Olanzapine-induced neutropenia

Malhotra, K. K.; Vu, Priscilla; Wang, Danielle H.; Lai, Hank; Faziola, Lawrence

doi:10.1108/mi.2015.5871

Cited by 6 publications

(6 citation statements)

References 11 publications

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“…Our analysis of olanzapine in combination with aprepitant, ondansetron and dexamethasone revealed a significantly higher incidence of grade ≥2 neutropenia in the olanzapine arm than in the standard arm, although this altered incidence was not associated with a significant difference in neutropenic fever. 9 A few cases of olanzapineinduced neutropenia have been reported 21 ; additionally, a recent randomised antiemetic study showed that patients who received an olanzapinecontaining regimen had a higher frequency of severe neutropenia (without an increased incidence of neutropenic fever). 22 Although the underlying mechanism remains unknown, the results of the aforementioned Japanese study 20 suggest that olanzapine 5 mg could reduce the incidence of neutropenia.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of contemporary olanzapine- and netupitant/palonosetron-containing antiemetic regimens for chemotherapy-induced nausea and vomiting

Yip

Lau

et al. 2023

Hong Kong Med J

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Introduction: This post-hoc analysis retrospectively assessed data from two recent studies of antiemetic regimens for chemotherapy-induced nausea and vomiting (CINV). The primary objective was to compare olanzapine-based versus netupitant/ palonosetron (NEPA)-based regimens in terms of controlling CINV during cycle 1 of doxorubicin/ cyclophosphamide (AC) chemotherapy; secondary objectives were to assess quality of life (QOL) and emesis outcomes over four cycles of AC.Methods: This study included 120 Chinese patients with early-stage breast cancer who were receiving AC; 60 patients received the olanzapine-based antiemetic regimen, whereas 60 patients received the NEPA-based antiemetic regimen. The olanzapinebased regimen comprised aprepitant, ondansetron, dexamethasone, and olanzapine; the NEPA-based regimen comprised NEPA and dexamethasone. Patient outcomes were compared in terms of emesis control and QOL. Results:During cycle 1 of AC, the olanzapine group exhibited a higher rate of 'no use of rescue therapy' in the acute phase (olanzapine vs NEPA: 96.7% vs 85.0%, P=0.0225). No parameters differed between groups in the delayed phase. The olanzapine group had significantly higher rates of 'no use of

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Section: Discussionmentioning

confidence: 99%

Evaluation of contemporary olanzapine- and netupitant/palonosetron-containing antiemetic regimens for chemotherapy-induced nausea and vomiting

Yip

Lau

et al. 2023

Hong Kong Med J

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“…In contrast, the concentration of olanzapine required to activate the same TCC exceeded the plasma concentration of 0.16 mM by 30-50 fold. This suggests that the lower daily dose of olanzapine might be in part responsible for the lack of T cell activation in patients and the significantly lower incidence of blood dyscrasias when compared with clozapine (48,49). To further investigate the nature of the T cell response induced with clozapine and olanzapine, TCC were stimulated with both compounds at therapeutic and T cell stimulatory concentrations, and drug-induced changes in protein expression were analyzed at 8, 24, and 48 h using iTRAQ.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Clozapine-Responsive Human T Cells

Ogese

Lister

Jenkins

et al. 2020

The Journal of Immunology

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Use of the atypical antipsychotic clozapine is associated with life-threatening agranulocytosis. The delayed onset and the association with HLA variants are characteristic of an immunological mechanism. The objective of this study was to generate clozapine-specific T cell clones (TCC) and characterize pathways of T cell activation and cross-reactivity with clozapine metabolites and olanzapine. TCC were established and characterized by culturing PBMCs from healthy donors and patients with a history of clozapine-induced agranulocytosis. Modeling was used to explore the drug–HLA binding interaction. Global TCC protein changes were profiled by mass spectrometry. Six well-growing clozapine-responsive CD4+ and CD8+ TCC were used for experiments; activation of TCC required APC, with clozapine interacting directly at therapeutic concentrations with several HLA-DR molecules. TCC were also activated with N-desmethylclozapine and olanzapine at supratherapeutic concentrations. Marked changes in TCC protein expression profiles were observed when clozapine treatment was compared with olanzapine and the medium control. Docking of the compounds into the HLA-DRB1*15:01 and HLA-DRB1*04:01 binding clefts revealed that clozapine and olanzapine bind in a similar conformation to the P4–P6 peptide binding pockets, whereas clozapine N-oxide, which did not activate the TCC, bound in a different conformation. TCC secreted Th1, Th2, and Th22 cytokines and effector molecules and expressed TCR Vβ 5.1, 16, 20, and 22 as well as chemokine receptors CXCR3, CCR6, CCR4, and CCR9. Collectively, these data show that clozapine interacts at therapeutic concentrations with HLA-DR molecules and activates human CD4+ T cells. Olanzapine only activates TCC at supratherapeutic concentrations.

