Mechanism of species differences in sensitivity of monkeys and dogs to the emetic action of various drugs

Legeza, V I; Shagoyan, M. G.; Kamynina, M F; Marko'skaya, I. V.; Martirosov, K.S.

doi:10.1007/bf00830668

Cited by 3 publications

(1 citation statement)

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“…A likely mechanism for LMN-NKA induced emesis is activation of gastrointestinal vagal afferent pathways via NK1 receptors on enteric neurons and/or enterochromaffin cells (see Darmani et al, 2008). Since there are marked species differences in susceptibility to different emetogens, with dogs being more sensitive to certain pharmacological classes than primates (Legeza et al, 1982), the present findings may not be predictive of an emetic effect of NK2R agonists in human subjects. Indeed, LMN-NKA was administered subcutaneously to macaques twice daily for 7 days at doses 10-fold higher than those given to dogs, and emesis was almost never observed despite achieving similar plasma concentrations (10-40 ng/ml); blood pressure was not monitored in this study and hypoactivity was not noted (unpublished observations).…”

Section: Discussionmentioning

confidence: 74%

[Lys⁵,MeLeu⁹,Nle¹⁰]-NKA_(4–10) Elicits NK2 Receptor–Mediated Micturition and Defecation, and NK1 Receptor–Mediated Emesis and Hypotension, in Conscious Dogs

Rupniak

Katofiasc

Walz

et al. 2018

J Pharmacol Exp Ther

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Tachykinin neurokinin 2 (NK2) receptor agonists may have potential to alleviate clinical conditions associated with bladder and gastrointestinal underactivity by stimulating contraction of visceral smooth muscle. The ability of [Lys,MeLeu,Nle]-neurokinin A (LMN-NKA) to elicit micturition and defecation was examined after repeated administration in groups of 2-10 conscious dogs. Administration of 10-100 g/kg, i.v., four times daily for six consecutive days, reliably elicited micturition after ≥90% of doses and defecation after ≥50% of doses. Voiding occurred<4 minutes after dosing and was short lasting (<10 minutes). LMN-NKA was well tolerated, with emesis after ∼25% of doses at 100 g/kg, i.v. Hypotension was induced by 100g/kg, i.v., of LMN-NKA but not by lower doses. Administration of 30-300 g/kg, s.c., twice daily for seven consecutive days, reliably elicited both urination and defecation after 88%-100% of doses, and was accompanied by a high rate of emesis (50%-100%). The onset of voiding was rapid (<7 minutes) but was more prolonged than after intravenous administration (30-60 minutes). Emesis induced by 30 or 300 g/kg, s.c., of LMN-NKA was significantly reduced (from 58% to 8% and from 96% to 54%, respectively) by a 30-minute pretreatment with the neurokinin 1 (NK1) receptor antagonist, (2,3)--(2-methoxybenzyl)-2-phenylpiperidin-3-amine (CP-99,994; 1 mg/kg, s.c.). The ability of selective NK2 receptor agonists to elicit on-demand voiding could potentially address a major unmet need in people lacking voluntary control of micturition and/or defecation. LMN-NKA unexpectedly activated NK1 receptors at doses that stimulated voiding, causing emesis and hypotension that may limit the clinical utility of nonselective NK2 receptor agonists.

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Section: Discussionmentioning

confidence: 74%

[Lys⁵,MeLeu⁹,Nle¹⁰]-NKA_(4–10) Elicits NK2 Receptor–Mediated Micturition and Defecation, and NK1 Receptor–Mediated Emesis and Hypotension, in Conscious Dogs

Rupniak

Katofiasc

Walz

et al. 2018

J Pharmacol Exp Ther

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Area Postrema: Chemoreceptor circumventricular organ of the medulla oblongata

Borison

1989

Progress in Neurobiology

232

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Translation of new cancer treatments from pet dogs to humans

2008

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Naturally occurring cancers in pet dogs and humans share many features, including histological appearance, tumour genetics, molecular targets, biological behaviour and response to conventional therapies. Studying dogs with cancer is likely to provide a valuable perspective that is distinct from that generated by the study of human or rodent cancers alone. The value of this opportunity has been increasingly recognized in the field of cancer research for the identification of cancer-associated genes, the study of environmental risk factors, understanding tumour biology and progression, and, perhaps most importantly, the evaluation and development of novel cancer therapeutics.

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Mechanism of species differences in sensitivity of monkeys and dogs to the emetic action of various drugs

Cited by 3 publications

References 10 publications

[Lys⁵,MeLeu⁹,Nle¹⁰]-NKA_(4–10) Elicits NK2 Receptor–Mediated Micturition and Defecation, and NK1 Receptor–Mediated Emesis and Hypotension, in Conscious Dogs

[Lys⁵,MeLeu⁹,Nle¹⁰]-NKA_(4–10) Elicits NK2 Receptor–Mediated Micturition and Defecation, and NK1 Receptor–Mediated Emesis and Hypotension, in Conscious Dogs

Area Postrema: Chemoreceptor circumventricular organ of the medulla oblongata

Translation of new cancer treatments from pet dogs to humans

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Mechanism of species differences in sensitivity of monkeys and dogs to the emetic action of various drugs

Cited by 3 publications

References 10 publications

[Lys5,MeLeu9,Nle10]-NKA(4–10) Elicits NK2 Receptor–Mediated Micturition and Defecation, and NK1 Receptor–Mediated Emesis and Hypotension, in Conscious Dogs

[Lys5,MeLeu9,Nle10]-NKA(4–10) Elicits NK2 Receptor–Mediated Micturition and Defecation, and NK1 Receptor–Mediated Emesis and Hypotension, in Conscious Dogs

Area Postrema: Chemoreceptor circumventricular organ of the medulla oblongata

Translation of new cancer treatments from pet dogs to humans

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[Lys⁵,MeLeu⁹,Nle¹⁰]-NKA_(4–10) Elicits NK2 Receptor–Mediated Micturition and Defecation, and NK1 Receptor–Mediated Emesis and Hypotension, in Conscious Dogs

[Lys⁵,MeLeu⁹,Nle¹⁰]-NKA_(4–10) Elicits NK2 Receptor–Mediated Micturition and Defecation, and NK1 Receptor–Mediated Emesis and Hypotension, in Conscious Dogs