Cisplatin-induced Emesis In Dogs Research Articles

The Antiemetic Profile of Zacopride

The antiemetic activity of zacopride against a variety of emetogenic agents has been determined in dogs. Zacopride was highly effective in inhibiting emesis due to a wide range of cancer chemotherapeutic agents, particularly cisplatin. It was well absorbed orally since the dose of zacopride required to inhibit cisplatin-induced emesis in dogs by 90% was 28 micrograms kg-1 both by i.v. and p.o. routes. Further, zacopride (1 mg kg-1 p.o.), administered after the onset of cisplatin-induced emesis, reduced the number of subsequent emetic episodes by 91%. Zacopride at 0.1, 1, or 3.16 mg kg-1 p.o. or i.v., reduced the number of emetic episodes due to dacarbazine, mechlorethamine, adriamycin, actinomycin D, or peptide YY by 100, 100, 86, 96 and 79%, respectively. However, zacopride was not effective in inhibiting emesis due to either apomorphine, copper sulphate, protoveratrine A, histamine, or pilocarpine. No adverse effects attributed to zacopride were observed. Zacopride is thus a unique and potent antiemetic agent as it selectively inhibits the emetic response to cancer chemotherapy agents and peptide YY.

Short pulse gastric electrical stimulation for cisplatin‐induced emesis in dogs

In a previous study, we investigated the ameliorating effect of gastric electrical stimulation (GES) with a single set of parameters on emesis and behaviors suggestive of nausea induced by cisplatin in dogs. The aim of this study was to investigate the effects of GES with different parameters on cisplatin-induced emesis in dogs. Seven dogs implanted with gastric serosal electrodes were studied in six randomized sessions: one control session with cisplatin (2 mg kg(-1)) and five sessions with cisplatin plus GES of different parameters: GES-A: 14 Hz, 5 mA, 0.3 ms, 0.1 s on and 5 s off; GES-B: increased frequency and on-time; GES-C: increased frequency; GES-D: increased frequency and pulse width; and GES-E: increased frequency and amplitude. Gastric slow waves and emetic responses were recorded in each session. (i) Cisplatin induced emetic responses and gastric dysrhythmia. The peak time of the emetic response was during the fourth hour after cisplatin. (ii) GES with appropriate parameters reduced cisplatin-induced emesis. The number of vomiting times during the 6 h after cisplatin was 7.0 ± 1.4 in the control, 4.7 ± 1.2 with GES-A (P = 0.179), 4.2 ± 1.2 with GES-B (P = 0.109), 7.0 ± 0.8 with GES-C (P = 0.928), 2.1 ± 0.3 with GES-D (P = 0.005) and 4.7 ± 1.5 with GES-E (P = 0.129). However, none of the GES parameters could improve gastric dysrhythmia. Gastric electrical stimulation with appropriate parameters reduces cisplatin-induced emetic responses and behaviors suggestive of nausea in dogs. Among the tested parameters, GES with increased pulse width seems to produce better relief of cisplatin-induced emesis.

W2028 Role of GES in Cisplatin-Induced Emesis in Dogs and Possible Mechanisms

W2028 Role of GES in Cisplatin-Induced Emesis in Dogs and Possible Mechanisms

Cisplatin-Induced Gastric Dysrhythmia and Emesis in Dogs and Possible Role of Gastric Electrical Stimulation

The aim of this study was to investigate the effect of cisplatin on gastric myoelectrical activity and the role of gastric electrical stimulation in the treatment of cisplatin-induced emesis in dogs. Seven dogs implanted with electrodes on the gastric serosa were used in a two-session study. Cisplatin was infused in both the control session and the gastric electrical stimulation session, and gastric electrical stimulation was applied in the gastric electrical stimulation session. Gastric slow waves and emesis, as well as behaviors suggestive of nausea, were recorded during each session. The results were as follows: (1) cisplatin induced vomiting and other symptoms and induced gastric dysrhythmia. The percentage of normal slow waves decreased significantly during the 2.5 h before vomiting (P=0.01) and the period of vomiting (P<0.001). (2) Gastric electrical stimulation reduced emesis and the symptoms score. The total score in the control session was higher than that in the gastric electrical stimulation session (P=0.02). However, gastric electrical stimulation had no effects on gastric dysrhythmia. It is concluded that cisplatin induces emesis and gastric dysrhythmia. Gastric electrical stimulation may play a role in relieving chemotherapy-induced emetic responses and deserves further investigation.

