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Keywords:

  • Chemotherapy;
  • Gastrointestinal adverse event;
  • Gastrointestinal motility disorder;
  • Prokinetics

Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Background

Vincristine induces gastrointestinal motility disorders in humans. Adverse gastrointestinal events are commonly observed in dogs receiving vincristine.

Objectives

To evaluate gastric motility after vincristine administration in dogs and the prophylactic effect of a prokinetic agent, mosapride.

Animals

Five healthy Beagle dogs.

Methods

Five dogs received vincristine IV at a dosage of 0.75 mg/m2. The motility index (MI) of the antral contraction was ultrasonographically evaluated 30 minutes postfeeding before administration of vincristine and for 6 days after vincristine treatment. After a 6-week washout period, the dogs received vincristine with mosapride (2 mg/kg PO, q24h for 6 days), and the MI was re-evaluated. Adverse gastrointestinal events were evaluated according to the Veterinary Co-operative Group Common Terminology Criteria for Adverse Events (VCOG-CTCAE).

Results

After vincristine administration, a significant decrease (P < .05) in MI was observed on days 3 (6.64 ± 0.30) and 4 (8.02 ± 0.94), compared with pretreatment levels (10.00 ± 0.62). Gastrointestinal adverse events were observed in 4 dogs (grade 2 decreased appetite: 3 dogs; grade 1 vomiting: 2 dogs; and grade 1 diarrhea and grade 2 hematochezia: 1 dog). When mosapride citrate was administered with vincristine and for the next 5 days, no decrease in MI was observed. Furthermore, adverse gastrointestinal events occurred less frequently (grade 1 vomiting and grade 2 hematochezia in 1 dog each).

Conclusions and Clinical Importance

Vincristine (0.75 mg/m2) induces gastric hypomotility in dogs. Preventive administration of mosapride citrate (2.0 mg/kg PO, q24h) improves hypomotility and may decrease the adverse gastrointestinal effects of vincristine.

Abbreviations
CRTZ

chemoreceptor trigger zone

5-HT4R

5-hydroxytryptamine 4 receptor

MI

motility index

VCOG-CTCAE

Veterinary Co-operative Group Common Terminology Criteria for Adverse Events

Vincristine is an anticancer agent that is used in chemotherapy for canine lymphoma or hematopoietic tumors.[1] Vincristine administration is known to have several adverse effects in dogs, including hematologic, gastrointestinal, and neurologic effects.[1] Among them, adverse gastrointestinal events are commonly observed. It was reported that 50% of dogs with lymphoma receiving vincristine experienced at least 1 adverse gastrointestinal event during treatment using the University of Wisconsin-Madison chemotherapy protocol.[2] Severe gastrointestinal toxicity may lead to dose reduction or drug withholding and may impair ideal chemotherapy outcomes.

In humans, vincristine is known to cause gastrointestinal motility disorders that may be associated with neurotoxicity.[3] However, the effect of vincristine on canine gastrointestinal motility is poorly understood. Use of the gastroprokinetic agent metoclopramide may be recommended for treating chemotherapy-induced adverse upper gastrointestinal events in dogs.[4] No reports have evaluated the efficacy of gastrointestinal prokinetic drugs for the prevention or treatment of vincristine-induced adverse effects. The 5-hydroxytryptamine 4 receptor (5-HT4R) agonist mosapride enhances gastrointestinal motility and is used as a prokinetic agent in humans.[5] The prokinetic action of this drug also has been confirmed in the canine upper gastrointestinal tract, and it has been approved as a prokinetic agent for dogs in Japan.[6]

The aim of this study was to determine the effect of vincristine administration on canine gastric motility and the prokinetic effect of mosapride in vincristine-treated dogs. We hypothesized that vincristine induces gastric hypomotility, and that mosapride may attenuate the vincristine effect on gastric motility and adverse gastrointestinal events.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Five healthy Beagles (2 males and 3 females) were used in this study. The dogs ranged in age from 3 to 4 years and their body weights ranged from 9.7 to 13.0 kg. The dogs were acclimated for at least 1 month before the experiment. No gastrointestinal clinical signs were observed in any of the dogs before the experiment. During the study period, the dogs were fasted for at least 12 hours before ultrasonographic evaluation of postprandial gastric motility. After assessment, the dogs were given additional commercial dry food. The experiments and animal care were carried out in compliance with the guidelines outlined by the Guide to Animal Use and Care of the University of Tokyo.

