piperidines and Intestinal-Diseases--Parasitic

Recent studies have illustrated the burden Cryptosporidium infection places on the lives of malnourished children and immunocompromised individuals. Treatment options remain limited, and efforts to develop a new therapeutic are currently underway. However, there are unresolved questions about the ideal pharmacokinetic characteristics of new anti-Cryptosporidium therapeutics. Specifically, should drug developers optimize therapeutics and formulations to increase drug exposure in the gastrointestinal lumen, enterocytes, or systemic circulation? Furthermore, how should researchers interpret data suggesting their therapeutic is a drug efflux transporter substrate? In vivo drug transporter-mediated alterations in efficacy are well recognized in multiple disease areas, but the impact of intestinal transporters on therapeutic efficacy against enteric diseases has not been established. Using multiple in vitro models and a mouse model of Cryptosporidium infection, we characterized the effect of P-glycoprotein efflux on bumped kinase inhibitor pharmacokinetics and efficacy. Our results demonstrated P-glycoprotein decreases bumped kinase inhibitor enterocyte exposure, resulting in reduced in vivo efficacy against Cryptosporidium. Furthermore, a hollow fiber model of Cryptosporidium infection replicated the in vivo impact of P-glycoprotein on anti-Cryptosporidium efficacy. In conclusion, when optimizing drug candidates targeting the gastrointestinal epithelium or gastrointestinal epithelial infections, drug developers should consider the adverse impact of active efflux transporters on efficacy.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport, Active; Caco-2 Cells; Cell Membrane Permeability; Cryptosporidiosis; Cryptosporidium; Disease Models, Animal; Drug Discovery; Enterocytes; Female; Gastrointestinal Absorption; Humans; Interferon-gamma; Intestinal Diseases, Parasitic; Mice; Mice, Knockout; Naphthalenes; Piperidines; Pyrazoles; Pyrimidines; Quinolines; Treatment Outcome

Distension of the rat intestine causes a depressor response which is predictive of nociception. This study investigated the effects of previous infection with Nippostrongylus (N.) brasiliensis on the sensitivity to intestinal distension and the role of tachykinin NK2 receptors. The tachykinin NK2 receptor antagonist, SR48968 (S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichloropheny l)butyl]benzamide) inhibited the nociceptive response (ED50 = 0.7 mg/kg) in control rats. In post-N. brasiliensis-infected rats sensitivity to intestinal distension was increased which was accompanied by an increase in the apparent potency value of SR48968 (ED50 = 0.1 mg/kg). The hypersensitivity was limited to areas of hypermastocytosis. It is concluded that the post-inflammatory changes that occur in post-infected rats increase visceral sensitivity and the apparent potency of tachykinin NK2 receptor antagonists.

Topics: Animals; Benzamides; Colon; Colonic Diseases; Dilatation, Pathologic; Intestinal Diseases, Parasitic; Jejunal Diseases; Jejunum; Male; Mast Cells; Nippostrongylus; Pain Measurement; Peroxidase; Piperidines; Rats; Rats, Wistar; Receptors, Neurokinin-2; Strongylida Infections

Topics: Ancylostoma; Animals; Anthelmintics; Dog Diseases; Dogs; Evaluation Studies as Topic; Feces; Female; Intestinal Diseases, Parasitic; Male; Nematode Infections; Parasite Egg Count; Piperidines; Species Specificity; Sulfides; Toluidines; Toxascaris; Toxocara; Trichuris

Topics: Adult; Chronic Disease; Colitis; Enterocolitis, Pseudomembranous; Female; Humans; Intestinal Diseases, Parasitic; Male; Middle Aged; Piperidines