Efficacy of maropitant for treatment and prevention of emesis caused by intravenous infusion of cisplatin in dogs

To evaluate the efficacy of maropitant, a novel neurokinin-1 receptor antagonist, to treat and prevent emesis caused by IV infusion of a chemotherapeutic dose of cisplatin (70 mg/m(2)) in dogs. 64 healthy 6-month-old Beagles (32 males and 32 females). To evaluate the effect of maropitant on ongoing emesis, 24 dogs were randomized to 2 treatment groups (12 dogs each). Saline (0.9% NaCl) solution or maropitant (1 mg/kg) was administered once by SC injection immediately following the first emetic event after cisplatin infusion. Dogs were assessed for emesis for 6 hours after initiation of cisplatin infusion. To evaluate the use of maropitant for the prevention of emesis, 40 dogs were randomized to 4 treatment groups (10 dogs each). Placebo or maropitant (1, 2, or 3 mg/kg) was administered PO as a tablet. Cisplatin infusion was initiated at 19 hours after treatment, and dogs were assessed for emesis for 6 hours. No treatment-related adverse events were observed in either study. For the treatment of ongoing emesis, significantly fewer emetic events were observed for maropitant-treated dogs, compared with placebo-treated dogs (mean, 5.2 vs 15.8), and the mean time to cessation of emesis was significantly shorter (0.65 vs 1.65 hours). In the prevention of emesis, maropitant-treated dogs had significantly fewer emetic events (means, 2.7, 1.1, and 0.5 for maropitant at 1, 2, and 3 mg/kg, respectively), compared with placebo-treated dogs (mean, 20.3). Results suggest that maropitant is safe and effective in the treatment and prevention of cisplatin-induced emesis in dogs.

Resiniferatoxin antagonizes cisplatin-induced emesis in dogs and ferrets

We evaluated the antiemetic activity of resiniferatoxin, an ultrapotent capsaicin analogue, on cisplatin- and apomorphine-induced emesis in dogs, and on cisplatin-induced acute and delayed emesis in ferrets. In the dog, resiniferatoxin (10 μg/kg, s.c.) 30 min before the injection of cisplatin markedly prevented acute emesis induced by cisplatin. When animals were given resiniferatoxin (10 μg/kg, s.c.) 24 h prior to cisplatin, the emesis was still inhibited, but not significantly. Resiniferatoxin (10 μg/kg, s.c.) 30 min before the administration of apomorphine also significantly reduced the emetic responses induced by apomorphine in dogs. In the ferret, resiniferatoxin (10 μg/kg, s.c.) 30 min prior to cisplatin completely inhibited acute emesis caused by cisplatin (10 mg/kg, i.p.). When ferrets were given resiniferatoxin (10 μg/kg, s.c.) 16 h prior to cisplatin, the emesis was still significantly inhibited. Cisplatin (5 mg/kg, i.p.) induced both acute (0–24 h) and delayed (24–72 h) phase emesis, and a single injection of resiniferatoxin (10 μg/kg, s.c.) at 36 h after cisplatin significantly reduced subsequent emetic responses during the 36–72 h period. These results suggest that resiniferatoxin-related vanilloids may be useful drugs against both acute and delayed emesis induced by cancer chemotherapy.

Reversal of cisplatin-induced delay in gastric emptying in rats by ginger ( Zingiber officinale)

Cisplatin causes nausea, vomiting and inhibition of gastric emptying. We have demonstrated the antiemetic effect of the acetone and ethanolic extract of ginger ( Zingiber officinale, Roscoe, Zingiberacae) against cisplatin-induced emesis in dogs. In the present study, the acetone and 50% ethanolic extract of ginger in the doses of 100, 200 and 500 mg/kg (p.o.) and ginger juice, in the doses of 2 and 4 ml/kg, were investigated against cisplatin effect on gastric emptying in rats. All three ginger preparations significantly reversed cisplatin-induced delay in gastric emptying. The ginger juice and acetone extract were more effective than the 50% ethanolic extract. The reversal produced by the ginger acetone extract was similar to that caused by the 5-HT 3 receptor antagonist ondansetron; however, ginger juice produced better reversal than ondansetron. Therefore, ginger, an antiemetic for cancer chemotherapy, may also be useful in improving the gastrointestinal side effects of cancer chemotherapy.

Antiemetic efficacy of ginger (Zingiber officinale) against cisplatin-induced emesis in dogs

Effect of ginger (Zingiber officinale Roscoe, Zingiberaceae) extracts (acetone, 50% ethanolic and aqueous) were investigated for antiemetic activity against emesis induced by 3 mg/kg cisplatin (the 100% emetic dose i.v.) in healthy mongrel dogs. The acetone and 50% ethanolic extract at the doses of 25, 50, 100 and 200 mg/kg p.o. exhibited significant protection while aqueous extract at these doses was ineffective against cisplatin emesis. The acetone extract was more effective than ethanolic extract. However, both were less effective when compared to 5-HT3 receptors antagonist—granisetron. Neither of the ginger extract was effective against apomorphine-induced emesis. The findings suggest that ginger could be an effective and cheap antiemetic adjunct to cancer chemotherapy.

