Establishment and Validation of a Rabbit Model for In Vivo Pharmacodynamic Screening of Tachykinin NK2 Antagonists

Abstract

Abstract. We attempted to establish and validate an in vivo pharmacodynamic (PD) rabbit model to screen tachykinin NK 2 receptor (NK 2 -R) antagonists using pharmacological and pharmacokinetic (PK)/PD analyses. Under urethane anesthesia, changes in intracolonic pressure associated with intravenous (i.v.) administration of a selective NK 2 -R agonist, βAla 8 -neurokinin A(4-10) (βA-NKA), was monitored as a PD marker. The analgesic effects of NK 2 -R antagonists were evaluated by monitoring visceromotor response (VMR) to colorectal distension in a rabbit model of visceral hypersensitivity induced by intracolonic treatment of acetic acid. Intravenous administration of βA-NKA induced transient colonic contractions dose-dependently, which were inhibited by the selective NK 2 -R antagonists in dose-and/or plasma concentration-dependent manners. The correlation between PD inhibition and plasma concentration normalized with the corresponding in vitro binding affinity was relatively high (r 2 = 0.61). Furthermore, the minimum effective doses on the VMR and ID 50 values calculated in the PD model were highly correlated (r 2 = 0.74). In conclusion, we newly established and validated a rabbit model of agonist-induced colonic contractions as a screening tool for NK 2 -R antagonists. In a drug discovery process, this PD model could enhance the therapeutic candidate selection for irritable bowel syndrome, pharmacologically connecting in vitro affinity for NK 2 -R with in vivo therapeutic efficacy.

Effects of TAK-480, a Novel Tachykinin NK2^|^ndash;Receptor Antagonist, on Visceral Hypersensitivity in Rabbits and Ricinoleic Acid^|^ndash;Induced Defecation in Guinea Pigs

“…We have previously demonstrated the inhibitory effect of a series of NK 2 -receptor antagonists on VMR to CRD in this model, correlating to their corresponding in vivo NK 2 -receptor antagonistic activities (23). In the present study, instead of intracolonic acetic acid treatment employed in the previous report, zymosan, a protein-carbohydrate cell wall derivative of the yeast Saccharomyces cerevisiae, was administered intracolonically to induce visceral hypersensitivity (24,25).…”

“…Initially we attempted to investigate the in vivo NK 2 -receptor antagonistic activity of TAK-480. For this purpose, we employed a rabbit model of agonist-induced colonic contractions which we validated previously as an in vivo screening assay for NK 2 -receptor antagonists (23). In this model, TAK-480 inhibited βA-NKA-induced colonic contractions in a dose-dependent manner.…”

Preanesthesia, Anesthesia, Analgesia, and Euthanasia

“…Urethane continues to be used alone and in combination with other agents (e.g., Tanaka et al, 2012). Among its characteristics are a long duration of action, excellent muscle relaxation, numerous endocrine effects, hemolysis, prolonged recovery, carcinogenic potential, and reduced response of vascular smooth muscle to norepinephrine (Bree and Cohen, 1965;Maggi et al, 1984).…”

Experimental Lab Tests on Rabbits for the Optimization and Redesign of Low-Cost Equipment for Automated Peritoneal Dialysis

“…Pharmacological elements are discovered to prevent or eradicate diseases; a significant difference from the past is that animal studies have increased the effectiveness of those medicines. This is because they have undergone all of the necessary improvements to ensure they do not harm the human body, even detecting toxins or elements harmful to humans [1]. Moreover, the advances in technology and biomaterials that can be used to repair or substitute elements in humans best demonstrate the importance of animal experimentation.…”

“…The first feature to be improved will be the heat bed for increased heat transfer to the bag. It would be better to use a single element instead of two parts (1). Then, the positioning of the components attached to the structure will be made permanent for patient safety purposes (2).…”