Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Nursing

First Advisor

Bart C. De Jonghe

Abstract

OLANZAPINE AS A NOVEL TREATMENT FOR CHEMOTHERAPY-INDUCED

NAUSEA AND VOMITING

Rosario B. Jaime-Lara

Bart C. De Jonghe

Background: Chemotherapy-Induced Nausea and Vomiting (CINV) is a prevalent adverse effect of chemotherapy, reducing quality of life and resulting in considerable healthcare resource utilization costs. Olanzapine, historically used as an antipsychotic, is now added to cancer antiemetic guidelines due to its effectiveness in preventing and managing CINV. While therapeutic options have improved CINV treatment, the literature highlights a substantial gap in knowledge regarding the pathophysiology of CINV and the biological basis of olanzapine’s effect on CINV. The primary objective of this dissertation was to better understand how olanzapine alleviates CINV. These data can increase knowledge of the pathophysiology of CINV and help identify potential biological mediators to target for therapeutic interventions.

Methods/Results: To address our objective, we conducted a literature review of CINV with a focus on olanzapine and identified potential biological mediators of olanzapine’s effects on CINV: ghrelin and serotonin g. Subsequently, we conducted a series of behavioral experiments in rats to study the antiemetic effects of olanzapine. Olanzapine in rats (as in humans) decreased chemotherapy-induced malaise/nausea, anorexia, and body weight loss. To test the effect of olanzapine on potential biological mediators of these chemotherapy-induced adverse effects, we assessed the effects of olanzapine on ghrelin and serotonin. We found that olanzapine decreases the number of cisplatin (a chemotherapeutic agent known to induce CINV in almost 100% of people and animals in the absence of antiemetic prophylaxis) activated neurons in the hindbrain and determined olanzapine’s effect on chemotherapy-induced malaise is at least in part mediated by the hindbrain. Additionally, we found olanzapine counteracts cisplatin-induced decreases in circulating ghrelin and central ghrelin receptor [GHSR] gene expression six hours post chemotherapy. Lastly, we report olanzapine decreased serotonin 2C receptor [5-HT2C] gene expression in the hindbrain and the hypothalamus.

Conclusion: These findings suggest that olanzapine may alleviate CINV by counteracting the effects of cisplatin on the hindbrain, circulating ghrelin, ghrelin receptor expression, and 5-HT2C receptor gene expression in the hindbrain and hypothalamus. Future research should further define the role of these potential biological mediators in CINV and determine whether counteracting cisplatin-induced alterations of ghrelin and 5-HT2C signaling are sufficient to help control CINV.

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Available to all on Monday, October 25, 2021

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