Cisplatin-induced pica behaviour in rats is prevented by antioxidants with antiemetic activity

Pica, eating of non-nutritive substances such as kaolin in rats has been suggested as an illness response behaviour, analogous to vomiting in species that have developed emetic reflex. We have recently demonstrated that antioxidants—glutathione, N-(2- mercaptopropionyl)glycine (tiopronin), vitamin C and vitamin E—exert antiemetic effect against cisplatin-induced emesis in dogs. In the present study, the effect of these antioxidants was investigated against pica model in rats. Pretreatment with these agents significantly inhibited the cisplatin induced enhanced kaolin intake. However, these agents failed to exert any significant improvement in the decreased food intake by cisplatin. The findings confirm the potential of these antioxidants as antiemetics against cancer chemotherapy induced vomiting, though they may not improve the anorexia. The experiments further support that pica in rats can be used as a good alternative rodent model to dogs and cats particularly for preliminary and rapid screening of antiemetic agents.

Antiemetic activity of antioxidants against cisplatin-induced emesis in dogs

Antioxidants such as glutathione, N-(2-mercaptopropionyl)glycine (MPG), vitamin E, vitamin C and a combination of vitamin E and vitamin C in different treatment schedules were evaluated for their antiemetic activity against cisplatin-induced emesis in dogs. While cisplatin-induced emesis was significantly reduced by all these agents, glutathione, MPG and combination of vitamin E and vitamin C produced maximum reduction. The antiemetic activity of antioxidants may be attributable to their ability to react with free radicals generated by cisplatin. The present study provides further evidence that free radicals play a role in cancer chemotherapy induced emesis and warrant clinical evaluation.

New 5-HT3 (serotonin-3) receptor antagonists. I. Synthesis and structure-activity relationships of pyrido[1,2-a]indoles.

A series of pyrido[1,2-alpha]indol-6(7-H)-ones was prepared and evaluated for 5-HT3 receptor antagonist activity. The structural requirements for the 5-HT3 receptor antagonist have been defined as an aromatic moiety, a basic nitrogen, and a linking acyl group. The (5-methylimidazol-4-yl)methyl group as a basic nitrogen moiety was an important element for high potency. The highest potency was observed for compounds which have 7- and 10-methyl substituents on the pyrido[1,2-alpha]indol-6(7H)-one ring. From this series, (+)-11b (FK 1052) was selected for further evaluation. FK 1052 was a potent 5-HT3 receptor antagonist in the Bezold-Jarisch reflex test in rats (ED50 0.9 microgram/kg, i.v.) and a very effective antiemetic agent against cisplatin-induced emesis in dogs (ED50 1.2 x 2 micrograms/kg, i.v. and 2.7 x 2 micrograms/kg, p.o.).

Novel 5-HT3 antagonists. Isoquinolinones and 3-aryl-2-pyridones.

Synthesis and pharmacological evaluation of a series of 1,2-dihydro-1-[(5-methyl-1-imidazol-4-yl)methyl]-2-oxopyridine 5-HT3 antagonists are described. The key pharmacophoric elements were defined as a basic nitrogen, a linking group capable of hydrogen bonding interactions, and an aromatic moiety. 1,2-Dihydro-2-oxopyridine moiety could be a good linking group because of its nicely planar structure. The steric limitations of the aromatic moiety were investigated by X-ray analysis and computer analysis and shown to be optimal when the aromatic moiety was constrained within an arched planar system, which could be successfully replaced by 3-(2-thienyl)-2-oxopyridine function or 6-amino-7-chloro-1-isoquinolinone function without any loss of the activity. Among the synthesized compounds, 42 showed the most potent activity in the inhibition of Bezold-Jarisch reflex in rats. Compounds 44a and 64 were orally active in the protection against cisplatin-induced emesis in dogs or ferrets. Structure-activity relationships are discussed.

P-330 - Effect of FK1052, a novel potent 5-hydroxytryptamine 3 receptor antagonist, on cisplatin-induced emesis in dogs

P-330 - Effect of FK1052, a novel potent 5-hydroxytryptamine 3 receptor antagonist, on cisplatin-induced emesis in dogs

Synthesis and pharmacology of 3,4-dihydro-3-oxo-1,4-benzoxazine-8-carboxamide derivatives, a new class of potent serotonin-3 (5-HT3) receptor antagonists.

