Cholecystokinin-1 receptor agonist induced pathological findings in the exocrine pancreas of non-human primates
| Autor: | Anne Sietske de Boer, David Wederkinck Andersen, Birgitte Schjellerup Wulff, Anne Bugge, Inger Thorup, Trine R. Clausen, Niels C. Berg Nyborg, Rikke Kaae Kirk |
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| Rok vydání: | 2020 |
| Předmět: |
Primates
0301 basic medicine Agonist medicine.medical_specialty medicine.drug_class Acinar Cells In situ hybridization Biology Toxicology digestive system 03 medical and health sciences 0302 clinical medicine Internal medicine Chlorocebus aethiops medicine Animals Humans Receptor Pancreas Cholecystokinin Pharmacology digestive oral and skin physiology medicine.disease Pancreas Exocrine In vitro Rats Macaca fascicularis 030104 developmental biology Endocrinology medicine.anatomical_structure 030220 oncology & carcinogenesis COS Cells Acute pancreatitis Pancreatitis Receptors Cholecystokinin hormones hormone substitutes and hormone antagonists |
| Zdroj: | Toxicology and Applied Pharmacology. 399:115035 |
| ISSN: | 0041-008X |
| Popis: | Background and aims Cholecystokinin (CCK) may potentially be used to treat obesity. However, it is well-known to induce acute pancreatitis and pancreas neoplasia in rodents, but not in primates. Here we report the nonclinical safety profile of a long-acting CCK-1 receptor (CCK-1R) agonist, NN9056, in rats and monkeys to support a First-in-Man clinical trial with NN9056. Methods Thirteen-week toxicological studies were conducted in rats and non-human primates followed by histopathological evaluation of affected tissues. NN9056 was characterised in vitro, and CCK-1R expression was assessed by in situ hybridization in cynomolgus monkey and human pancreas tissues. Results Affinity and potency of NN9056 was comparable to native sulphated CCK-8 (CCK-8) across species on the CCK-1R while it had no effect on the CCK-2 receptor (CCK-2R). In situ hybridization demonstrated abundant expression of CCK-1Rs in the exocrine pancreas of the rat. In contrast, it was only discreetly expressed on pancreatic acinar cells in the periphery of scattered lobules in monkeys. A similar expression pattern was observed in human pancreas. 13-weeks daily dosing with NN9056 produced the expected pancreatic pathological findings in rats. In monkeys, NN9056 increased pancreas weight and induced histopathological changes despite the low expression level of CCK-1Rs. Conclusion Surprisingly, chronic CCK-1R activation constitutes a risk for pancreatitis and trophic actions on the exocrine pancreas in monkeys. Since similar CCK-1R expression patterns were found in pancreas of monkeys and humans this risk is likely translatable to humans and clinical development of NN9056 was therefore halted. |
| Databáze: | OpenAIRE |
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