Vascular origin of vildagliptin-induced skin effects in Cynomolgus monkeys: pathomechanistic role of peripheral sympathetic system and neuropeptide Y.
The purpose of this article is to characterize skin lesions in cynomolgus monkeys following vildagliptin (dipeptidyl peptidase-4 inhibitor) treatment. Oral vildagliptin administration caused dose-dependent and reversible blister formation, peeling and flaking skin, erosions, ulcerations, scabs, and sores involving the extremities at ≥5 mg/kg/day and necrosis of the tail and the pinnae at ≥80 mg/kg/day after 3 weeks of treatment. At the affected sites, the media and the endothelium of dermal arterioles showed hypertrophy/hyperplasia. Skin lesion formation was prevented by elevating ambient temperature. Vildagliptin treatment also produced an increase in blood pressure and heart rate likely via increased sympathetic tone. Following treatment with vildagliptin at 80 mg/kg/day, the recovery time after lowering the temperature in the feet of monkeys and inducing cold stress was prolonged. Ex vivo investigations showed that small digital arteries from skin biopsies of vildagliptin-treated monkeys exhibited an increase in neuropeptide Y-induced vasoconstriction. This finding correlated with a specific increase in NPY and in NPY1 receptors observed in the skin of vildagliptin-treated monkeys. Present data provide evidence that skin effects in monkeys are of vascular origin and that the effects on the NPY system in combination with increased peripheral sympathetic tone play an important pathomechanistic role in the pathogenesis of cutaneous toxicity.
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA peterk.hoffmann@novartis.com.
Peter
P
Hoffmann
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
Phil
P
Bentley
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
Pritam
P
Sahota
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
Heidi
H
Schoenfeld
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
Lori
L
Martin
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
Linda
L
Longo
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
Robert
R
Spaet
Novartis Pharma AG, Basel, Switzerland.
Pierre
P
Moulin
Novartis Pharma AG, Basel, Switzerland.
Serafino
S
Pantano
Novartis Pharma AG, Basel, Switzerland.
Valerie
V
Dubost
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
Dan
D
Lapadula
Novartis Pharmaceuticals Corporation, Cambridge, Massachusetts, USA.
Bryan
B
Burkey
Novartis Pharmaceuticals Corporation, Cambridge, Massachusetts, USA.
Virendar
V
Kaushik
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
Wei
W
Zhou
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
Michael
M
Hayes
Department of Anesthesiology, Johns Hopkins University, Baltimore, Maryland, USA.
Nick
N
Flavahan
Novartis Pharmaceuticals Corporation, Cambridge, Massachusetts, USA.
Salah-Dine
SD
Chibout
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
Steve
S
Busch
D000218:Adamantane / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003080:Cold Temperature; D004150:Dipeptidases / Q000097:blood; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D008252:Macaca fascicularis; D009478:Neuropeptide Y / Q000008:administration & dosage / Q000009:adverse effects*; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects*; D009638:Norepinephrine / Q000652:urine; D011759:Pyrrolidines / Q000008:administration & dosage / Q000009:adverse effects*; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D012871:Skin Diseases / Q000139:chemically induced / Q000473:pathology*; D013312:Stress, Physiological; D057772:Vascular System Injuries / Q000139:chemically induced / Q000473:pathology*; D014661:Vasoconstriction / Q000187:drug effects; D000077597:Vildagliptin
D054873:Dipeptidyl-Peptidase IV Inhibitors; D009478:Neuropeptide Y; D009570:Nitriles; D011759:Pyrrolidines; D004150:Dipeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D018819:Dipeptidyl Peptidase 4; D000077597:Vildagliptin; D000218:Adamantane; D009638:Norepinephrine
dipeptidyl peptidase-4; monkey; neuropeptide Y; skin lesions; vascular; vildagliptin.