title: Acute Toxicity of Vildagliptin.
abstract: This article describes acute toxicity data in cynomolgus monkeys following oral treatment with vildagliptin, a dipeptidyl peptidase-4 inhibitor. Acute toxicity symptoms in cynomolgus monkeys include edema formation of the extremities, tails, and face associated with skeletal muscle necrosis, and elevations of lactate dehydrogenase, creatine kinase, alanine transaminase, and aspartate aminotransferase activities in the serum; hypothermia; hypotension; tachycardia; moribundity; and death in a few isolated instances. In surviving animals, symptoms were reversible even if treatment was continued. Cynomolgus monkeys from Mauritius appear more sensitive than monkeys of Asian origin. The underlying mechanism(s) of these symptoms in cynomolgus monkeys is currently not well understood, although a vascular mechanism including initial vasoconstriction and subsequent vascular leakage in distal extremities may play a role. The monkey data are reviewed and discussed in the context of other preclinical and clinical data, and it is concluded that acute toxicity following vildagliptin treatment is a monkey-specific phenomenon without relevance for humans.
authors.affiliation: 1 Novartis Pharmaceuticals Corp., East Hanover, New Jersey, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: 1 Novartis Pharmaceuticals Corp., East Hanover, New Jersey, USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Martin
authors.affiliation: 1 Novartis Pharmaceuticals Corp., East Hanover, New Jersey, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Keselica
authors.affiliation: 1 Novartis Pharmaceuticals Corp., East Hanover, New Jersey, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Gunson
authors.affiliation: 1 Novartis Pharmaceuticals Corp., East Hanover, New Jersey, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Skuba
authors.affiliation: 1 Novartis Pharmaceuticals Corp., East Hanover, New Jersey, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Lapadula
authors.affiliation: 1 Novartis Pharmaceuticals Corp., East Hanover, New Jersey, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Hayes
authors.affiliation: 1 Novartis Pharmaceuticals Corp., East Hanover, New Jersey, USA.
authors.forename: Phil
authors.initials: P
authors.lastname: Bentley
authors.affiliation: 1 Novartis Pharmaceuticals Corp., East Hanover, New Jersey, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Busch
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000633:toxicity; D000284:Administration, Oral; D000818:Animals; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000633:toxicity*; D004487:Edema / Q000139:chemically induced; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D009570:Nitriles / Q000633:toxicity*; D011759:Pyrrolidines / Q000633:toxicity*; D013045:Species Specificity; D023382:Toxicity Tests, Acute; D014661:Vasoconstriction / Q000187:drug effects; D000077597:Vildagliptin
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D011759:Pyrrolidines; D000077597:Vildagliptin; D000218:Adamantane
keywords: Mauritian; acute toxicity; cardiovascular; cynomolgus; dipeptidyl peptidase-4; monkey strain; vascular injury; vildagliptin