Inhibitory Effect of Zacopride on Cisplatin-Induced Delayed Emesis in Ferrets

Yamakuni, Hisashi; Nakayama, Hiroe; Matsui, Shigeo; Imazumi, Katsunori; Matsuo, Makoto; Mutoh, Seitaro

doi:10.1254/jphs.scj05007x

Cited by 11 publications

(8 citation statements)

References 8 publications

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“…We employed the 10 mg/kg and 5 mg/kg cisplatin models for acute and delayed emesis, respectively. 21,22) It has been reported that 5-HT 3 receptor antagonists completely abolish cisplatin-induced acute emesis, but only modestly inhibit the delayed emesis in experimental animal models.…”

Section: Discussionmentioning

confidence: 99%

“…injected with cisplatin (5 mg/kg) at 08 : 30 h and their behavior was recorded with a video camera equipped with automatic night vision for 3 d. 22) During the experiments, ferrets were supplied with food (70 g/day) and water ad libitum. In prophylactic protocol experiments, FK886 (1.6 and 5 mg/kg, p.o.)…”

Section: )mentioning

confidence: 99%

“…A stainless steel guide cannula (23-gauge, 13 mm in length) was inserted vertically 9 mm below the skull surface and was fixed to the skull with dental cement and two holding screws. 22) Following the intramuscular (i.m.) administration of the antibiotic Cefamezin (Astellas Pharma Inc., Tokyo, Japan; 50 mg), the ferrets were returned to holding pens and allowed to recover for at least one week.…”

Section: )mentioning

confidence: 99%

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Antiemetic Effect of a Potent and Selective Neurokinin-1 Receptor Antagonist, FK886, on Cisplatin-Induced Acute and Delayed Emesis in Ferrets

Furukawa

Nakayama

Imazumi

et al. 2014

Biological & Pharmaceutical Bulletin

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The antiemetic effect of a potent and selective neurokinin-1 (NK 1 ) receptor antagonist, FK886 ([3,5-bis(trifluoromethyl) phenyl][(2R)-2-(3-hydroxy-4-methylbenzyl)-4-{2-[(2S)-2-(methoxymethyl)morpholin-4-yl]ethyl}piperazin-1-yl] methanone dihydrochloride), on cisplatin-induced acute and delayed emesis in ferrets was studied. Intravenous administration of FK886 dose-dependently inhibited cisplatin (10 mg/kg)-induced acute emesis with a minimum effective dose (MED) of 0.32 mg/kg. In the same study, oral FK886 administered 8 h prior to cisplatin also dose-dependently inhibited the acute emesis during the 4-h observation period with an MED of 3.2 mg/kg. Further, when given by repeated oral administration of ≥1.6 mg/kg at 12-h intervals, the first dose being administered 1 min before cisplatin, FK886 significantly decreased the number of emetic responses in cisplatin (5 mg/kg)-induced delayed emesis. In the same study, oral FK886 (3.2 mg/kg) repeatedly administrated at 12-h intervals, the first dose being administered 36 h post cisplatin, also significantly attenuated the delayed emesis. Pharmacokinetic data in ferrets showed that plasma FK886 reached a maximum concentration within 0.5 h of administration, suggesting rapid oral absorption. In addition, rapid brain penetration of FK886 was suggested by complete and near complete inhibition of GR73632-and copper sulfate-induced emesis, respectively, by low-dose intravenous FK886 administered shortly before the emetogens. These results suggest that FK886 is an orally available NK 1 receptor antagonist which is effective against both the acute and delayed emesis induced by cisplatin. Because of its therapeutic efficacy on the delayed emesis and rapid brain distribution after oral administration, FK886 may have potential as an antiemetic agent that can be used for interventional treatment of chemotherapy-induced delayed emesis.Key words FK886; neurokinin-1 antagonist; ferret emesis; cisplatin; GR73632; copper sulfate Nausea and vomiting are distressing symptoms that significantly detract from a patient's overall quality of life and their recovery during medical treatment. Nausea and vomiting both occur as symptoms of many diseases and as side effects of medical treatments, including cancer chemotherapy, radiotherapy, and general anesthesia in surgery. 1) Chemotherapy-induced nausea and vomiting (CINV) is perceived to be a major adverse effect of treatment by patients. 2) CINV may occur within hours of chemotherapy (acute phase) or be delayed until after the first 24 h, and then persist for several days (delayed phase). During the acute phase, chemotherapeutic agents induce serotonin (5-HT) release from enterochromaffin cells which stimulates local 5-HT 3 receptors on gastrointestinal vagal afferent nerves to initiate the vomiting reflex. [3][4][5] This may explain why 5-HT 3 antagonists have been shown to sufficiently control chemotherapy-induced acute emesis. [6][7][8] In contrast, 5-HT 3 antagonists are poorly effective against delayed emesis, 9,10) and the underlying ...

