Administration of Olanzapine as an Antiemetic Agent Changes Glucose Homeostasis in Cisplatin-Treated Rats

Abstract

We investigated the effects of olanzapine on cisplatin-induced pica (the consumption of non-nutrient materials such as kaolin) and glucose homeostasis in rats to clarify the effects of olanzapine when used as an anti-emetic drug. Rats were injected intraperitoneally (i.p.) with either 5 mg/kg cisplatin or saline. Additionally, 2 or 10 mg/kg olanzapine were administered i.p. to the rats 10 min before the administration of cisplatin and subsequently administered every 24 h for 3 d. Kaolin and food intake was measured using an automatic monitoring apparatus. Plasma glucose levels were measured by an enzyme electrode method. The plasma levels of insulin and intact proinsulin were measured by enzyme-linked immunosorbent assay (ELISA). The proinsulin-to-insulin (P/I) ratio was calculated. Cisplatin significantly increased kaolin intake, but decreased food intake and body weight up to 72 h. Olanzapine had no effect on these parameters. Neither olanzapine nor cisplatin alone had a significant effect on the plasma levels of glucose, insulin, or proinsulin. However, a combination of olanzapine and cisplatin significantly decreased plasma insulin levels, but increased plasma intact proinsulin levels and the P/I ratio. Our results suggest that an additive deterioration of insulinsecreting beta-cell function and disturbance of glucose homeostasis should be considered during treatment of patients with olanzapine for cisplatin-induced nausea and vomiting.Key words chemotherapy-induced nausea and vomiting; olanzapine; cisplatin; pica; glucose homeostasis Chemotherapy-induced nausea and vomiting (CINV) is a major adverse event that affects patients' quality of life and is closely related to tolerance of chemotherapy and the rate of success. Therefore, the outcome of chemotherapy itself is influenced by anti-emetic treatments for CINV.1) Animal experimental models and human studies show that acute emesis, which is evoked within the first 24 h after highly emetogenic chemotherapy (HEC), is controlled by the use of selective 5-hydroxytryptamine 3 (5-HT 3 ) receptor antagonists, such as granisetron and ondansetron.2,3) Delayed emesis, occurring at 1 d to 1 week after HEC, cannot be controlled by serotonin 5-HT 3 receptor antagonists alone, but can be controlled by the combination of a 5-HT 3 receptor antagonist, dexamethasone, and/or a tachykinin NK 1 receptor antagonist in both human patients 4,5) and ferrets. [6][7][8] In fact, the use of these drugs is widely recommended in the guidelines for CINV prevention, including those of the National Comprehensive Cancer Network. However, CINV is still experienced by patients: approximately 20% of patients experience acute emesis and approximately 30% experience delayed emesis that is uncontrolled by the antiemetic therapy recommended in these guidelines. [9][10][11] Currently, the use of olanzapine is recommended as an alternative option for CINV prophylaxis in such patients. [12][13][14] The detailed mechanism by which olanzapine reduces CINV is still unknown. However, blockade of the ac...

Olanzapine Administration Reduces Chemotherapy-Induced Nausea Behavior in Rats

“…More generally, these data also support the use of rats as a model to address gaps in the literature examining the efficacy of olanzapine and other anti-emetics. For example, only one previous study by Machida et al (2015) examined systemic OLZ on malaise in young Wistar rats and observed only a marginally significant cisplatin-induced pica, making determinations of OLZ effectiveness limited. We report IP OLZ significantly reduced cisplatin-induced pica (*30% reduction) at 24 hr and both IP and ICV OLZ decreased pica (by *28% and *42%; respectively) 48 hr following cisplatin treatment, suggesting that OLZ successfully reduces pica under more robust experimental conditions (i.e., when a strong and reliable induction of cisplatin-induced pica is observed).…”