This study was composed of 2 trials. In the 1st trial, vincristine1 (0.75 mg/m2, IV) alone was administered to 5 dogs. Postprandial gastric motility was assessed 1 day before the injection as baseline (day 0) and then daily for 6 days (days 1–6). In the 2nd trial, vincristine was administered on day 1 and mosapride2 (2 mg/kg, PO, q24h) was administered to the same dogs on days 1–6. The tablet of mosapride was ground into powder, dissolved in 10 mL of distilled water, and administered PO to the dogs. Gastric motility was evaluated in the same manner. Adverse gastrointestinal events observed during the 6-day study period were recorded in each trial. A 6-week washout period was carried out between the 2 trials. We observed the 5 dogs for 1 week before the 2nd trial to confirm that none had clinical signs. Blood tests (CBC, neutrophil count, plasma blood urea nitrogen, and creatinine concentrations, and alkaline phosphatase and alanine aminotransferase activity) were performed before both trials. This study was performed as an open-label study.

Postprandial gastric motility was evaluated as described in earlier reports in dogs[7] using ultrasonography3 with a 7.5 MHz-phased array sector transducer. Commercial canned food4 (10 g/kg) was given 30 minutes before the ultrasound examination. A cross-section of the antral area was measured by tracing the serosal side of the antrum with a built-in caliper. The antral area was measured 3 times in both the contracted and relaxed phases. The number of contractions in 3 minutes then was counted. The amplitude was calculated using the following formula: (mean of area relaxed – mean of area contracted)/mean of area relaxed. Frequency was defined as the number of contractions in 3 minutes. The motility index (MI), an indicator of postprandial gastric antral motility, was expressed as the product of amplitude and frequency. All ultrasound examinations were performed by a single operator. On day 1 in both trials, vincristine was administered 30 minutes before the ultrasonographic assessment. In the 2nd trial, mosapride was administered 1 hour before ultrasonography.

Adverse gastrointestinal events observed during the study were estimated based on the VCOG-CTCAE, an objective grading system of adverse gastrointestinal events in dogs and cats.[8] Following the criteria, adverse gastrointestinal events were classified into 5 grades on the basis of the clinical signs recorded (Table 1). Dogs were observed carefully at least 3 times a day during the 6 day study period in each trial. We also monitored the dogs during the 6 week washout period to confirm disappearance of these clinical signs.

Table 1. The grading of gastrointestinal adverse events (anorexia, vomiting, diarrhea, and colitis) based on the VCOG-CTCAE.[8]
 Grade 1Grade 2Grade 3Grade 4Grade 5
  1. ADL, activities of daily living; PPN, peripheral parenteral nutrition; TPN, total parenteral nutrition.

AnorexiaCoaxing or dietary change required to maintain appetiteOral intake altered (<3 days) without significant weight loss; oral nutritional supplements indicatedOf 3–5 days duration. Associated with significant weight loss or malnutrition; IV fluids, tube feeding or TPNLife-threatening consequences; >5 days durationDeath
Vomiting<3 episodes in 24 hours3–5 episodes in 24 hours; <3 episodes/d for >2 days but <5 days; parenteral indicated <24 hours (IV or SC)>5 episodes in 24 hours; vomiting >4 days IV fluids or PPN/TPN indicated >24 hoursLife-threatening (eg, hemodynamic collapse)Death
DiarrheaIncrease of >2 feces per day over baselineIncrease of 2–6 feces per day over baseline; parenteral (IV or SC) fluids indicated <24 hours; not interfering with ADLIncrease of >6 feces per day over baseline; IV fluids >24 hours; hospitalization; interfering with ADLLife-threatening (eg, hemodynamic collapse)Death
ColitisAsymptomatic, pathologic, or radiograpic findings onlyAbdominal cramping/pain; mucus or blood in stoolAbdominal pain, fever, change in bowel habits, ileus, peritoneal signsLife-threatening consequences (eg, perforation, bleeding)Death