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“…Hence, all formulation factors (A, B, and C) were found significant for responses Y 1 to Y 3 and are shown in Eqs. ( 6), (7), and (8).…”

Section: Selection Of Componentsmentioning

confidence: 99%

“…Agranulocytosis study of OLZ was performed on experimental animals, which was treated by low (1 mg/kg), medium (2 mg/kg), and high (4 mg/kg) doses of OLZ nanoformulations for 28 days. The OLZ is associated with agranulocytosis and leukopenia (5,7). The animals were regularly examined for mortality and toxicity during the study period.…”

Section: Agranulocytosis and Cytotoxic Effect On Wbcsmentioning

confidence: 99%

“…The mechanism of OLZ-induced agranulocytosis is not clear, but the previous reports suggest that this drug affects the level of granulocyte-colony-stimulating factor (G-CSF), which causes granulocytopenia, whereas OLZ-induced neutropenia occurs due to the formation of nitrenium cations, which is catalyzed by a flavincontaining monoxenage-3 system of leukocytes. Thus, leukopenia and neutropenia are serious and potentially life-threatening hematological side effects of conventional OLZ delivery (5,7).…”

Section: Introductionmentioning

confidence: 99%

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Agranulocytosis-Protective Olanzapine-Loaded Nanostructured Lipid Carriers Engineered for CNS Delivery: Optimization and Hematological Toxicity Studies

2019

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Potential risk of agranulocytosis is one of the drug-induced adverse effects of the second-generation antipsychotic agents. The present investigation aimed to formulate and investigate olanzapine (OLZ)-loaded nanostructured lipid carriers (OLZ-NLCs) via intranasal (i.n.) route. The NLC was prepared by melt emulsification method and optimized by Box-Behnken design. Mucoadhesive NLC was prepared by using 0.4% Carbopol 974P (OLZ-MNLC (C)) and the combination of 17% poloxamer 407 and 0.3% of HPMC K4M (OLZ-MNLC (P+H)). The particle size, zeta potential, and entrapment efficiency were found to be 88.95 nm ± 1.7 nm, − 22.62 mV ± 1.9 mV, and 88.94% ± 3.9%, respectively. Ex vivo permeation of OLZ-NLC, OLZ-MNLC (P+H), and OLZ-MNLC (C) was found to be 545.12 μg/cm 2 ± 12.8 μg/cm 2 , 940.02 μg/cm 2 ± 15.5 μg/cm 2 , and 820.10 μg/cm 2 ± 11.3 μg/cm 2 , respectively, whereas the OLZ-MNLC (P+H) formulation showed rapid drug permeation than the OLZ-NLC and OLZ-MNLC (C) formulations. The OLZ-MNLC (P+H) formulation was shown to have 13.57-and 27.64-fold more J ss than the OLZ-MNLC (C) and OLZ-NLC formulations. The OLZ nanoformulations showed sustained release of up to 8 h. Finally, the brain C max of technetium-99m ( 99m Tc)-OLZ-MNLC (i.n.) and 99m Tc-OLZ-NLC (i.v.) was found to be 936 ng and 235 ng, respectively, whereas the C max of i.n. administration was increased 3.98-fold more than the C max of i.v. administration. The in vivo hematological study of OLZ-MNLC (P+H) confirmed that the i.n. formulation did not reflect any variation in leukocyte, RBC and platelet counts. Hence, it can be concluded that the nose-to-brain delivery of OLZ-MNLC (P+H) can be considered as an effective and safe delivery for CNS disorders.

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Olanzapine-induced neutropenia

Cited by 6 publications

References 11 publications

Evaluation of contemporary olanzapine- and netupitant/palonosetron-containing antiemetic regimens for chemotherapy-induced nausea and vomiting

Evaluation of contemporary olanzapine- and netupitant/palonosetron-containing antiemetic regimens for chemotherapy-induced nausea and vomiting

Characterization of Clozapine-Responsive Human T Cells

Agranulocytosis-Protective Olanzapine-Loaded Nanostructured Lipid Carriers Engineered for CNS Delivery: Optimization and Hematological Toxicity Studies

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