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1.
Toxicol Pathol ; 42(4): 684-95, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24448599

ABSTRACT

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.


Subject(s)
Adamantane/analogs & derivatives , Neuropeptide Y/adverse effects , Nitriles/adverse effects , Pyrrolidines/adverse effects , Skin Diseases/pathology , Skin/drug effects , Vascular System Injuries/pathology , Adamantane/administration & dosage , Adamantane/adverse effects , Administration, Oral , Animals , Blood Pressure/drug effects , Cold Temperature , Dipeptidases/blood , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/blood , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Macaca fascicularis , Neuropeptide Y/administration & dosage , Nitriles/administration & dosage , Norepinephrine/urine , Pyrrolidines/administration & dosage , Skin/pathology , Skin Diseases/chemically induced , Stress, Physiological , Vascular System Injuries/chemically induced , Vasoconstriction/drug effects , Vildagliptin
2.
Toxicol Pathol ; 32(5): 577-90, 2004.
Article in English | MEDLINE | ID: mdl-15603542

ABSTRACT

Kidney slices represent an in vitro model that has the cellular complexity of in vivo tissue to provide insights into mechanisms of organ injury, as shown in this study with the model nephrotoxicant cisplatin. Cell pathways altered by cisplatin exposure are assessed by gene expression analysis, cell function, and morphology in human and rat kidney slices in comparison to rat kidney from an in vivo study. The acute nephrosis of the tubular epithelium induced by cisplatin in vivo was reproduced in both human and rat kidney slices, while the glomerulus appeared resistant even at high concentrations. Kidney gene expression changes of in vivo and in vitro samples were indicative of transcription, DNA damage, cell cycle, proliferation, and apoptosis that are in agreement with the mechanism of cisplatin causing DNA damage, growth arrest, and apoptosis; while genes indicative of protein damage, the disruption of transport and calcium homeostasis, cellular metabolism, and oxidative stress are pathways linked with cisplatin binding to various cellular proteins and macromolecules. Both concentration and time-dependent gene expression changes evident in the in vitro model preceded a change in tissue morphology. Functional assays confirming cell dysfunction and increased apoptosis revealed the rat kidney to be more sensitive to the effects of cisplatin than human kidney as demonstrated by significant decreases in slice ATP and GSH levels, significant increases in caspase 9 and 3 activity, p53 protein levels, and increased DNA laddering. The regional markers of proximal and distal tubular injury, alpha- and pi-glutathione S-transferases, were shown for the human kidney slices to be significantly increased by cisplatin. In this study, cisplatin-induced nephrotoxicity was demonstrated morphologically in rat and human kidney slices, and the associated gene expression and functional changes characterized the cellular pathways involved.


Subject(s)
Antineoplastic Agents/toxicity , Cisplatin/toxicity , Kidney Cortex/drug effects , Kidney Tubular Necrosis, Acute/chemically induced , Kidney/drug effects , Adult , Animals , Antineoplastic Agents/administration & dosage , Cisplatin/administration & dosage , Culture Media/chemistry , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Gene Expression Profiling , Humans , Injections, Intravenous , Kidney/metabolism , Kidney/pathology , Kidney Cortex/metabolism , Kidney Cortex/pathology , Kidney Function Tests , Kidney Tubular Necrosis, Acute/genetics , Kidney Tubular Necrosis, Acute/pathology , Male , Middle Aged , Oligonucleotide Array Sequence Analysis , Organ Culture Techniques , Rats , Rats, Wistar
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