIs. During the follow-up, 23% discontinued and 52% suspended the TKI. Patients received a mean of 16.7 (Standard Deviation (SD) 9.6) medications over the first year of follow-up, and a mean of 2.7 (SD 2.3) concomitant medications on the day of first TKI prescription: 24.4% of the patients received allopurinol, 6.4% proton pump inhibitors (PPI) and 6.5% antihypertensive agents. When treatment with TKI was initiated, incident CML patients presented with comorbidities and polypharmacy, which merits attention because of the persistent use of these concomitant drugs and the potential increased risk of drug-drug interactions.

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Section: Patterns Of Tki Treatment and Healthcare Resources Consumptionsupporting

confidence: 88%

Patterns of Tyrosine Kinase Inhibitor Utilization in Newly Treated Patients With Chronic Myeloid Leukemia: An Exhaustive Population-Based Study in France

et al. 2021

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“…There are several advantages of SAR over the other FDA-approved Src kinase inhibitors for neurological diseases. Dasatinib (Sprycel) and imatinib (Gleevec) are FDA-approved ATP-competitive Src tyrosine kinase inhibitors for the treatment of certain cancers ( Bettiol et al, 2018 ; Shah et al, 2015 ; Waller, 2018 ). However, these drugs failed in clinical trials for glioma due to poor BBB permeability.…”

Section: Discussionmentioning

confidence: 99%

“…The ATP-binding cassette (ABC) efflux transporters, ABCG2 and ABCB1, at the BBB restrict brain penetration ( Kast and Focosi, 2010 ; Mittapalli et al, 2016 ; Tyryshkin et al, 2014 ). Moreover, both drugs have wide off-targets, predominantly the cytosolic c-Abl, ephrin receptor kinases, PDGF receptors, and many others ( Bettiol et al, 2018 ; Shah et al, 2015 ; Waller, 2018 ). In contrast, SAR has a > 10-fold preference for Fyn/Src over c-Abl ( Lindauer and Hochhaus, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of disease-modifying effect of saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor, in the rat kainate model of temporal lobe epilepsy

Sharma

Carlson

Gregory-Flores

et al. 2021

Neurobiology of Disease

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We have recently demonstrated the role of the Fyn-PKCδ signaling pathway in status epilepticus (SE)-induced neuroinflammation and epileptogenesis in experimental models of temporal lobe epilepsy (TLE). In this study, we show a significant disease-modifying effect and the mechanisms of a Fyn/Src tyrosine kinase inhibitor, saracatinib (SAR, also known as AZD0530), in the rat kainate (KA) model of TLE. SAR treatment for a week, starting the first dose (25 mg/kg, oral) 4 h after the onset of SE, significantly reduced spontaneously recurring seizures and epileptiform spikes during the four months of continuous video-EEG monitoring. Immunohistochemistry of brain sections and Western blot analyses of hippocampal lysates at 8-day (8d) and 4-month post-SE revealed a significant reduction of SE-induced astrogliosis, microgliosis, neurodegeneration, phosphorylated Fyn/Src-419 and PKCδ-tyr311, in SAR-treated group when compared with the vehicle control. We also found the suppression of nitroxidative stress markers such as iNOS, 3-NT, 4-HNE, and gp91 phox in the hippocampus, and nitrite and ROS levels in the serum of the SAR-treated group at 8d post-SE. The qRT-PCR (hippocampus) and ELISA (serum) revealed a significant reduction of key proinflammatory cytokines TNFα and IL-1β mRNA in the hippocampus and their protein levels in serum, in addition to IL-6 and IL-12, in the SAR-treated group at 8d in contrast to the vehicle-treated group. These findings suggest that SAR targets some of the key biomarkers of epileptogenesis and modulates neuroinflammatory and nitroxidative pathways that mediate the development of epilepsy. Therefore, SAR can be developed as a potential disease-modifying agent to prevent the development and progression of TLE.

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“…Nevertheless, as in every repurposing study, main indications, contraindications, interactions, adverse effects and toxicity in general must be taken into account (Cha et al, 2018;Oprea et al, 2011). This especially holds true when the investigation focuses on a class of drugs for which the use of medication is often accompanied by intolerance and adverse effects (Bettiol et al, 2018;Fachi et al, 2018).…”

Section: Docking Studymentioning

confidence: 99%

A computational approach to drug repurposing against SARS-CoV-2 RNA dependent RNA polymerase (RdRp)

Ribaudo

Ongaro

Oselladore

et al. 2020

Journal of Biomolecular Structure and Dynamics

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The spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) caused a worldwide outbreak of coronavirus disease 19 (COVID-19), which rapidly evolved as a global concern. The efforts of the scientific community are pointed towards the identification of promptly available therapeutic options. RNA-dependent RNA polymerase (RdRp) is a promising target for developing small molecules to contrast SARS-CoV-2 replication. Modern computational tools can boost identification and repurposing of known drugs targeting RdRp. We here report the results regarding the screening of a database containing more than 8800 molecules, including approved, experimental, nutraceutical, illicit, withdrawn and investigational compounds. The molecules were docked against the cryo-electron microscopy structure of SARS-CoV-2 RdRp, optimized by means of molecular dynamics (MD) simulations. The adopted three-stage ensemble docking study underline that compounds formerly developed as kinase inhibitors may interact with RdRp.

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Pattern of Use and Long-Term Safety of Tyrosine Kinase Inhibitors: A Decade of Real-World Management of Chronic Myeloid Leukemia

Cited by 9 publications

References 28 publications

Patterns of Tyrosine Kinase Inhibitor Utilization in Newly Treated Patients With Chronic Myeloid Leukemia: An Exhaustive Population-Based Study in France

Patterns of Tyrosine Kinase Inhibitor Utilization in Newly Treated Patients With Chronic Myeloid Leukemia: An Exhaustive Population-Based Study in France

Mechanisms of disease-modifying effect of saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor, in the rat kainate model of temporal lobe epilepsy

A computational approach to drug repurposing against SARS-CoV-2 RNA dependent RNA polymerase (RdRp)

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