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Generated Narrative: Citation 267500
version: 2; Last updated: 2024-11-22 19:28:54+0000
Profile: JournalArticleCitation
url: Citation 26502880 A novel nasal powder formulation of glucagon: toxicology studies in animal models.
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title: 26502880 A novel nasal powder formulation of glucagon: toxicology studies in animal models.
status: Active
date: 2024-12-19 14:29:51+0000
publisher: HL7 International / Clinical Decision Support
contact: HL7 International / Clinical Decision Support: http://www.hl7.org/Special/committees/dss
description:
This Citation Resource is referenced in an example for the EBMonFHIR Implementation Guide.
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approvalDate: 2016-07-11
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/10.1186/s40360-015-0026-9, pii/10.1186/s40360-015-0026-9Titles
Type Language Text Primary title English A novel nasal powder formulation of glucagon: toxicology studies in animal models.
Abstracts
Text BACKGROUND: Glucagon nasal powder (GNP), a novel intranasal formulation of glucagon being developed to treat insulin-induced severe hypoglycemia, contains synthetic glucagon (10% w/w), beta-cyclodextrin, and dodecylphosphocholine. The safety of this formulation was evaluated in four studies in animal models. METHODS: The first study evaluated 28-day sub-chronic toxicology in rats treated intranasally with 1 and 2 mg of GNP/day (0.1 and 0.2 mg glucagon/rat/day). The second study evaluated 28-day sub-chronic toxicology in dogs administered 20 and 40 mg of formulation/dog/day (2 and 4 mg glucagon/dog/day) intranasally. A pulmonary insufflation study assessed acute toxicology following intra-tracheal administration of 0.5 mg of GNP (0.05 mg glucagon) to rats. Local tolerance to 30 mg of GNP (equivalent to 3 mg glucagon, the final dose for humans) was tested through direct administration into the eyes of rabbits. RESULTS: There were no test article-related adverse effects on body weight and/or food consumption, ophthalmology, electrocardiography, hematology, coagulation parameters, clinical chemistry, urinalysis, or organ weights, and no macroscopic findings at necropsy in any study. In rats, direct intra-tracheal insufflation at a dose of 0.5 mg of GNP/rat (0.05 mg glucagon/rat) did not result in adverse clinical, macroscopic, or microscopic effects. In dogs, the only adverse findings following sub-chronic use were transient (<30 s) salivation and sneezing immediately post-treatment and mild to moderate reversible histological changes to the nasal mucosa. Daily dosing over 28 days in rats resulted in mild to moderate, unilateral or bilateral erosion/ulceration of the olfactory epithelium, frequently with minimal to mild, acute to sub-acute inflammation of the lamina propria at the dorsal turbinates of the nasal cavity in 2/10 males and 3/10 females in the high-dose group (0.2 mg glucagon/day). These lesions resolved completely over 14 days. Histological examination of tissues from both sub-chronic studies in dogs and rats revealed no microscopic findings. In rabbits, clinical observations noted in the GNP-treated eye and/or surrounding areas included ≥1 of the following: clear discharge, red conjunctiva, partial closure, and swelling of the peri-orbital area, which correlated with erythema and edema noted during ocular observations and grading. <AbstractText Label="DISCUSSION" NlmCategory="CONCLUSIONS">The studies reported here revealed no safety concerns associated with GNP in animal models. Studies published earlier have highlighted the local safety profile of intranasally administered cyclodextrins (a component of GNP). The choline group, the phosphate group, and the saturated 12-carbon aliphatic chain that are present in the dodecylphosphocholine excipient used in GNP are all present in the phospholipids and lecithins seen ubiquitously in mammalian cell membranes and are unlikely to pose safety concerns; this notion is supported by several studies conducted by the authors that revealed no safety concerns. Taken together, these results suggest that intranasal delivery of GNP holds promise as a future rescue medication for use by caregivers to treat insulin-induced hypoglycemic episodes in patients with type 1 or type 2 diabetes. CONCLUSION: This novel drug product is well tolerated in animal models.
relatesTo
type: cites
classifier: Journal Article
citation:
Cryer PE. Hypoglycaemia: the limiting factor in the glycaemic management of Type I and Type II Diabetes. Diabetologia. 2002;45:937–48. doi: 10.1007/s00125-002-0822-9.
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UK Hypoglycemia Study Group Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia. 2007;50:1140–7. doi: 10.1007/s00125-007-0599-y.
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GLUCACON (glucagon for injection, rDNA origin) Product Monograph. Toronto, Ontario: Eli Lilly Canada Inc.; 2012 http://www.lilly.ca/en/pdf/product-monograph/04_rglucagon-pm_9july2012.pdf. Accessed 26 September 2015.
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GLUCAGEN® and GLUCAGEN® Hypokit 1 mg (glucagon) Product Monograph. Mississauga, Ontario: Novo Nordisk Canada Inc.; 2014. http://www.paladin-labs.com/our_products/PM_GlucaGen_EN.pdf. Accessed 26 September 2015.
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citation:
Eistrup C, Hjortkjaer RK, Pickersgill N, Virgo DM, Woolley AP. Glucagon produced by recombinant DNA technology: repeated dose toxicity studies, intravenous administration to CD rats and beagle dogs for four weeks. Pharmacol Toxicol. 1993;73:103–8. doi: 10.1111/j.1600-0773.1993.tb01544.x.
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classifier: Journal Article
citation:
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Documents
Url https://pubmed.ncbi.nlm.nih.gov/12270606/ resourceReference: Identifier:
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identifier: Electronic ISSN Type/2050-6511, ISOAbbreviation/BMC Pharmacol Toxicol, ISSN Linking/2050-6511, Medline Title Abbreviation/BMC Pharmacol Toxicol, NLM Unique ID/101590449
title: BMC pharmacology & toxicology
publisherLocation: England
citedMedium: Internet
volume: 16
articleDate: 2015-10-26
publicationDateText: 2015-Oct-26
language: English
pageString: 29
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classifier: Powders, beta-Cyclodextrins, Phosphorylcholine, dodecylphosphocholine, Glucagon, betadex
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affiliation: , 130 Macaw Lane, Merritt Island, FL, 32952, USA. freno1@cfl.rr.com.
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affiliation: ITR Laboratories Canada Inc. (ITR), 19601 Clark Graham Blvd, Baie d'Urfe, Quebec, Canada. pnormand@itrlab.com.
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affiliation: ITR Laboratories Canada Inc. (ITR), 19601 Clark Graham Blvd, Baie d'Urfe, Quebec, Canada. kmcinally@itrlab.com.
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affiliation: CiToxLAB North America, 445 Armand-Frappier Blvd, Laval, Québec, Canada. silos@ca.citoxlab.com.
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contributor: Stotland P
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affiliation: Locemia Solutions ULC., 8505 Dalton, Montreal, QC, Canada. patricia.stotland@locemia.com.
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affiliation: Locemia Solutions ULC., 8505 Dalton, Montreal, QC, Canada. myriam.triest@locemia.com.
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affiliation: Locemia Solutions ULC., 8505 Dalton, Montreal, QC, Canada. dolores.carballo@locemia.com.
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affiliation: Locemia Solutions ULC., 8505 Dalton, Montreal, QC, Canada. claude.piche@locemia.com.
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