The Shapiro–Wilk test was used to confirm that the data were normally distributed. The MI differences between treatments at baseline (day 0) were tested using a paired t-test. Repeated-measures ANOVA was performed to assess the MI differences between treatments. When there was a significant difference, at-test using Dunnett's multiple comparison method was performed to assess the MI differences between baseline and other time points of each treatment. The MI differences among treatments at each time point were analyzed using the paired t-test with the Bonferroni multiple comparison method. The results were expressed as mean ± SD. Values of P < .05 were considered significant. Statistical analysis was performed using a statistical software program.5

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

There were no fatal events in any of the dogs, and all of the adverse gastrointestinal events disappeared within 1 week after vincristine administration in both trials. There were no blood test abnormalities before the trials. In the 1st trial (vincristine alone was administered), mean ± SD values of MI from day 0 to 6 were 10.00 ± 0.62, 9.17 ± 1.01, 8.58 ± 1.19, 6.64 ± 0.30, 8.02 ± 0.94, 8.39 ± 1.24, and 9.25 ± 0.87, respectively. In the 2nd trial (mosapride was administered with vincristine), mean ± SD values of MI from day 0 to 6 were 9.93 ± 1.17, 11.71 ± 1.57, 11.58 ± 1.09, 11.20 ± 0.70, 11.11 ± 1.84, 10.32 ± 1.18, and 11.55 ± 0.56, respectively (Fig 1). There was no significant difference in MI between the 2 trials at day 0 (10.00 ± 0.62 versus 9.93 ± 1.17, P > .05). The results of repeated-measures ANOVA showed significant differences between trials (P < .01). In the 1st trial, a significant decrease in MI was observed on days 3 and 4 compared with day 0. In the 2nd trial, no significant decrease in MI was observed at any time point compared with day 0, and significant increases in MI were observed on days 3 and 4 compared with the same MI time point in the 1st trial. Gastrointestinal clinical signs observed in this study included decreased appetite, vomiting, diarrhea, and hematochezia. The grades and frequencies of the gastrointestinal clinical signs observed in this study are shown in Table 2. In the 1st trial, 4 of the 5 dogs displayed some clinical sign. The following signs were observed: grade 2 decreased appetite in 3 dogs, grade 1 vomiting in 2 dogs, grade 1 diarrhea in 1 dog, and grade 2 colitis in 1 dog. In the 2nd trial, decreased appetite and diarrhea were not observed in any of the dogs, and only grade 1 vomiting and grade 2 colitis were observed in 1 dog each.

image

Figure 1. Change of gastric motility index (MI) in each treatment in 5 dogs. (A) The data indicated with mean ± SD value of 5 dogs. (B–F) Represent data from individual dogs. Close squares (■) indicate MI in 1st trial (vincristine alone was administered) in each day. Open triangles (△) indicate MI in 2nd trial (mosapride was administered with vincristine) in respective days. In either trial, vincristine (0.75mg/m2) was administered on day 1. *Significant difference (P < .05) from baseline (day 0). †Significant difference (P < .05) between the 2 trials on the same day.

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Table 2. The grades and numbers of gastrointestinal adverse events observed in 5 dogs in each trial.
 VincristineVincristine + Mosapride
Total72
Anorexia3 (grade 2)0
Vomiting2 (grade 1)1 (grade 1)
Diarrhea1 (grade 1)0
Colitis1 (grade 2)1 (grade 2)

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

We have shown that vincristine (0.75 mg/m2) administration causes gastric hypomotility in dogs. Chemotherapy-induced gastrointestinal toxicity can be caused by direct damage to mucosal epithelial cells or by stimulation of the vomiting center or chemoreceptor trigger zone (CRTZ).[1] In addition, some anti-cancer drugs like vincristine are known to induce gastrointestinal motility disorders and be one of the causes of gastrointestinal toxicity in humans.[3, 9] Vincristine has a potent action that causes autonomic neuropathy.[3] In humans, vincristine-induced neuropathy can be associated with gastrointestinal motility disorders such as constipation, abdominal pain, and paralytic ileus.[3, 9] Confirmation of the association between neurotoxicity and gastric motility disorders in dogs requires further electrophysiologic and histopathologic studies.

