Methotrexate causes a change in intestinal 5-hydroxytryptamine metabolism in rats

Miyamura

Biological & Pharmaceutical Bulletin

et al. 2015

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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...

Section: Discussionmentioning

confidence: 99%

“…[18][19][20][21][22] However, to our knowledge, the effect of olanzapine on anti-cancer druginduced pica behavior has not been studied.…”

Section: )mentioning

confidence: 99%

Section: Measurement Of Kaolin and Food Intakementioning

confidence: 99%

mentioning

confidence: 99%

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

Miyamura

Biological & Pharmaceutical Bulletin

et al. 2015

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“…Generally, methotrexate-induced gastrointestinal mucositis is a moderately severe but common side effect in routine clinical use. 10) We previously reported that the administration of methotrexate at a dose of 50 mg/kg in rats caused significant kaolin intake, which is indicative of emesis in rats, and hyperplasia of the enterochromaffin cells in the ileal tissue. 11,12) Although a 50-mg/kg dose of methotrexate in rats is nearly equivalent to the dosage that associated with an increased risk of emesis in humans, there was no severe histologic injury due to the methotrexate observed in the ileal tissue at 96 h after the initial administration.…”

Section: Introductionmentioning

confidence: 98%

Potentiation of Glucagon-Like Peptide-2 Dynamics by Methotrexate Administration in Rat Small Intestine

Shiga

Biological & Pharmaceutical Bulletin

et al. 2019

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The aim of this study was to clarify the relationship between chemotherapy-induced mucositis and endogenous glucagon-like peptide-2 (GLP-2) dynamics in the small intestine following treatment with either methotrexate or 5-fluorouracil. Rats were injected intraperitoneally with a single dose of either 50 mg/kg methotrexate or 100 mg/kg 5-fluorouracil. At 24 and 72 h after drug administration, ileal tissues and plasma were used to investigate GLP-2 dynamics. Administration of methotrexate caused moderate but not significant intestinal injury within 72 h, while administration of 5-fluorouracil caused severe injury in a time-dependent manner. Methotrexate significantly increased proglucagon mRNA expression and the number of anti-GLP-2 antibody-positive cells in the ileal tissue at 24 h after administration. Methotrexate also significantly induced GLP-2 receptor, insulin-like growth factor-1 (IGF-1), and transforming growth factor-β2 (TGF-β2) mRNA expression in ileal tissue. In contrast, 5-fluorouracil significantly inhibited proglucagon, GLP-2 receptor, IGF-1, and TGF-β2 mRNA expression as well as the number of anti-GLP-2 antibody-positive cells. Methotrexate slightly increased dipeptidyl peptidase IV (DPP-4) mRNA expression, whereas 5-fluorouracil significantly increased DPP-4 mRNA expression. These results suggest that potentiation of endogenous GLP-2 dynamics by methotrexate is associated with a mechanism that preserves gastrointestinal mucosal integrity at a moderate level.

Cisplatin increases the number of enterochromaffin cells containing substance P in rat intestine

Obara

Naunyn-Schmiedeberg's Arch Pharmacol

Takano

et al. 2018

We previously reported that cisplatin potentiated ileal 5-hydroxytryptamine (5-HT) metabolism and caused pathological changes with an inflammatory response in the delayed phase (72 h) after administration to rats. In the present study, we further investigated the time-dependent effect of cisplatin on ileal 5-HT metabolism and the effects of combining cisplatin and anti-inflammatory drugs on ileal tryptophan hydroxylase expression and pica (the consumption of non-nutritive materials such as kaolin). Cyclooxygenase-2 (COX-2) expression was significantly increased at 24 h after cisplatin (5 mg/kg, intraperitoneal) administration. Cisplatin significantly increased ileal 5-HT content at 48 h after administration and the number of L-tryptophan hydroxylase-expressing cells (i.e., enterochromaffin cells) in the ileal mucosa within 24 h after administration. It also caused a significant increase in the number of substance P-expressing cells. Immunohistochemical double staining revealed that most of the enterochromaffin cells contained substance P. Neither daily treatment with dexamethasone (1 mg/kg, subcutaneous) nor meloxicam (3 mg/kg, subcutaneous), a selective COX-2 inhibitor, affected the cisplatin-induced increase in the number of enterochromaffin cells. Meloxicam had no effect on cisplatin-induced pica, although dexamethasone almost completely inhibited it. This study demonstrated that cisplatin administration induced COX-2 expression and increased the number of enterochromaffin cells in the acute phase (i.e., within 24 h). However, COX-2 expression in the ileum seems to have little direct effect on the mechanism of the induction of enterochromaffin cells and pica.