A series of 3,4-dihydro-3-oxo-1,4-benzoxazine-8-carboxamide derivatives was synthesized and evaluated for serotonin-3 (5-HT3) receptor antagonistic activity assessed by their ability to antagonize the von Bezold-Jarish (BJ) effect in rats. Derivatives bearing 1-azabicyclo[2.2.2]oct-3-yl moiety as a basic function attached to the carboxamide at position 8 showed more potent antagonistic activity than those bearing the other three basic moieties. Structure-activity relationships of this series showed that methyl and chloro groups were more effective as substituents at positions 4 and 6, respectively. The representative compound 15 (Y-25130) in this series showed potent antagonistic activity on the BJ effect (ED50 = 1.3 micrograms/kg i.v.), high affinity for 5-HT3 receptor (Ki = 2.9 nM) and complete protection against cisplatin-induced emesis in dogs at a dose of 0.1 mg/kg i.v.

Vagal Afferent Fibers and Peripheral 5-HT3 Receptors Mediate Cisplatin-Induced Emesis in Dogs

The involvement of visceral afferent fibers and 5-HT3 receptors in the emesis induced by cisplatin was studied in beagle dogs. The emesis induced by dsplatin (3 mg/kg, i.v.) was inhibited by the intravenous administration of ICS205930 (2 × 0.01 or 2 × 0.1 mg/kg) and MDL72222 (2 × 0.5 mg/kg), 5-HT3 receptor antagonists, but not by the intravenous administration of metoclopramide (2 × 0.5 mg/kg), a dopamine D2 receptor antagonist. The cisplatin-induced emesis was also suppressed by the intravenous administration of para-chlorophenylalanine (300 mg/kg/day for 3 days), an inhibitor of 5-HT synthesis. On the other hand, the administration of ICS205930 into the IVth ventricle (2 × 0.01 mg/animal) had no effects on the cisplatin-induced emesis. The cisplatin-induced emesis was completely inhibited by abdominal vagotomy and splanchnicectomy, but not by splanchnicectomy alone. On the contrary, the emesis induced by apomorphine was suppressed by the intravenous (0.1 mg/kg) or intracerebroventricular (0.05 mg/animal) administration of metoclopramide, but not by visceral nerve section. These results strongly suggest that cisplatin evokes emesis mainly by acting on the vagal afferent terminals through the release of 5-HT and that peripheral 5-HT3 receptors are involved in this action.

Pharmacological properties of a novel class of 5-HT 3 receptor antagonists

The pharmacological profile of six representative members of a novel class of 5-HT 3 receptor antagonists is described. The compounds are esters and amides of benzimidazolone-1-carboxylic acid with a basic azabicycioalkyi moiety (compounds 1–3) and their respective ethyl derivatives (compounds 4–6). In isolated preparations (rabbit heart and guinea pig ileum) all compounds antagonized the 5-HT 3 receptor-mediated effects of serotonin, with potencies comparable with those of the reference compounds, ICS 205.930 and GR 38032F (−log ID 50 9.30–11.9 and 6.8–8.20, in heart and iieum, respectively). In the anaesthetised rat, all agents potently inhibited the Bezold-Jarisch reflex whether given i.v. or i.d. I.v. administration of compounds prevented cisplatin-induced emesis in dogs (ID 50 ranging from 3.7 to 147 μg/kg). All agents accelerated gastric emptying of solids in rats (ed 50 about 10–160 μg/kg i.p.). In addition, compounds 4 and 5 were able to stimulate 5-HT 4 receptors in the isolated guinea pig ileum, as well as enhance contractile activity in the Heidenhain gastric pouch of dogs, showing clearcut prokinetic properties.

The antiemetic profile of Y-25130, a new selective 5-HT 3 receptor antagonist

Y-25130 ((±)N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide hydrochloride) is a potent and selective 5-HT 3 receptor antagonist free of dopamine receptor blocking activity. This compound was effective against emesis induced in animals by cytotoxic drugs or by total body X-radiation. When given prophylactically, the doses required to completely inhibit cisplatin-induced emesis in dogs and doxorubicin and cyclophosphamide-induced emesis in ferrets were 0.1 and 0.3 mg/kg i.v., respectively. Y-2S130, at the dose of 0.3 mg/kg i.v., almost completely inhibited X-radiation-induced emesis in ferrets. When given during emesis, the doses required to completely inhibit cisplatin-induced emesis in dogs and doxorubicin- and cyclophosphamide-induced emesis in ferrets were 0.1 and 0.3 mg/kg i.v., respectively. The i.v. dose of 0.3 mg/kg of Y-25130 was enough to almost completely inhibit cisplatin-induced emesis in dogs for 24 h. From these results, it is suggested that Y-2S130 may become an effective antiemetic drug against emesis induced by anticancer therapy.

O-263 - Visceral afferent fibers and peripheral 5-HT3 receptor mediate cisplatin-induced emesis in dogs.

O-263 - Visceral afferent fibers and peripheral 5-HT3 receptor mediate cisplatin-induced emesis in dogs.