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Section: Discussionmentioning

confidence: 99%

Section: )mentioning

confidence: 99%

Section: )mentioning

confidence: 99%

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Antiemetic Effect of a Potent and Selective Neurokinin-1 Receptor Antagonist, FK886, on Cisplatin-Induced Acute and Delayed Emesis in Ferrets

Furukawa

Nakayama

Imazumi

et al. 2014

Biological & Pharmaceutical Bulletin

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“…Zacopride, as an activator of the I K1 , was found originally to be a potent 5‐HT 3 receptor antagonist (18) and 5‐HT 4 receptor agonist (19). Proper dosage of Zacopride was applied to gastrointestinal (GI) system as an antiemetic (20,21) or a GI prokinetic (22) agent. Zacopride could also act as an anxiolytic drug (23,24).…”

Section: Discussionmentioning

confidence: 99%

The Protective Effect of St. Thomas Cardioplegia Enriched With Zacopride on the Isolated Rat Heart

Long

Hei

et al. 2012

Artificial Organs

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The activation of the heart inward rectifier potassium channel (I(K1) ) can reduce the injury of myocardial cells by shortening the action potential duration and reducing intracellular calcium overload. Zacopride is a selective I(K1) agonist and suppresses triggered arrhythmias in rat hearts. This investigation studied the effects of St. Thomas (ST) cardioplegia enriched with Zacopride on the isolated rat heart model. Sprague-Dawley rat hearts were harvested and perfused for 20 minutes with 37°C Krebs-Henseleit (KH) buffer followed by 15 minute perfusion with 4°C calcium-free KH buffer in the Control group (Con, n = 8), ST cardioplegia in the ST group (ST, n = 8) and ST cardioplegia with Zacopride in the STZ group (STZ, n = 8). After 45 minutes of arresting, all hearts were reperfused with 37°C KH buffer for 60 minutes. Hearts in the STZ group arrested faster than the Con and ST groups (9.25 ± 2.38 s vs. 72.25 ± 8.1 s, 12.75 ± 2.87 s). The recovery of the left ventricular developed pressure, ± dP/dtmax, heart rate, and coronary flow in the STZ group is significantly better than the other two groups during reperfusion. Compared with the Con and ST groups, the STZ group showed significant decreases in the maximum carciac troponin I level (P < 0.05) and the infarct size (P < 0.05). The superoxide dismutase level in the STZ group increased during the first 20 minutes of reperfusion (P < 0.05). ST cardioplegia enriched with Zacopride has beneficial effects against ischemia-reperfusion injury in this isolated rat heart model.

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“…Taken together, this may suggest that glucocorticoids exert their antiemetic action in the ferret via mechanisms not directly related to their known action to prevent eicosanoid synthesis. The anti-emetic action of the glucocorticoids could involve a suppression of other mediators involved at other points in the inflammatory cascade (6,20) or could be facilitated by other unknown mechanisms (3); such mechanisms may involve alterations in 5-HT function (38). Certainly, the number of genes directly activated by glucocorticoids is estimated to be between 10 and 100, with many genes being indirectly regulated through an interaction with other transcription factors and coactivators (39), meaning that future research on glucocorticoids may open new exciting possibilities for emesis control.…”

Section: Using Cox Inhibitors (21) and A Leukotriene Biosynthesis Inhmentioning

confidence: 99%

Action of Cyclooxygenase Inhibitors and a Leukotriene Biosynthesis Inhibitor on Cisplatin-Induced Acute and Delayed Emesis in the Ferret

Sam¹,

Ngan²,

Riendeau³

et al. 2007

J Pharmacol Sci

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Abstract. Cisplatin at 5 mg / kg, i.p. induced an acute (day 1) and delayed (days 2 and 3) emetic response in the ferret that was used to investigate the anti-emetic activity of the non-selective cyclooxygenase inhibitor indomethacin (3 -30 mg / kg, i.p., three times per day) and two cyclooxygenase-2 inhibitors, DFU [5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone; 1 -10 mg / kg, i.p. administered at 40 and 48 h] and L-745,337 [5-methanesulphonamido-6-(2,4-diflurothiophenyl)-1-indanone; 10 mg / kg, i.p., administered at 40 and 48 h]. Only indomethacin potentiated significantly cisplatin-induced retching + vomiting (P<0.05); DFU antagonized delayed emesis (P<0.05) but the action was not dose-related and L-745,337 was inactive (P>0.05). However, indomethacin alone (30 mg / kg) also induced emesis (P<0.05). The leukotriene biosynthesis inhibitor, MK-886 {3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-tert-butylthioindol-2-yl]-2,2-dimethylpropanoic acid; 1 -10 mg / kg, i.p., three times per day} had no action to modify cisplatin-induced emesis (P>0.05). The combination treatment of indomethacin (10 mg / kg, i.p., three times per day) with MK-886 (10 mg / kg, i.p., three times per day) did not antagonize cisplatin-induced acute delayed retching + vomiting and had a different profile compared to the action of dexamethasone (1 mg / kg, i.p., three times per day; P<0.05). Inhibition of the cyclooxygenase and lipoxygenase pathways does not account for the anti-emetic of dexamethasone.

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Inhibitory Effect of Zacopride on Cisplatin-Induced Delayed Emesis in Ferrets

Cited by 11 publications

References 8 publications

Antiemetic Effect of a Potent and Selective Neurokinin-1 Receptor Antagonist, FK886, on Cisplatin-Induced Acute and Delayed Emesis in Ferrets

Antiemetic Effect of a Potent and Selective Neurokinin-1 Receptor Antagonist, FK886, on Cisplatin-Induced Acute and Delayed Emesis in Ferrets

The Protective Effect of St. Thomas Cardioplegia Enriched With Zacopride on the Isolated Rat Heart

Action of Cyclooxygenase Inhibitors and a Leukotriene Biosynthesis Inhibitor on Cisplatin-Induced Acute and Delayed Emesis in the Ferret

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