In this study, mosapride prevented vincristine-induced gastric motility disorders in dogs. Previous studies have shown that the prokinetic agent metoclopramide is one of the treatment options for vincristine-induced adverse gastrointestinal events in humans and also is empirically used to treat chemotherapy-induced gastrointestinal toxicity in dogs.[4, 9] Metoclopramide has 2 potent actions: a prokinetic action and an anti-emetic effect because of its antagonistic effect on the dopamine-2 receptor in the CRTZ and vomiting center. Because metoclopramide has these 2 functional mechanisms that improve clinical signs, the association between its prokinetic action and alleviation of adverse events remains unclear. In contrast, mosapride acts only on the upper gastrointestinal tract and does not have a central antiemetic action.[5] This study demonstrated that mosapride improved vincristine-induced gastric hypomotility and tended to attenuate upper gastrointestinal clinical signs, suggesting that gastric hypomotility is associated with vincristine-induced adverse upper gastrointestinal events and that use of gastroprokinetic agents such as mosapride may be a treatment option for these adverse events.

A limitation of this study is that the experiment was not carried out as a randomized blinded trial. Because the order of the 1st and 2nd trial was not randomized, we should consider whether or not order effect influenced the result of this study. Therefore, we set a longer washout period (6 weeks) to exclude the possibility that vincristine administration in the 1st trial affected the result of the 2nd trial. We confirmed that there was no significant difference between the baseline MIs of the 2 trials. Adverse gastrointestinal events disappeared within a week in all dogs after vincristine administration, and blood tests did not show any abnormalities before the 2nd trial. Based on these results, the order effect in this study was negligible.

To our knowledge, this is the 1st report showing the efficacy of mosapride on gastric motility disorders in dogs. In humans, mosapride is used to treat gastrointestinal disorders, including chronic gastritis, functional dyspepsia, and gastroesophageal reflux disease.[5] The pharmacological action of mosapride is similar to that of cisapride.[5] Both drugs have high affinity to 5-HT4R of enteric postganglionic neurons and enhance gastrointestinal motility. The difference in their action in dogs is that mosapride does not act on the large intestine, whereas cisapride stimulates the motor activity of the entire gastrointestinal tract.[5] Cisapride has been withdrawn from most markets because of the occurrence of cardiac arrhythmias in humans and is only available through compounding pharmacies. In contrast, mosapride has no effect on cardiac function both in humans and dogs.[5, 10] Mosapride may be an alternative prokinetic agent for the treatment of upper gastrointestinal motility disorders in dogs.[5]

In conclusion, vincristine induces gastric hypomotility in dogs. Preventive administration of mosapride improves gastric motility and possibly attenuates vincristine-induced adverse upper gastrointestinal events. Additional large-scale clinical studies are required to assess the efficacy of mosapride on vincristine-induced gastrointestinal toxicity.

Notes
  1. 1

    Oncovin; Nippon Kayaku Co, Ltd, Tokyo, Japan

  2. 2

    Pronamid; DS Pharma Animal Health Co, Ltd, Osaka, Japan

  3. 3

    ProSound SSD-5000 SV; Aloka Co, Ltd, Tokyo, Japan

  4. 4

    SPECIFIC CIW; Intervet Schering-Plough Animal Health, Tokyo, Japan

  5. 5

    SAS system, version 9.2; SAS Institute Inc, Cary, NC

Acknowledgments

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Conflict of interest: At the time this study was conducted, none of the authors had any conflicts of interest to declare.

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
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    Yatera S, Koujitani T, Yasuba M, et al. Toxicity study of mosapride citrate (3). Thirteen-week repeated dose oral toxicity study in Beagle dogs. Jpn Pharmacol Ther 1993;21:5773.